Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Um, Yoo Hyun | Wang, Sheng-Min | Kang, Dong Woo | Kim, Nak-Young | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: Despite the important associations among sleep, Alzheimer’s disease (AD), subcortical structures, and the cerebellum, structural and functional magnetic resonance imaging (MRI) with regard to these regions and sleep on patients in AD trajectory are scarce. Objective: This study aimed to evaluate the influence of prolonged sleep latency on the structural and functional alterations in the subcortical and cerebellar neural correlates in amyloid-β positive amnestic mild cognitive impairment patients (Aβ +aMCI). Methods: A total of 60 patients with aMCI who were identified as amyloid positive ([18 F] flutemetamol+) were recruited in the study, 24 patients …with normal sleep latency (aMCI-n) and 36 patients prolonged sleep latency (aMCI-p). Cortical thickness and volumes between the two groups were compared. Volumetric analyses were implemented on the brainstem, thalamus, and hippocampus. Subcortical and cerebellar resting state functional connectivity (FC) differences were measured between the both groups through seed-to-voxel analysis. Additionally, group x Aβ interactive effects on FC values were tested with a general linear model. Result: There was a significantly decreased brainstem volume in aMCI-p subjects. We observed a significant reduction of the locus coeruleus (LC) FC with frontal, temporal, insular cortices, hippocampus, and left thalamic FC with occipital cortex. Moreover, the LC FC with occipital cortex and left hippocampal FC with frontal cortex were increased in aMCI-p subjects. In addition, there was a statistically significant group by regional standardized uptake value ratio interactions discovered in cerebro-cerebellar networks. Conclusion: The aforementioned findings suggest that prolonged sleep latency may be a detrimental factor in compromising structural and functional correlates of subcortical structures and the cerebellum, which may accelerate AD pathophysiology. Show more

Keywords: Cerebellum, hippocampus, locus coeruleus, mild cognitive impairment, sleep latency, thalamus

DOI: 10.3233/JAD-215460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Yang, Zhiyuan | Sheng, Xiaoning | Qin, Ruomeng | Chen, Haifeng | Shao, Pengfei | Xu, Hengheng | Yao, Weina | Zhao, Hui | Xu, Yun | Bai, Feng

Article Type: Research Article

Abstract: Background: Stimulating superficial brain regions highly associated with the hippocampus by repetitive transcranial magnetic stimulation (rTMS) may improve memory of Alzheimer’s disease (AD) spectrum patients. Objective: We recruited 16 amnesic mild cognitive impairment (aMCI) and 6 AD patients in the study. All the patients were stimulated to the left angular gyrus, which was confirmed a strong link to the hippocampus through neuroimaging studies, by the neuro-navigated rTMS for four weeks. Methods: Automated fiber quantification using diffusion tensor imaging metrics and graph theory analysis on functional network were employed to detect the neuroplasticity of brain networks. …Results: After neuro-navigated rTMS intervention, the episodic memory of aMCI patients and Montreal Cognitive Assessment score of two groups were significantly improved. Increased FA values of right anterior thalamic radiation among aMCI patients, while decreased functional network properties of thalamus subregions were observed, whereas similar changes not found in AD patients. It is worth noting that the improvement of cognition was associated with the neuroplasticity of thalamic system. Conclusion: We speculated that the rTMS intervention targeting left angular gyrus may be served as a strategy to improve cognitive impairment at the early stage of AD patients, supporting by the neuroplasticity of thalamic system. Show more

Keywords: Alzheimer’s disease, amnesic mild cognitive impairment, neuro-navigated repetitive transcranial magnetic stimulation, thalamic system

DOI: 10.3233/JAD-215390

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2022

Authors: Khan, Noreen | Garcia, Nelda | Mehdipanah, Roshanak | Briceño, Emily M. | Heeringa, Steven G. | Levine, Deborah A. | Gonzales, Xavier F. | Langa, Kenneth M. | Longoria, Ruth | Morgenstern, Lewis B.

Article Type: Short Communication

Abstract: Older adults with significant cognitive impairment require help with activities of daily living. The BASIC-Cognitive Project, set in Nueces County, Texas, is a community-based study examining trends in cognition among Mexican Americans and non-Hispanic Whites. Using cross-sectional data from a cohort study, we found that at least 7% of individuals aged 65 and older with a Montreal Cognitive Assessment (MoCA) score of <  20 (or <  15 for telephone MoCA), did not receive any caregiving help. This conservative estimate highlights an important community need for those with significant cognitive impairment and has implications regarding safety and care for older adults.

Keywords: Activities of daily living, caregiving, dementia, Hispanic, underserved populations

DOI: 10.3233/JAD-215418

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2022

Authors: Richter, Nils | David, Lara-Sophia | Grothe, Michel J. | Teipel, Stefan | Dietlein, Markus | Tittgemeyer, Marc | Neumaier, Bernd | Fink, Gereon R. | Onur, Oezguer A. | Kukolja, Juraj

Article Type: Research Article

Abstract: Background: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer’s disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. Objective: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11 C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei …in non-demented AD patients. Methods: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Results: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman’s rho (17)   = –0.596, 95% -CI [–0.905, –0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Conclusion: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures. Show more

Keywords: Acetylcholinesterase, aging, MP4A, nucleus basalis of Meynert, positron emission tomography

DOI: 10.3233/JAD-210261

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Zhang, Wei | Zhang, Minghui | Wu, Qin | Shi, Jing-Shan

Article Type: Research Article

Abstract: Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ 25-35 -induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway. Methods: Sprague-Dawley rats received a single Aβ 25-35 injection (10μ g) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically …administrated 7d prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ 25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ 1-42 and PSD95. Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro , probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity. Show more

Keywords: Aβ-induced synaptic injury, amyloidogenesis, Dendrobium nobile Lindl. alkaloids, mitochondrial dysfunction, spatial learning and memory, Wnt/β-catenin pathways

DOI: 10.3233/JAD-215433

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Teixeira, Antonio L. | Salem, Haitham | Martins, Lais B. | Gonzales, Mitzi M. | Seshadri, Sudha | Suchting, Robert

Article Type: Research Article

Abstract: Background: Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer’s disease (AD). Objective: To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Methods: This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory–Questionnaire applied …to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. Results: From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Conclusion: Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation. Show more

Keywords: Alzheimer’s disease, apathy, inflammation, interleukin-6, interleukin-10

DOI: 10.3233/JAD-215314

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Mesa-Herrera, Fátima | Marín, Raquel | Torrealba, Eduardo | Díaz, Mario

Article Type: Research Article

Abstract: Background: There exists considerable interest in the identification of molecular traits during early stages of Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is considered the closest prodromal stage of AD, and to develop gradually from earlier stages although not always progresses to AD. Classical cerebrospinal fluid (CSF) AD biomarkers, amyloid-β peptides and tau/p-tau proteins, have been measured in prodromal stages yet results are heterogeneous and far from conclusive. Therefore, there exists a pressing need to identify a neurochemical signature for prodromal stages and to predict which cases might progress to AD. Objective: Exploring potential CSF biomarkers related …to brain oxidative and inorganic biochemistry during prodromal stages of the disease. Methods: We have analyzed CSF levels of lipoxidative markers (MDA and 8-isoF2α ), biometals (Cu, Zn, Se, Mn, and Fe), iron-transport protein transferrin (TFER), antioxidant enzymes (SOD and GPx4), detoxifying enzymes (GST and BuChE), as well as classical amyloid-β and total and phosphorylated tau, in cognitively healthy controls, patients with MCI, and subjects exhibiting subjective memory complaints (SMC). Results: Inter-group differences for several variables exhibit differentiable trends along the HC ⟶ SMC ⟶ MCI sequence. More interestingly, the combination of Se, Cu, Zn, SOD, TFER, and GST variables allow differentiable fingerprints for control subjects and each prodromal stage. Further, multivariate scores correlate positively with neurocognitive In-Out test, hence with both episodic memory decline and prediction to dementia. Conclusion: We conclude that changes in the CSF biochemistry related to brain oxidative defense and neurometallomics might provide more powerful and accurate diagnostic tools in preclinical stages of AD. Show more

Keywords: Alzheimer’s disease, butyrylcholinesterase, extracellular superoxide dismutase, glutathione-S-transferase, lipoxidative markers, mild cognitive impairment, neurometalomics, oxidative stress, subjective memory complaints, transferrin

DOI: 10.3233/JAD-215437

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Pedersen, Frederik Nørregaard | Stokholm, Lonny | Pouwer, Frans | Hass Rubin, Katrine | Peto, Tunde | Frydkjær-Olsen, Ulrik | Thykjær, Anne Suhr | Andersen, Nis | Andresen, Jens | Bek, Toke | La Cour, Morten | Heegaard, Steffen | Højlund, Kurt | Kawasaki, Ryo | Hajari, Javad Nouri | Ohm Kyvik, Kirsten | Laugesen, Caroline Schmidt | Schielke, Katja Christina | Simó, Rafael | Grauslund, Jakob

Article Type: Research Article

Abstract: Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes …were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR. Show more

Keywords: Alzheimer’s disease, cognitive impairment, diabetes mellitus, diabetic retinopathy

DOI: 10.3233/JAD-215313

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Reed, Marilyn | Freedman, Morris | Mark Fraser, Amy E. | Bromwich, Matthew | Santiago, Anna Theresa | Gallucci, Christina Elizabeth | Frank, Andrew

Article Type: Research Article

Abstract: Background: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults. Objective: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians’ awareness of hearing loss and improve access to timely hearing care. Methods: Patients …referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology. Results: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology. Conclusion: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia. Show more

Keywords: Dementia, hearing loss, memory clinic, older adults, screening

DOI: 10.3233/JAD-215377

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: McNerney, M. Windy | Heath, Alesha | Narayanan, Sindhu | Yesavage, Jerome

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a debilitating disorder involving the loss of plasticity and cholinergic neurons in the cortex. Pharmaceutical treatments are limited in their efficacy, but brain stimulation is emerging as a treatment for diseases of cognition. More research is needed to determine the biochemical mechanisms and treatment efficacy of this technique. Objective: We aimed to determine if forebrain repetitive transcranial magnetic stimulation can improve cortical BDNF gene expression and cholinergic signaling in the 3xTgAD mouse model of AD. Methods: Both B6 wild type mice and 3xTgAD mice aged 12 months were given daily treatment …sessions for 14 days or twice weekly for 6 weeks. Following treatment, brain tissue was extracted for immunological stains for plaque load, as well as biochemical analysis for BDNF gene expression and cholinergic signaling via acetylcholinesterase and choline acetyltransferase ELISA assays. Results: For the 3xTgAD mice, both 14 days and 6 weeks treatment regimens resulted in an increase in BDNF gene expression relative to sham treatment, with a larger increase in the 6-week group. Acetylcholinesterase activity also increased for both treatments in 3xTgAD mice. The B6 mice only had an increase in BDNF gene expression for the 6-week group. Conclusion: Brain stimulation is a possible non-invasive and nonpharmaceutical treatment option for AD as it improves both plasticity markers and cholinergic signaling in an AD mouse model. Show more

Keywords: Acetylcholinesterase, brain-derived neurotrophic factor, cortex, mouse, transcranial magnetic stimulation

DOI: 10.3233/JAD-215361

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Levy, Boaz | Priest, Amanda | Delaney, Tyler | Hogan, Jacqueline | Herrawi, Farahdeba

Article Type: Research Article

Abstract: Background: Preventing dementia warrants the pragmatic engagement of primary care. Objective: This study predicted conversion to dementia 12 months before diagnosis with indicators that primary care can utilize within the practical constraints of routine practice. Methods: The study analyzed data from the Alzheimer’s Disease Neuroimaging Initiative (Total sample = 645, converting participants = 54). It predicted the conversion from biological (plasma neurofilament light chain), cognitive (Trails Making Test– B), and functional (Functional Activities Questionnaire) measures, in addition to demographic variables (age and education). Results: A Gradient Booster Trees classifier effectively predicted the conversion, based on a Synthetic Minority …Oversampling Technique (n  = 1,290, F1 Score = 92, AUC = 94, Recall = 87, Precision = 97, Accuracy = 92). Subsequent analysis indicated that the MCI False Positive group (i.e., non-converting participants with cognitive impairment flagged by the model for prospective conversion) scored significantly lower on multiple cognitive tests (Montreal Cognitive Assessment, p  < 0.002; ADAS-13, p  < 0.0004; Rey Auditory Verbal Learning Test, p  < 0.002/0.003) than the MCI True Negative group (i.e., correctly classified non-converting participants with cognitive impairment). These groups also differed in CSF tau levels (p  < 0.04), while consistent effect size differences emerged in the all-pairwise comparisons of hippocampal volume and CSF Aβ1 - 42 . Conclusion: The model effectively predicted 12-month conversion to dementia and further identified non-converting participants with MCI, in the False Positive group, at relatively higher neurocognitive risk. Future studies may seek to extend these results to earlier prodromal phases. Detection of dementia before diagnosis may be feasible and practical in primary care settings, pending replication of these findings in diverse clinical samples. Show more

Keywords: Alzheimer’s disease, dementia, pre-diagnostic detection, prevention, primary care, screening

DOI: 10.3233/JAD-215242

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Josephs, Kennedy A. | Pham, Nha Trang Thu | Graff-Radford, Jonathan | Machulda, Mary M. | Lowe, Val J. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18 F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). Objective: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. Methods: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS …and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Results: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. Conclusion: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA. Show more

Keywords: Cingulate island sign, FDG-PET, hippocampus, MRI, visual assessment

DOI: 10.3233/JAD-215263

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Kuksa, Pavel P. | Liu, Chia-Lun | Fu, Wei | Qu, Liming | Zhao, Yi | Katanic, Zivadin | Clark, Kaylyn | Kuzma, Amanda B. | Ho, Pei-Chuan | Tzeng, Kai-Teh | Valladares, Otto | Chou, Shin-Yi | Naj, Adam C. | Schellenberg, Gerard D. | Wang, Li-San | Leung, Yuk Yee

Article Type: Research Article

Abstract: Background: Recent Alzheimer’s disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations. Objective: Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations. Methods: We developed the Alzheimer’s Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer’s Disease Genetics Consortium and other consortia. Genetic associations were systematically …extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories. Results: ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings. Conclusion: ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org . Show more

Keywords: AD GWAS literature curation, Alzheimer’s disease, data curation, database, genome-wide association studies, harmonization

DOI: 10.3233/JAD-215055

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Mukaetova-Ladinska, Elizabeta B. | Abdullah, Shahbaz | Critchfield, Mathew | Maltby, John

Article Type: Research Article

Abstract: Background: Memory complaints are frequent among young adults presenting in general practice. Many of them will have reversable, functional cognitive impairment that can easily be mistaken for dementia. Its accurate and timely identification is warranted to prevent further escalation to overt dementia syndrome. Objective: To evaluate the recommended primary care screening cognitive tools for dementia for use in younger people. Methods: 2.5 years clinical data were collected during the course of ongoing patient care for all assessed face-to-face patients in a secondary care memory service for younger adults. Cognitive screening and assessment tests used in primary …[General Practice Assessment of Cognition (GPCOG)] and secondary [Addenbrooke’s Cognitive Examination-III (ACE-III), Rowland Universal Dementia Assessment Scale (RUDAS), Salzburg Dementia Test Prediction (SDTP)] care were analyzed for their accuracy to identify dementia and memory complaints. Area under the curve in receiver operating characteristic curves was used to measure predictive value of tests for a clinical diagnosis of dementia. Results: 348 young adults were assessed for cognitive impairment. Following comprehensive Memory Clinic assessments, 241 (69.25%) were diagnosed with memory complaints in the absence of relevant neuropathology and 107 with dementia. GPCOG, especially the informant part, and RUDAS had low accuracy to identify dementia (AUC = 0.465 and AUC = 0.698, respectively). In contrast, ACE-III and SDTP demonstrated the highest accuracy (AUC = 0.799 and AUC = 0.809/0.817, respectively). Conclusion: Dementia screening in younger people will benefit from SDTP incorporated as part of the screening cognitive toolset. The national guidance on dementia screening tools, diagnostic pathways, and management should also refer to younger adults. Show more

Keywords: Cognitive impairment, cognitive screening, dementia, primary health care, suspected dementia, young adults

DOI: 10.3233/JAD-215514

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sohn, Bo Kyung | Byun, Min Soo | Yi, Dahyun | Jeon, So Yeon | Lee, Jun Ho | Choe, Young Min | Lee, Dong Woo | Lee, Jun-Young | Kim, Yu Kyeong | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE Research Group

Article Type: Research Article

Abstract: Background: Physical activities (PA) have been suggested to reduce the risk of Alzheimer‘s disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. Objective: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. Methods: This study included participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer’s disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11 C] Pittsburgh Compound B positron emission tomography (PET), [18 F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal …brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. Results: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. Conclusion: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults. Show more

Keywords: Amyloid, cortical thickness, neurodegeneration, physical activity

DOI: 10.3233/JAD-215258

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Premi, Enrico | Costa, Tommaso | Gazzina, Stefano | Benussi, Alberto | Cauda, Franco | Gasparotti, Roberto | Archetti, Silvana | Alberici, Antonella | van Swieten, John C. | Sanchez-Valle, Raquel | Moreno, Fermin | Santana, Isabel | Laforce, Robert | Ducharme, Simon | Graff, Caroline | Galimberti, Daniela | Masellis, Mario | Tartaglia, Carmela | Rowe, James B. | Finger, Elizabeth | Tagliavini, Fabrizio | de Mendonça, Alexandre | Vandenberghe, Rik | Gerhard, Alexander | Butler, Chris R. | Danek, Adrian | Synofzik, Matthis | Levin, Johannes | Otto, Markus | Ghidoni, Roberta | Frisoni, Giovanni | Sorbi, Sandro | Peakman, Georgia | Todd, Emily | Bocchetta, Martina | Rohrer, Johnathan D. | Borroni, Barbara | GENFI Consortium Members

Collaborators: Afonso, Sónia | Rosario Almeida, Maria | Anderl-Straub, Sarah | Andersson, Christin | Antonell, Anna | Arighi, Andrea | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robart | Bender, Benjamin | Benussi, Luisa | Bessi, Valentina | Binetti, Giuliano | Black, Sandra | Borrego-Ecija, Sergi | Bras, Jose | Bruffaerts, Rose | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Convery, Rhian | Cope, Thomas | de Arriba, María | Di Fede, Giuseppe | Díaz, Zigor | Duro, Diana | Fenoglio, Chiara | Ferrari, Camilla | B. Ferreira, Catarina | Fox, Nick | Freedman, Morris | Fumagalli, Giorgio | Gabilondo, Alazne | Gauthier, Serge | Giaccone, Giorgio | Gorostidi, Ana | Greaves, Caroline | Guerreiro, Rita | Heller, Carolin | Hoegen, Tobias | Indakoetxea, Begoña | Jelic, Vesna | Jiskoot, Lize | Karnath, Hans-Otto | Keren, Ron | Langheinrich, Tobias | João Leitão, Maria | Lladó, Albert | Lombardi, Gemma | Loosli, Sandra | Maruta, Carolina | Mead, Simon | Meeter, Lieke | Miltenberger, Gabriel | van Minkelen, Rick | Mitchell, Sara | Moore, Katrina | Nacmias, Benedetta | Nicholas, Jennifer | Öijerstedt, Linn | Olives, Jaume | Panman, Jessica | Papma, Janne | Pievani, Michela | Pijnenburg, Yolande | Polito, Cristina | Prioni, Sara | Prix, Catharina | Rademakers [as London Ontario geneticist], Rosa | Redaelli, Veronica | Rittman, Tim | Rogaeva, Ekaterina | Rosa-Neto, Pedro | Rossi, Giacomina | Rossor, Martin | Santiago, Beatriz | Scarpini, Elio | Schönecker, Sonja | Semler, Elisa | Shafei, Rachelle | Shoesmith, Christen | Tábuas-Pereira, Miguel | Tainta, Mikel | Taipa, Ricardo | Tang-Wai, David | L Thomas, David | Thompson, Paul | Thonberg, Hakan | Timberlake, Carolyn | Tiraboschi, Pietro | Van Damme, Philip | Vandenbulcke, Mathieu | Veldsman, Michele | Verdelho, Ana | Villanua, Jorge | Warren, Jason | Wilke, Carlo | Woollacott, Ione | Wlasich, Elisabeth | Zetterberg, Henrik | Zulaica, Miren

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, …real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. Show more

Keywords: Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic

DOI: 10.3233/JAD-215447

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Siddiqui, Fatima | Nistala, Kameswara Rishi Yeshayahu | Quek, Chrystie Wan Ning | Shi Ying Leong, Victoria | Ying Shan Tan, Amarinda | En Tan, Christopher Yu | Hilal, Saima

Article Type: Research Article

Abstract: Background: Dementia is the decline in cognitive function sufficient to impair one’s accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents. Objective: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia. Methods: An online anonymous cross-sectional questionnaire …was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions. Results: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females = 69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions. Conclusion: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support. Show more

Keywords: Attitudes, dementia, knowledge, middle age, practices

DOI: 10.3233/JAD-215262

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Che, Bizhong | Chen, Haichang | Wang, Aili | Peng, Hao | Bu, Xiaoqing | Zhang, Jintao | Ju, Zhong | Xu, Tan | He, Jiang | Zhong, Chongke | Zhang, Yonghong

Article Type: Research Article

Abstract: Background: L-carnitine has been shown to exert neuroprotective effects on cerebral ischemia, mainly by improving mitochondrial function and reducing inflammation. L-carnitine supplementation has also been promoted to enhance cognitive function. However, the relationship between L-carnitine and cognitive impairment after ischemic stroke has seldom been studied. Objective: We aimed to evaluate the association between plasma L-carnitine and poststroke cognitive impairment. Methods: The study sample population was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke. Plasma L-carnitine were measured at baseline in 617 patients with ischemic stroke using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Cognitive function was …evaluated using the Montreal Cognitive Assessment at 3-month follow-up after ischemic stroke. Results: Plasma L-carnitine were inversely associated with cognitive impairment at 3 months after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartiles of L-carnitine was 0.60 (0.37, 0.98; p for trend = 0.04). Each 1-SD increase in log-transformed L-carnitine concentration was significantly associated with a 15% (95% CI: 1%, 29%) reduction in the risk of cognitive impairment after stroke. The addition of L-carnitine to the model including conventional risk factors significantly improved the risk reclassification for cognitive impairment (net reclassification improvement: 17.9%, integrated discrimination improvement: 0.8% ; both p  <  0.05). Furthermore, joint effects of L-carnitine and inflammation markers were observed, and patients with higher L-carnitine and a lower inflammatory status simultaneously had the lowest risk of poststroke cognitive impairment. Conclusion: The present study provided prospective evidence on the inverse association between plasma L-carnitine and cognitive impairment after ischemic stroke. Show more

Keywords: Acute ischemic stroke, cognitive impairment, inflammation, L-carnitine

DOI: 10.3233/JAD-215376

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, …insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients. Show more

Keywords: Antidiabetics, dementia, diabetes, hyperglycemia, mortality, propensity-score

DOI: 10.3233/JAD-215337

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Liu, Mingjing | Guo, Shipeng | Huang, Daochao | Hu, Dongjie | Wu, Yili | Zhou, Weihui | Song, Weihong

Article Type: Research Article

Abstract: Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the …effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD. Show more

Keywords: Brain, chronic alcohol consumption, gene expression, neurodegeneration

DOI: 10.3233/JAD-215508

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Stepler, Kaitlyn E. | Gillyard, Taneisha R. | Reed, Calla B. | Avery, Tyra M. | Davis, Jamaine S. | Robinson, Renã A.S.

Article Type: Review Article

Abstract: African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7 ) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE ) ɛ 4 allele in African American/Black adults. ABCA7 …is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted. Show more

Keywords: African Americans, Alzheimer’s disease, Blacks, health status disparities, human ABCA7 protein, proteomics, single nucleotide polymorphism, subfamily A of ATP binding cassette transporter

DOI: 10.3233/JAD-215306

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Miron, Justin | Picard, Cynthia | Labonté, Anne | Auld, Daniel | Poirier, Judes | for the PREVENT-AD research group

Article Type: Research Article

Abstract: Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ 1 - 42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. …CSF Aβ 1 - 42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1 , APOE , and CLU (ApoJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ 1 - 42 , ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ 1 - 42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, inflammation, MSR1, NEP

DOI: 10.3233/JAD-215410

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Bakker, Els D. | van Maurik, Ingrid S. | Mank, Arenda | Zwan, Marissa D. | Waterink, Lisa | van den Buuse, Susanne | van den Broeke, Jennifer R. | Gillissen, Freek | van de Beek, Marleen | Lemstra, Evelien | van den Bosch, Karlijn A. | van Leeuwenstijn, Mardou | Bouwman, Femke H. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic poses enormous social challenges, especially during lockdown. People with cognitive decline and their caregivers are particularly at risk of lockdown consequences. Objective: To investigate psychosocial effects in (pre-)dementia patients and caregivers during second lockdown and compare effects between first and second lockdown. Methods: We included n  = 511 (pre-)dementia patients and n  = 826 caregivers from the Amsterdam Dementia Cohort and via Alzheimer Nederland. All respondents completed a self-designed survey on psychosocial effects of COVID-19. We examined relations between experienced support and psychosocial and behavioral symptoms using logistic regression. In a subset of patients …and caregivers we compared responses between first and second lockdown using generalized estimating equation. Results: The majority of patients (≥58%) and caregivers (≥60%) reported that family and friends, hobbies, and music helped them cope. Support from family and friends was strongly related to less negative feelings in patients (loneliness: OR = 0.3[0.1–0.6]) and caregivers (loneliness: OR = 0.2[0.1–0.3]; depression: OR = 0.4[0.2–0.5]; anxiety: OR = 0.4[0.3–0.6]; uncertainty: OR = 0.3[0.2–0.5]; fatigue: OR = 0.3[0.2–0.4]; stress: OR = 0.3[0.2–0.5]). In second lockdown, less psychosocial and behavioral symptoms were reported compared to first lockdown (patients; e.g., anxiety: 22% versus 13%, p  = 0.007; apathy: 27% versus 8%, p  < 0.001, caregivers; e.g., anxiety: 23% versus 16%, p  = 0.033; patient’s behavioral problems: 50% versus 35%, p  < 0.001). Patients experienced more support (e.g., family and friends: 52% versus 93%, p  < 0.001; neighbors: 28% versus 66%, p  < 0.001). Conclusion: During second lockdown, patients and caregivers adapted to challenges posed by lockdown, as psychosocial and behavioral effects decreased, while patients experienced more social support compared to first lockdown. Support from family and friends is a major protective factor for negative outcomes in patients and caregivers. Show more

Keywords: Behavioral effects, caregiver, COVID-19, dementia, experienced support, lockdown, mild cognitive impairment, psychosocial effects, subjective cognitive decline

DOI: 10.3233/JAD-215342

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Schaffert, Jeff | LoBue, Christian | Hynan, Linda S. | Hart Jr., John | Rossetti, Heidi | Carlew, Anne R. | Lacritz, Laura | White III, Charles L. | Cullum, C. Munro

Article Type: Research Article

Abstract: Background: Life expectancy (LE) following Alzheimer’s disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses. Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study. Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer’s Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. …Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death. Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12. Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. Show more

Keywords: Alzheimer’s disease, autopsy-confirmed, dementia, life expectancy, mortality

DOI: 10.3233/JAD-215200

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Eastman, Guillermo | Sharlow, Elizabeth R. | Lazo, John S. | Bloom, George S. | Sotelo-Silveira, José R.

Article Type: Research Article

Abstract: Background: Defining cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI ;NOS2 -/- ) and Tg2576 (APPSw ), …and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain. Show more

Keywords: Alzheimer’s disease, amyloid, microglia, RNA-Seq, mRNA translation, transcriptome regulation

DOI: 10.3233/JAD-215357

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2021

Authors: Lerch, Ondrej | Pařízková, Martina | Vyhnálek, Martin | Nedelská, Zuzana | Hort, Jakub | Laczó, Jan

Article Type: Research Article

Abstract: Background: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer’s disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOE ɛ 4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. Objective: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they …operate on aSN through MTL and PFC or independently from these structures. Methods: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). Results: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2  = 0.039; pch4p  = 0.042) and PFC (pch4ai  = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p  = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p  = 0.035). Conclusion: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations. Show more

Keywords: Allocentric spatial navigation, apolipoprotein E, basal forebrain, entorhinal cortex, hippocampus, magnetic resonance imaging, prefrontal cortex

DOI: 10.3233/JAD-215034

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Pritchard, Anna Barlach | Fabian, Zsolt | Lawrence, Clare L. | Morton, Glyn | Crean, StJohn | Alder, Jane E.

Article Type: Research Article

Abstract: Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis ) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a …primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains). Show more

Keywords: Alzheimer’s disease, blood-brain barrier, human brain microvascular endothelial cells, in vitro BBB model, microbiome, periodontal disease

DOI: 10.3233/JAD-215054

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2021

Authors: Manivannan, Madhumitha | Heunis, Julia | Hooper, Sarah M. | Bernstein Sideman, Alissa | Lui, Kristi P. | Possin, Katherine L. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Financial mismanagement and abuse in dementia have serious consequences for patients and their families. Vulnerability to these outcomes reflects both patient and contextual factors. Objective: Our study aimed to assess how multidisciplinary care coordination programs assist families in addressing psychosocial vulnerabilities and accessing needed resources. Methods: Our study was embedded in a clinical trial of the Care Ecosystem, a telephone- and internet-based supportive care intervention for patients with dementia and caregivers. This program is built around the role of the Care Team Navigator (CTN), an unlicensed dementia care guide who serves as the patient and …caregiver’s primary point of contact, screening for common problems and providing support. We conducted a qualitative analysis of case summaries from a subset of 19 patient/caregiver dyads identified as having increased risk for financial mismanagement and abuse, to examine how Care Ecosystem staff identified vulnerabilities and provided support to patients and families. Results: CTNs elicited patient and caregiver needs using templated conversations to address common financial and legal planning issues in dementia. Sources of financial vulnerability included changes in patients’ behavior, caregiver burden, intrafamily tension, and confusion about resources to facilitate end-of-life planning. The Care Ecosystem staff’s rapport with their dyads helped them address these issues by providing emotional support, information on how to access financial, medical, and legal resources, and improving intra-familial communication. Conclusion: The Care Ecosystem offers a scalable way to address vulnerabilities to financial mismanagement and abuse in patients and caregivers through coordinated care by unlicensed care guides supported by a multidisciplinary team. Show more

Keywords: Care navigation, caregivers, dementia, financial management

DOI: 10.3233/JAD-215284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Nami, Mohammad | Thatcher, Robert | Kashou, Nasser | Lopes, Dahabada | Lobo, Maria | Bolanos, Joe F. | Morris, Kevin | Sadri, Melody | Bustos, Teshia | Sanchez, Gilberto E. | Mohd-Yusof, Alena | Fiallos, John | Dye, Justin | Guo, Xiaofan | Peatfield, Nicholas | Asiryan, Milena | Mayuku-Dore, Alero | Krakauskaite, Solventa | Soler, Ernesto Palmero | Cramer, Steven C. | Besio, Walter G. | Berenyi, Antal | Tripathi, Manjari | Hagedorn, David | Ingemanson, Morgan | Gombosev, Marinela | Liker, Mark | Salimpour, Yousef | Mortazavi, Martin | Braverman, Eric | Prichep, Leslie S. | Chopra, Deepak | Eliashiv, Dawn S. | Hariri, Robert | Tiwari, Ambooj | Green, Ken | Cormier, Jason | Hussain, Namath | Tarhan, Nevzat | Sipple, Daniel | Roy, Michael | Yu, John S. | Filler, Aaron | Chen, Mike | Wheeler, Chris | Ashford, J. Wesson | Blum, Kenneth | Zelinsky, Deborah | Yamamoto, Vicky | Kateb, Babak

Article Type: Review Article

Abstract: The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a …methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales. Show more

Keywords: Brain mapping, brain screening, cMEG, mental health screening, neuro-screening, neurotechnologies, preventive medicine, qEEG

DOI: 10.3233/JAD-215240

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2021

Authors: Zhang, Li-Na | Li, Meng-Jie | Shang, Ying-Hui | Liu, Yun-Ru | Han-Chang, Huang | Lao, Feng-Xue

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) characterized by neurofibrillary tangles caused by hyperphosphorylated tau is the most common cause of dementia. Zeaxanthin (Zea), derived from fruits and vegetables, may reduce the risk of AD. Endoplasmic reticulum stress (ERS) might cause memory impairment in AD. Objective: Here, we studied protective role of Zea on the relationship among ERS, activity of glycogen synthase kinase 3β (GSK-3β, tau phosphorylated kinase), and p-Tau (Ser 396 and Thr 231). Methods: The results were obtained in non-RA and RA group by using different treatment, such as 9-cis-retinoic acid (RA), TM (ERS inducer), Zea, 4-PBA …(ERS inhibitor), and SB216763 (GSK-3β inhibitor). The methods included flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] for the detections of cell cycle and cell viability and western blot as a third measure of proteins in relation to ERS and tau phosphorylation. We have collected and analyzed all the data that suggested application of drugs for the treatment in non-RA and RA group. Results: Zea displays its protection on TM-induced cell injury, upregulation of GRP78 expression, and change of GSK-3β activity and tau phosphorylation when 4-PBA and SB216763 interfere with the process. Conclusion: These studies indicated that Zea is in vicious circle in ERS, GSK-3β, and tau phosphorylation, and further reflect its potential value in AD. Show more

Keywords: Alzheimer’s disease, glycogen synthase kinase 3β, SB216763, tau, Zeaxanthin

DOI: 10.3233/JAD-215408

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Dennison, Jessica L. | Volmar, Claude-Henry | Ke, Danbing | Wang, James | Gravel, Emilie | Hammond-Vignini, Sabrina | Li, Zuomei | Timmons, James A. | Lohse, Ines | Hayward, Marshall A. | Brothers, Shaun P. | Wahlestedt, Claes

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROLTM, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic …(APPSW /PS1M146V /TauP301L ; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1 ) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels. Show more

Keywords: Alzheimer’s disease, inflammation, neuroprotection, resveratrol, sex differences

DOI: 10.3233/JAD-215370

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Zhang, Qiaoyang | Zhang, Min | Chen, Yun | Cao, Yin | Dong, Guanzhong

Article Type: Research Article

Abstract: Background: Serum non-high-density lipoprotein-cholesterol (non-HDL-C) levels may be associated with cognitive function. Objective: The objective of this study was to evaluate the association between non-HDL-C and cognitive function among American elders. Methods: We used data from the 2011 to 2014 U.S. National Health and Nutrition Examination Survey (NHANES). A total of 3,001 participants aged over 60 years were enrolled in our analysis. The cognitive function was evaluated with the word learning subtest from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD W-L), the Animal Fluency Test (AFT), and the digit symbol substitution test (DSST). …We also created a composite cognitive z-score to represent a global cognition. We applied multivariate linear regression analyses to estimate the associations between non-HDL-C levels and all domains of cognitive function. Further, the generalized additive model and the smooth curve were conducted to investigate the dose-response relationship between non-HDL-C and global cognition. Results: Serum non-HDL-C was positively associated with global cognition (β = 0.20, 95% CI: 0.11, 0.28), AFT score (β = 0.54, 95% CI: 0.33, 0.76), and DSST score (β = 1.13, 95% CI: 0.56, 1.69) after fully adjusted. While non-HDL-C was not related to CERAD W-L score. In addition, an inverted U-shape curve was observed in the dose-response relationship between non-HDL-C and global cognition (p for non-linearity <  0.001). Conclusion: Serum non-HDL-C is positively and nonlinearly associated with cognitive function among American older adults. Maintaining serum cholesterol levels at an appropriate range may be helpful to the cognitive health of the elderly. Show more

Keywords: Cholesterol, cognitive function, NHANES, non-HDL-C, older adults

DOI: 10.3233/JAD-215250

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Bian, Zhihong | Liu, Xia | Feng, Tian | Yu, Haibo | Hu, Xiao | Hu, Xinran | Bian, Yuting | Sun, Hongming | Tadokoro, Koh | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Fukui, Yusuke | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer’s disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. Objective: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. Methods: In the …present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. Results: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. Conclusion: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy chronic cerebral hypoperfusion, rivaroxaban, warfarin

DOI: 10.3233/JAD-215318

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Johansen, Michelle C. | Wang, Wendy | Zhang, Michael J. | Alonso, Alvaro | Wong, Dean F. | Gottesman, Rebecca F. | Chen, Lin Y.

Article Type: Research Article

Abstract: The aim of this study is to determine if there is an association between atrial arrhythmias and brain amyloid-β (Aβ), measured on florbetapir (FBP) PET. 346 nondemented participants from the Atherosclerosis Risk in Communities study underwent FBP-PET, 185 also wore Zio® XT Patch. The associations between global cortical Aβ (>  1.2 standardized uptake value ratio) and history of atrial fibrillation, zio-defined atrial tachycardia and premature atrial contractions, each, were evaluated. Among nondemented community-dwelling older adults, we did not find an association between atrial arrhythmias and Aβ. Other brain pathology may underlie the association described between atrial arrhythmias and cognition.

Keywords: Arrhythmias, atrial fibrillation, cognitive impairment, imaging

DOI: 10.3233/JAD-215378

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Daly, Timothy | Mastroleo, Ignacio | Henry, Vincent | Bourdenx, Mathieu

Article Type: Research Article

Abstract: Two potential disease-modifying approaches for dementia are being vigorously tested: the early targeting of the neuropathology of Alzheimer’s disease (AD) and multi-domain lifestyle interventions to promote resilience to neuropathology. We apply the “web of information” model of clinical translation to both approaches to argue firstly that tests of treatments aiming to achieve clinically meaningful outcomes should remain simple, and secondly, that building clinically-meaningful treatments should be kept separate from public health policy which means promoting wide-reaching action against risk factors now with available information.

Keywords: Alzheimer’s disease, clinical trials, dementia, innovation, public health, treatment

DOI: 10.3233/JAD-215492

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Benca, Ruth | Herring, W. Joseph | Khandker, Rezaul | Qureshi, Zaina

Article Type: Research Article

Abstract: Background: Sleep disturbances are frequent in Alzheimer’s disease (AD). This review summarizes the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies. Methods: Published studies (January 1985–March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase and Cochrane Library and screened against inclusion criteria. Findings: This review included 58 studies which assessed patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances. Sleep disturbances were associated with worse cognition, functional …ability, and behavioral and neuropsychological functioning, including increased depression and anxiety. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances, with caregiver burden driven largely by disruptive nocturnal behaviors including nighttime awakenings and wanderings. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g. cognitive status). With respect to insomnia treatments, bright light, and behavioral therapies as well as drugs such as trazodone, risperidone and suvorexant showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to insomnia treatment effects on associated clinical burden. Interpretation: Sleep disturbances are a significant problem for AD patients and caregivers. They are associated with behavioral and psychological problems and cognitive decline and impose a burden on caregivers, but remain poorly characterized and under-researched. As the global population is aging and AD is on the rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact of insomnia treatments on AD patients and their caregivers. Show more

Keywords: Insomnia, Alzheimer’s disease, sleep disturbances, literature review, caregiver burden, clinical burden, institutionalization, treatment guidelines

DOI: 10.3233/JAD-215324

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2021

Authors: Posis, Alexander Ivan B. | Tarraf, Wassim | Gonzalez, Kevin A. | Soria-Lopez, Jose A. | Léger, Gabriel C. | Stickel, Ariana M. | Daviglus, Martha L. | Lamar, Melissa | Zeng, Donglin | González, Hector M.

Article Type: Research Article

Abstract: Background: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. Objective: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. Methods: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n  = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. …Results: Anticholinergic use was associated with lower cognitive global cognition (β= –0.21; 95% CI [–0.36; –0.05]), learning (β= –0.27; 95% CI [–0.47; –0.07]), memory (β= –0.22; 95% CI [–0.41; –0.03]), and executive functioning (β= –0.22; 95% CI [–0.40; –0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: –0.28 [95% CI: –0.55, –0.01]; β: –0.28 [95% CI: –0.55, –0.01]; β: –0.25, [95% CI –0.47, –0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F 3  = 3.59, F 3  = 2.84, F 3  = 3.88, respectively). Conclusion: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact. Show more

Keywords: Aging, cognition, cognitive function, cohort study, neurocognitive tests, hispanics, latinos

DOI: 10.3233/JAD-215247

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Liu, Ruijie | Gao, Chenhao | Shang, Junkui | Sun, Ruihua | Wang, Wenjing | Li, Wei | Gao, Dandan | Huo, Xuejing | Shi, Yingying | Wang, Yanliang | Wang, Fengyu | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear. Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL. Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro . The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD …) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis. Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G >  A, p. A564T) in two pedigrees. In vitro , the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis. Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations. Show more

Keywords: Apoptosis, CADASIL, cysteine-sparing NOTCH3 mutation, flow cytometry, mitochondrial dysfunction

DOI: 10.3233/JAD-215256

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Henderson, Catherine | Knapp, Martin | Martyr, Anthony | Gamble, Laura D. | Nelis, Sharon M. | Quinn, Catherine | Pentecost, Claire | Collins, Rachel | Wu, Yu-Tzu | Jones, Ian R. | Victor, Christina R. | Pickett, James A. | Jones, Roy W. | Matthews, Fiona E. | Morris, Robin G. | Rusted, Jennifer | Thom, Jeanette M. | Clare, Linda | on behalf of the IDEAL programme team

Article Type: Research Article

Abstract: Background: The drivers of costs of care for people with dementia are not well understood and little is known on the costs of care for those with rarer dementias. Objective: To characterize use and costs of paid and unpaid care over time in a cohort of people with dementia living in Britain. To explore the relationship between cohort members’ demographic and clinical characteristics and service costs. Methods: We calculated costs of health and social services, unpaid care, and out-of-pocket expenditure for people with mild-to-moderate dementia participating in three waves of the IDEAL cohort (2014– 2018). Latent …growth curve modelling investigated associations between participants’ baseline sociodemographic and diagnostic characteristics and mean weekly service costs. Results: Data were available on use of paid and unpaid care by 1,537 community-dwelling participants with dementia at Wave 1, 1,199 at Wave 2, and 910 at Wave 3. In models of paid service costs, being female was associated with lower baseline costs and living alone was associated with higher baseline costs. Dementia subtype and caregiver status were associated with variations in baseline costs and the rate of change in costs, which was additionally influenced by age. Conclusion: Lewy body and Parkinson’s disease dementias were associated with higher service costs at the outset, and Lewy body and frontotemporal dementias with more steeply increasing costs overall, than Alzheimer’s disease. Planners of dementia services should consider the needs of people with these relatively rare dementia subtypes as they may require more resources than people with more prevalent subtypes. Show more

Keywords: Dementia, dementia with Lewy bodies, frontotemporal dementia, health services, Parkinson’s disease dementia, social services, unpaid caregivers

DOI: 10.3233/JAD-215117

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Alatorre-Cruz, Graciela C. | Fernández, Thalía | Castro-Chavira, Susana A. | González-López, Mauricio | Sánchez-Moguel, Sergio M. | Silva-Pereyra, Juan

Article Type: Research Article

Abstract: Background: In healthy older adults, excess theta activity is an electroencephalographic (EEG) predictor of cognitive impairment. In a previous study, neurofeedback (NFB) treatment reinforcing reductions theta activity resulted in EEG reorganization and cognitive improvement. Objective: To explore the clinical applicability of this NFB treatment, the present study performed a 1-year follow-up to determine its lasting effects. Methods: Twenty seniors with excessive theta activity in their EEG were randomly assigned to the experimental or control group. The experimental group received an auditory reward when the theta absolute power (AP) was reduced. The control group received the reward …randomly. Results: Both groups showed a significant decrease in theta activity at the training electrode. However, the EEG results showed that only the experimental group underwent global changes after treatment. These changes consisted of delta and theta decreases and beta increases. Although no changes were found in any group during the period between the posttreatment evaluation and follow-up, more pronounced theta decreases and beta increases were observed in the experimental group when the follow-up and pretreatment measures were compared. Executive functions showed a tendency to improve two months after treatment which became significant one year later. Conclusion: These results suggest that the EEG and behavioral benefits of this NFB treatment persist for at least one year, which adds up to the available evidence contributing to identifying factors that increase its efficacy level. The relevance of this study lies in its prophylactic features of addressing a clinically healthy population with EEG risk of cognitive decline. Show more

Keywords: Biofeedback, cognitive aging, EEG, follow-up, healthy aging, neurofeedback, older adults

DOI: 10.3233/JAD-215538

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Morin, Alexandre | Pressat-Laffouilhere, Thibaut | Sarazin, Marie | Lagarde, Julien | Roue-Jagot, Carole | Olivieri, Pauline | Paquet, Claire | Cognat, Emmanuel | Dumurgier, Julien | Pasquier, Florence | Lebouvier, Thibaut | Ceccaldi, Matthieu | Godefroy, Olivier | Martinaud, Olivier | Grosjean, Julien | Zarea, Aline | Maltête, David | Wallon, David

Article Type: Research Article

Abstract: This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March–May 2020). The objective was to evaluate the effect of a telemedicine consultation on treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer’s disease. A control group of patients referred March–May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of –4% (p  = 0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.

Keywords: Alzheimer’s disease, COVID-19, psychoactive drugs, telemedicine, treatments in dementia

DOI: 10.3233/JAD-215459

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Jung, Keun-Hwa | Park, Kyung-Il | Lee, Woo-Jin | Son, Hyo-Shin | Chu, Kon | Lee, Sang Kun

Article Type: Research Article

Abstract: Background: Cerebral white matter lesions (WML) are related to a higher risk of vascular and Alzheimer’s dementia. Moreover, oligomerized amyloid-β (OAβ) can be measured from blood for dementia screening. Objective: We aimed to investigate the relationship of plasma OAβ levels with clinical and radiological variables in a health screening population. Methods: WML, other volumetric parameters of magnetic resonance images, cognitive assessment, and plasma OAβ level were evaluated. Results: Ninety-two participants were analyzed. The majority of participants’ clinical dementia rating was 0 or 0.5 (96.7%). White matter hyperintensities (WMH) increased with age, but OAβ levels …did not (r2  = 0.19, p  <  0.001, r2  = 0.03, p  = 0.10, respectively). No volumetric data, including cortical thickness/hippocampal volume, showed any significant correlation with OAβ. Log-WMH volume was positively correlated with OAβ (r  = 0.24, p  = 0.02), and this association was significant in the periventricular area. White matter signal abnormalities from 3D-T1 images were also correlated with the OAβ in the periventricular area (p  = 0.039). Multivariate linear regression showed that log-WMH values were independently associated with OAβ (B  = 0.879 (95% confidence interval 0.098 –1.660, p  = 0.028)). Higher tertiles of WMH showed higher OAβ levels than lower tertiles showed (p  = 0.044). Using a cutoff of 0.78 ng/mL, the high OAβ group had a larger WMH volume, especially in the periventricular area, than the low OAβ group (p  = 0.036). Conclusion: Both WML and plasma OAβ levels can be early markers for neurodegeneration in the healthcare population. The lesions, especially in the periventricular area, might be related to amyloid pathogenesis, which strengthens the importance of WML in the predementia stage. Show more

Keywords: Cortical thickness, healthcare population, plasma oligomerized amyloid-β, white matter hyperintensity

DOI: 10.3233/JAD-215399

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Kurano, Makoto | Tsukamoto, Kazuhisa | Sakai, Eri | Hara, Masumi | Yatomi, Yutaka

Article Type: Research Article

Abstract: Background: Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer’s disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer’s disease. Objective: We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system. Methods: We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4. Results: In the brains of Apoeshl …mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4. Conclusion: The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer’s disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ApoE isoforms, apolipoprotein M, ceramide, sphingosine 1-phosphate

DOI: 10.3233/JAD-215205

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Luo, Xiao | Hong, Hui | Wang, Shuyue | Li, Kaicheng | Zeng, Qingze | Hong, Luwei | Liu, Xiaocao | Li, Zheyu | Fu, Yanv | Jiaerken, Yeerfan | Xu, XiaoPei | Yu, Xinfeng | Huang, Peiyu | Zhang, Minming

Article Type: Research Article

Abstract: Background: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. Objective: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. Methods: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers …as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). Results: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p  < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = –0.25) and EC (r = –0.25) of middle temporal gyrus was related with SPPB in all participants (p  < 0.05, corrected). Conclusion: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions. Show more

Keywords: Cerebral microinfarcts, cerebral small vascular disease, degree centrality, eigenvector centrality, motor function, resting-state functional MRI

DOI: 10.3233/JAD-215227

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Ren, Yifei | Dong, Yi | Hou, Tingting | Han, Xiaolei | Liu, Rui | Wang, Yongxiang | Xu, Shan | Wang, Xiang | Monastero, Roberto | Cong, Lin | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Few studies have examined occurrence and progression of cognitive impairment, no dementia (CIND) in rural China. Objective: To determine the prevalence and incidence of CIND in rural-dwelling Chinese older adults, and to examine risk and protective factors associated with progression to CIND and dementia. Methods: This population-based study included 2,781 dementia-free participants (age≥65 years) who were examined at baseline (2014) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected following a structured questionnaire. We defined CIND according to subjective cognitive complaints and the age- and education-specific Mini-Mental State Examination (MMSE) score. Data …were analyzed with the multinomial logistic regression models. Results: The overall prevalence of CIND was 10.54% and the incidence was 28.26 per 1,000 person-years. CIND at baseline was associated with the multi-adjusted odds ratio (OR) of 2.06 (95% confidence interval = 1.23–3.47) for incident dementia. Multinomial logistic regression analysis suggested that compared with no CIND, the multi-adjusted OR of incident CIND was 2.21 (1.51–3.23) for women and 0.62 (0.38–0.99) for high social support, whereas the multi-adjusted OR of incident dementia was 1.14 (1.09–1.18) for older age, 0.29 (0.16–0.53) for high education, and 2.91 (1.47–5.74) for having a stroke history. Conclusion: CIND affects over one-tenth of older adults living in rural communities of western Shandong province. People with CIND are twice as likely to progress to dementia as people without CIND. Female sex, low education, stroke history, and low social support are associated with an increased risk of progression from normal cognition to CIND or dementia. Show more

Keywords: Cognitive impairments, incidence, population-based study, prevalence, risk factors, rural

DOI: 10.3233/JAD-215236

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Wang, Xiaoqi | Bi, Qiuhui | Lu, Jie | Chan, Piu | Hu, Xiaochen | Su, Li | Jessen, Frank | Lin, Hua | Han, Chunlei | Shu, Ni | Liu, Hesheng | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer’s disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. Objective: We aims to explore the differences in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. Methods: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18 F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was …quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n  = 34) and sd-SCD (n  = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. Results: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F  = 5.033, p  = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F  = 12.309, p  = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. Conclusion: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals. Show more

Keywords: Alzheimer’s disease, amyloid, multidomain, single memory domain, subjective cognitive decline

DOI: 10.3233/JAD-215373

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Wang, Jianlin | Wang, Pan | Jiang, Yuan | Wang, Zedong | Zhang, Hong | Li, Hongyi | Biswal, Bharat B.

Article Type: Research Article

Abstract: Background: The hippocampus with varying degrees of atrophy was a crucial neuroimaging feature resulting in the declining memory and cognitive function in Alzheimer’s disease (AD). However, the abnormal dynamic functional connectivity (DFC) in both white matter (WM) and gray matter (GM) from the left and right hippocampus remains unclear. Objective: To explore the abnormal DFC within WM and GM from the left and right hippocampus across the different stages of AD. Methods: Current study employed the OASIS-3 dataset including 43 mild cognitive impairment (MCI), 71 pre-mild cognitive impairment (pre-MCI), and matched 87 normal …cognitive (NC). Adopting the FMRIB’s Integrated Registration and Segmentation Tool, we obtained the left and right hippocampus mask. Based on above hippocampus mask as seed point, we calculated the DFC between left/right hippocampus and all voxel time series within whole brain. One-way ANOVA analysis was performed to estimate the abnormal DFC among MCI, pre-MCI, and NC groups. Results: We found that MCI and pre-MCI groups showed the common abnormalities of DFC in the Temporal_Mid_L, Cingulum_Mid_L, and Thalamus_L. Specific abnormalities were found in the Cerebelum_9_L and Precuneus of MCI group and Vermis_8 and Caudate_L of pre-MCI group. In addition, we found that DFC within WM regions also showed the common low DFC for the Cerebellum anterior lobe-WM, Corpus callosum, and Frontal lobe-WM in MCI and pre-MCI group. Conclusion: Our findings provided a novel information for discover the pathophysiological mechanisms of AD and indicate WM lesions were also an important cause of cognitive decline in AD. Show more

Keywords: Alzheimer’s disease, dynamic functional connectivity, hippocampus, mild cognitive impairment, white matter BOLD signal

DOI: 10.3233/JAD-215239

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Day, Sally | Roberts, Stefanie | Launder, Nathalie H. | Goh, Anita M.Y. | Draper, Brian | Bahar-Fuchs, Alex | Loi, Samantha M. | Laver, Kate | Withall, Adrienne | Cations, Monica

Article Type: Research Article

Abstract: Background: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning. Objective: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Methods: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. …Quantitative meta-analysis was conducted where studies reported sufficient data for pooling. Results: Thirty studies met all inclusion criteria (people with AD (n  = 26), FTD (n  = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = –0.07; 95% CI –0.14 to 0.00; p  = 0.045). Most studies that stratified their sample reported that younger AD onset (usually <  65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive. Conclusion: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias. Show more

Keywords: Alzheimer’s disease, disease progression, frontotemporal dementia, prognosis, vascular dementia

DOI: 10.3233/JAD-215360

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Giannakopoulos, Panteleimon | Rodriguez, Cristelle | Montandon, Marie-Louise | Garibotto, Valentina | Haller, Sven | Herrmann, François R.

Article Type: Research Article

Abstract: Background: Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. Objective: This study explores the impact of personality on widely used Alzheimer’s disease (AD) and vascular imaging markers. Methods: We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify …predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Results: Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Conclusion: Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age. Show more

Keywords: Amyloid load, cortical volume, gray matter density, normal aging, personality

DOI: 10.3233/JAD-215062

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Khorani, Mona | Bobe, Gerd | Matthews, Donald G. | Magana, Armando Alcazar | Caruso, Maya | Gray, Nora E. | Quinn, Joseph F. | Stevens, Jan F. | Soumyanath, Amala | Maier, Claudia S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: Gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were …linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse. Show more

Keywords: Alzheimer’s disease, excitatory and inhibitory imbalance, fatty acids, hAPP695SW , hippocampus, metabolomics, Tg2576

DOI: 10.3233/JAD-215084

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2021

Authors: Streit, Wolfgang J. | Rotter, Jonas | Winter, Karsten | Müller, Wolf | Khoshbouei, Habibeh | Bechmann, Ingo

Article Type: Research Article

Abstract: Background: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown. Objective: Elucidate neuritic plaque pathogenesis. Methods: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron. Results: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary …tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl’s Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly. Conclusion: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques. Show more

Keywords: Amyloid-β protein, ferritin, ferroptosis, iron, late-onset Alzheimer’s disease, microglia, neuron loss

DOI: 10.3233/JAD-215334

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Jang, Hyemin | Park, Yu-hyun | Choe, Young Sim | Kang, Sung Hoon | Kang, Eun-Sook | Lee, Seunghoon | Seo, Sang Won | Kim, Hee Jin | Na, Duk L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist. Objective: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET). Methods: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging …findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD. Results: Evans’ index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all. Conclusion: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, hydrocephalus, MRI, PET

DOI: 10.3233/JAD-215110

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Black, Stefanie A.G. | Stepanchuk, Anastasiia A. | Templeton, George W. | Hernandez, Yda | Ota, Tomoko | Roychoudhury, Shyamosree | Smith, Eric E. | Barber, Philip A. | Ismail, Zahinoor | Fischer, Karyn | Zwiers, Angela | Poulin, Marc J. | Blennow, Kaj | Zetterberg, Henrik | Stys, Peter K. | Tsutsui, Shigeki

Article Type: Research Article

Abstract: Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with …confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease. Show more

Keywords: Aβ42, Alzheimer’s disease, cerebrospinal fluid, conformationally-sensitive amyloid probes, p-Tau, peripheral blood mononuclear cells, spectral confocal microscopy, t-Tau

DOI: 10.3233/JAD-215402

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Broberg, Dana | Wong, Dickson | Bellyou, Miranda | Montero-Odasso, Manuel | Beauchet, Olivier | Annweiler, Cedric | Bartha, Robert

Article Type: Research Article

Abstract: Background: Altered gait is a frequent feature of Alzheimer’s disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective: Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods: Male APPswe/PS1dE9 mice were split into four groups (n  = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups …started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. Results: Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p  <  0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p  <  0.01), while mice treated with memantine and vitamin D did not (p  = 0.21). Conclusion: Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD. Show more

Keywords: Alzheimer’s disease, animal model, CatWalk, gait, memantine, vitamin D

DOI: 10.3233/JAD-215188

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Liu, Qingqing | Ling, Zaisheng | Zhang, Jinpeng | Yu, Hongli | Wang, Ye | Xue, Yang | Wang, Chunyan | Zhao, Jiwei | Cao, Jingwei | Duan, Shurong | Zhao, Jingkun

Article Type: Research Article

Abstract: Background: Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer’s disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Objective: Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. Methods: The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the …colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. Results: MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. Conclusion: MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research. Show more

Keywords: Alzheimer’s disease, autophagy, lncRNAs MIR600HG, mitochondrial dysfunction, PINK1

DOI: 10.3233/JAD-215194

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Wu, Benson | Toseef, Mohammad Usama | Stickel, Ariana M. | González, Hector M. | Tarraf, Wassim

Article Type: Research Article

Abstract: Background: Life-course approaches to identify and help improve modifiable risk factors, particularly in midlife, may mitigate cognitive aging. Objective: We examined how midlife self-rated physical functioning and health may predict cognitive health in older age. Methods: We used data from the Health and Retirement Study (1998–2016; unweighted-N  = 4,685). We used survey multinomial logistic regression and latent growth curve models to examine how midlife (age 50–64 years) activities of daily living (ADL), physical function, and self-reported health affect cognitive trajectories and cognitive impairment not dementia (CIND) and dementia status 18 years later. Then, we tested for sex …and racial/ethnic modifications. Results: After covariates-adjustment, worse instrumental ADL (IADL) functioning, mobility, and self-reported health were associated with both CIND and dementia. Hispanics were more likely to meet criteria for dementia than non-Hispanic Whites given increasing IADL impairment. Conclusion: Midlife health, activities limitations, and difficulties with mobility are predictive of dementia in later life. Hispanics may be more susceptible to dementia in the presence of midlife IADLs. Assessing midlife physical function and general health with brief questionnaires may be useful for predicting cognitive impairment and dementia in later life. Show more

Keywords: Cognitive function, cognitive impairment, dementia, midlife health risks

DOI: 10.3233/JAD-215192

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Sun, Yuqing | Wang, Meng | Zhao, Yuxin | Hu, Ke | Liu, Yong | Liu, Bing | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Tauopathy is a primary neuropathological hallmark of Alzheimer’s disease with a strong relationship to cognitive impairment. In the brain, tau aggregation is associated with the regulation of tau kinases and the binding ability of tau to microtubules. Objective: To explore the potential for using specific polygenic risk scores (PRSs), combining the genetic influences involved in tau-protein kinases and the tau-protein binding pathway, as predictors of tau pathology and cognitive decline in non-demented individuals. Methods: We computed a pathway-specific PRS using summary statistics from previous large-scale genome-wide association studies of dementia. We examined whether PRS is …related to tau uptake in positron emission tomography (PET), tau levels, and the rate of tau level changes in cerebrospinal fluid (CSF). We further assessed whether PRS is associated with memory impairment mediated by CSF tau levels. Results: A higher PRS was related to elevated CSF tau levels and tau-PET uptake at baseline, as well as greater rates of change in CSF tau levels. Moreover, PRS was associated with memory impairment, mediated by increased CSF tau levels. The association between PRS and tau pathology was significant when APOE was excluded, even among females. However, the effect of PRS on cognitive decline appeared to be driven by the inclusion of APOE . Conclusion: The influence of genetic risk in a specific tau-related biological pathway may make an individual more susceptible to tau pathology, resulting in cognitive dysfunction in an early preclinical phase of the disease. Show more

Keywords: Alzheimer’s disease, cognitive function genetic risk scores, pathway, tau

DOI: 10.3233/JAD-215163

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Dunk, Michelle M. | Driscoll, Ira | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: APOE ɛ 4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE , and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE -related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N  = 1,534) were classified as controls (cognitively normal; N  = 404), early mild cognitive impairment (MCI; N  = 294), late MCI (N … = 539), or AD (N  = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4 + compared to APOE3 and APOE2+ (p s < 0.04) carriers. Those with AD and late MCI (p s < 0.001) had higher total cholesterol than the control group. Comparing APOE4 + to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (p s < 0.05, F-statistics>10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cholesterol, dementia, lipid metabolism

DOI: 10.3233/JAD-215091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Ahn, Hyejin | Yi, Dahyun | Chu, Kyungjin | Joung, Haejung | Lee, Younghwa | Jung, Gi Jung | Sung, Kiyoung | Han, Dongkyun | Lee, Jun Ho | Byun, Min Soo | Young Lee, Dong

Article Type: Research Article

Abstract: Background: Total score (TS) of semantic verbal fluency test (SVFT) is generally used to interpret results, but it is ambiguous as to specific neural functions it reflects. Different SVFT strategy scores reflecting qualitative aspects are proposed to identify specific cognitive functions to overcome limitations of using the TS. Objective: Functional neural correlates of the TS as well as the other strategy scores in subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia using Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET). Methods: Correlations between various SVFT scores (i.e., TS, mean cluster size, switching (SW), …hard switching, cluster switching (CSW)) and cerebral glucose metabolism were explored using voxelwise whole-brain approach. Subgroup analyses were also performed based on the diagnosis and investigated the effects of disease severity on the associations. Results: Significant positive correlation between TS and cerebral glucose metabolism was found in prefrontal, parietal, cingulate, temporal cortex, and subcortical regions. Significantly increased glucose metabolism associated with the SW were found in similar but smaller regions, mainly in the fronto-parieto-temporal regions. CSW was only correlated with the caudate. In the subgroup analysis conducted to assess different contribution of clinical severity, differential associations between the strategy scores and regional glucose metabolism were found. Conclusion: SW and CSW may reflect specific language and executive functions better than the TS. The SVFT is influenced by brain dysfunction due to the progression of AD, as demonstrated by the SW with larger involvement of temporal lobe for the AD, and CSW with significant association only for the MCI. Show more

Keywords: Alzheimer’s disease, dementia fluorodeoxyglucose F18, mild cognitive impairment, neuropsychological tests, positron emission tomography

DOI: 10.3233/JAD-215292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Zhao, Yang | Bao, Jian | Liu, Wei | Gong, Xiaokang | Liang, Zheng | Li, Wenshuang | Wu, Mengjuan | Xiao, Yifan | Sun, Binlian | Wang, Xiaochuan | Wang, Jian-Zhi | Wang, Jun | Shu, Xiji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), with cognitive impairment as the main clinical manifestation, is a progressive neurodegenerative disease. The assembly of amyloid-β (Aβ) as senile plaques is one of the most well-known histopathological alterations in AD. Several studies reported that cognitive training reduced Aβ deposition and delayed memory loss. However, the long-term benefits of spatial training and the underlying neurobiological mechanisms have not yet been elucidated. Objective: To explore the long-term effects of spatial training on AD-related pathogenic processes in APP/PS1 mice. Methods: We used Morris water maze (MWM), Open Field, Barnes Maze, western blotting, qPCR, and …immunofluorescence. Results: One-month MWM training in APP/PS1 mice at 2.5 months of age could attenuate Aβ deposition and decrease the expression of β-secretase (BACE1) and amyloid-β protein precursor (AβPP) with long-term effects. Simultaneously, regular spatial training increased the expression of synapse-related proteins in the hippocampus. Moreover, MWM training increased adult hippocampal neurogenesis in AD model mice. Nonetheless, cognitive deficits in APP/PS1 transgenic mice at 7 months of age were not attenuated by MWM training at an early stage. Conclusion: Our study demonstrates that MWM training alleviates amyloid plaque burden and adult hippocampal neurogenesis deficits with long-term effects in AD model mice. Show more

Keywords: Adult hippocampal neurogenesis, Alzheimer’s disease, amyloid-β , AβPP, BACE1, spatial training

DOI: 10.3233/JAD-215016

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Abdelhamid, Mona | Zhou, Chunyu | Ohno, Kazuya | Kuhara, Tetsuya | Taslima, Ferdous | Abdullah, Mohammad | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer’s disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. Objective: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL -G -F mice. Methods: Three-month-old AppNL -G -F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its …metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. Results: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL -G -F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. Conclusion: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression. Show more

Keywords: ADAM10, Alzheimer’s disease, amyloid-β production, Bifidobacterium breve MCC1274, ERK, glial activation, HIF-1α , novel object recognition, synapses

DOI: 10.3233/JAD-215025

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Massetti, Noemi | Russo, Mirella | Franciotti, Raffaella | Nardini, Davide | Mandolini, Giorgio | Granzotto, Alberto | Bomba, Manuela | Delli Pizzi, Stefano | Mosca, Alessandra | Scherer, Reinhold | Onofrj, Marco | Sensi, Stefano L. | for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) | the Alzheimer’s Disease Metabolomics Consortium (ADMC)

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD. Objective: To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Alzheimer’s Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion. Methods: We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the …study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables. Results: The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects. Conclusion: Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex. Show more

Keywords: Alzheimer’s disease, conversion, dementia, machine learning, mild cognitive impairment, random forest

DOI: 10.3233/JAD-210573

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Botero-Rodríguez, Felipe | Córdoba Sastoque, Ana Melisa | Escudero, José Manuel Santacruz | Santamaría-García, Hernando

Article Type: Research Article

Abstract: Background: The neuropsychiatric symptoms (NPS) in patients with neurocognitive disorders (NCD) increases the risk of exhibiting significant cognitive and functional decline. However, to the best of our knowledge, few studies have evaluated to what extent the presence of chronic and early NPS impacts cognition and functionality in patients with minor or major stages of NCD. Objective: We aimed to assess the interplay between early and chronic NPS and cognitive and functional presentation of patients with mild and major forms of NCD. Methods: We used two NPS tools tracking early and late NPS and …assessed to what extent they determine cognitive and functional outcomes in patients with mild and major forms of NCD. Results: We found an inverse relationship between the presence of NPS, as measured by the Neuropsychiatric Inventory and Mild Behavioral Impairment Checklist (MBI-C), and cognitive and functional variables in major forms of NCD. In contrast, the minor stage of NCD was associated with increased MBI-C scores. Conclusion: Our results revealed that NPS are associated with cognitive and functional outcomes in mild and chronic forms of NCD. Crucially our results suggest that NPS could be considered as a pathological marker of the clinical course of dementia. Additionally, our study calls to study early and late forms of NPS as both impact cognition and functionality of NCD. Show more

Keywords: Assessment of cognitive disorders/dementia, behavioral disturbances, neurocognitive disorder, neurodegeneration, neuropsychiatric symptoms

DOI: 10.3233/JAD-215283

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Dong, Liling | Mao, Chenhui | Liu, Caiyan | Li, Jie | Huang, Xinying | Wang, Jie | Lei, Dan | Chu, Shanshan | Sha, Longze | Xu, Qi | Peng, Bin | Cui, Liying | Gao, Jing

Article Type: Research Article

Abstract: Background: The previous studies have identified several genes in relation to Alzheimer’s disease (AD), such as ABCA7 , CR1 , etc. A few studies have explored the association between the common variants, mainly in the non-coding regions of these genes, and cerebrospinal fluid (CSF) biomarkers. Fewer studies target the variants in the coding regions. Objective: To illustrate the association between the common variants within or adjacent to the coding regions of AD susceptible genes and CSF biomarkers in AD patients. Methods: 75 sporadic probable AD patients were extracted from the dementia cohort of Peking Union Medical …College Hospital. They all had history inquiry, physical examination, blood test, cognitive assessment, brain MRI, CSF testing of Aβ42 , 181 p-tau, and t-tau, and next-generation DNA sequencing. Sixty-nine common single nucleotide polymorphisms (SNPs) (minor allele frequency > 0.01) within or near the coding region of 13 AD susceptible genes were included in the analysis. Results: The rs7412-CC (APOE ) genotype showed lower CSF Aβ42 level and higher p-tau/Aβ42 ratio than the rs7412-CT genotype. The rs3752246-C (ABCA7 ) allele correlated with lower CSF Aβ42 level. The alternate alleles of six ABCA7 SNPs were related to lower CSF p-tau, including rs3745842, rs3764648, rs3764652, rs4147930, rs4147934 and rs881768. The rs11609582-TT (A2M ) genotype showed higher CSF p-tau than the rs11609582-TA genotype. The p-tau/Aβ42 ratio was higher in the rs490460-TT (BACE1 ) genotype relative to the rs490460-GT genotype. Conclusion: Some common variants within or near the coding regions of APOE , ABCA7 , A2M , and BACE1 are associated with CSF Aβ42 , p-tau. or p-tau/Aβ42 . Show more

Keywords: ABCA7 , Alzheimer’s disease, amyloid-beta, APOE , cerebrospinal fluid, phosphorylated tau, single nucleotide polymorphism

DOI: 10.3233/JAD-215067

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Cheng, Jauhtai | Fairchild, J. Kaci | McNerney, Margaret W. | Noda, Art | Ashford, J. Wesson | Suppes, Patricia | Chao, Steven Z. | Taylor, Joy | Rosen, Allyson | Durazzo, Timothy | Lazzeroni, Laura C. | Yesavage, Jerome

Article Type: Research Article

Abstract: Background: Despite decades of research efforts, current treatments for Alzheimer’s disease (AD) are of limited effectiveness and do not halt the progression of the disease and associated cognitive decline. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) may improve cognition. Objective: We conducted a pilot study to investigate the effect of rTMS on cognitive function in Veterans with numerous medical comorbidities. Methods: Participants underwent 20 sessions, over the course of approximately 4 weeks, of 10 Hz rTMS at the left dorsolateral prefrontal cortex with intensity of 120% resting motor threshold. Outcome measures including memory, language, …verbal fluency, and executive functions were acquired at baseline, end of treatment, and 4 months after the last rTMS session. Twenty-six Veterans completed the study (13 in the active rTMS group, 13 in the sham rTMS group). Results: The study protocol was well-tolerated. Active, compared to sham, rTMS showed improved auditory-verbal memory at the end of treatment and at 4-month follow-up. However, the active rTMS group demonstrated a trend in decreased semantic verbal fluency at the end of treatment and at 4-month follow up. Conclusion: These preliminary results show rTMS is safe in general in this elderly Veteran population with multiple co-morbidities. Patients in the sham group showed an expected, slight decline in the California Verbal Learning Test scores over the course of the study, whereas the active treatment group showed a slight improvement at the 4-month post-treatment follow up. These effects need to be confirmed by studies of larger sample sizes. Show more

Keywords: Brain stimulation, california verbal learning test, repetitive transcranial magnetic stimulation, veterans

DOI: 10.3233/JAD-210349

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Gerritsen, Lotte | Twait, Emma L. | Jonsson, Palmi V. | Gudnason, Vilmundur | Launer, Lenore J. | Geerlings, Mirjam I.

Article Type: Research Article

Abstract: Background: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. Objective: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. Methods: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter …hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. Results: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66–2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55–1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34–2.08). Conclusion: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia. Show more

Keywords: Cerebrovascular disorders, cohort studies, dementia, depression

DOI: 10.3233/JAD-215241

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Dhaynaut, Maeva | Sprugnoli, Giulia | Cappon, Davide | Macone, Joanna | Sanchez, Justin S. | Normandin, Marc | Guehl, Nicolas | Koch, Giacomo | Paciorek, Rachel | Connor, Ann | Press, Daniel | Johnson, Keith | Pascual-Leone, Alvaro | El-Fakhri, Georges | Santarnecchi, Emiliano

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia …PET imaging with [11 C]-PiB, [18 F]-FTP, and [11 C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18 F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11 C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11 C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression. Show more

Keywords: Amyloid, dementia, electroencephalography, gamma, neurostimulation, positron-emission tomography, protein clearance, protein misfolding, tau, transcranial electrical stimulation

DOI: 10.3233/JAD-215072

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: McGrath, Emer R. | Himali, Jayandra J. | Levy, Daniel | Yang, Qiong | DeCarli, Charles S. | Courchesne, Paul | Satizabal, Claudia L. | Finney, Rebecca | Vasan, Ramachandran S. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. Objective: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer’s disease (AD) dementia. Methods: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998–2001 and subsequently followed them for incident dementia. Secondary outcomes included …stroke, structural MRI brain measures and neurocognitive test performance. Results: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18–2.64) and AD dementia (HR 1.76, 95% CI 1.11–2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, –0.28±0.11, p  = 0.01) and hippocampal volumes (–0.006±0.003, p  = 0.04) and impaired abstract reasoning (Similarities test, –0.18±0.08, p  = 0.018 per standard deviation increment in EFEMP1). Conclusion: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted. Show more

Keywords: Alzheimer disease, biomarkers, dementia, vascular brain injury

DOI: 10.3233/JAD-215053

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Khan, Naazneen | Alimova, Yelena | Clark, Sophie J. | Vekaria, Hemendra | Walsh, Adeline E. | Williams, Holden C. | Hawk, Gregory S. | Sullivan, Patrick | Johnson, Lance A. | McClintock, Timothy S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive age-dependent disorder whose risk is affected by genetic factors. Better models for investigating early effects of risk factors such as apolipoprotein E (APOE) genotype are needed. Objective: To determine whether APOE genotype produces neuropathologies in an AD-susceptible neural system, we compared effects of human APOE ɛ3 (E3) and APOE ɛ4 (E4) alleles on the mouse olfactory epithelium. Methods: RNA-Seq using the STAR aligner and DESeq2, immunohistochemistry for activated caspase-3 and phosphorylated histone H3, glucose uptake after oral gavage of 2-[1,2-3 H (N)]-deoxy-D-glucose, and Seahorse Mito …Stress tests on dissociated olfactory mucosal cells. Results: E3 and E4 olfactory mucosae show 121 differentially abundant mRNAs at age 6 months. These do not indicate differences in cell type proportions, but effects on 17 odorant receptor mRNAs suggest small differences in tissue development. Ten oxidoreductases mRNAs important for cellular metabolism and mitochondria are less abundant in E4 olfactory mucosae but this does not translate into differences in cellular respiration. E4 olfactory mucosae show lower glucose uptake, characteristic of AD susceptibility and consistent with greater expression of the glucose-sensitive gene, Asns . Olfactory sensory neuron apoptosis is unaffected at age 6 months but is greater in E4 mice at 10 months. Conclusion: Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD. Show more

Keywords: Alzheimer’s disease, apoptosis, glucose metabolic disorder, mitochondria, odorant receptors, olfaction, oxidoreductases

DOI: 10.3233/JAD-215152

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Goldsmith, Harry S.

Article Type: Research Article

Abstract: Normally, an adequate cerebral blood flow arrives at individual cerebral neurons in which the blood flow augments activity of intraneuronal mitochondria, which is the source of intraneuronal ATP, the energy source of cerebral neurons. With a decrease in cerebral blood flow that can occur as a function of normal aging phenomena, less blood results in decreased mitochondria, decreased ATP, and a decrease in neuronal activity, which can eventually lead to Alzheimer’s disease. It has been found that placement of the omentum directly on an Alzheimer’s disease brain can lead to improved cognitive function.

Keywords: ATP, cerebral blood flow, mitochondria, omentum

DOI: 10.3233/JAD-215479

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Schaefer, Sydney Y. | Malek-Ahmadi, Michael | Hooyman, Andrew | King, Jace B. | Duff, Kevin

Article Type: Short Communication

Abstract: Hippocampal atrophy is a widely used biomarker for Alzheimer’s disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic mild cognitive impairment, and 15 AD) completed six motor task trials and a structural MRI. Several measures of motor task performance significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.

Keywords: Alzheimer’s disease, hippocampus, mild cognitive impairment, psychomotor performance

DOI: 10.3233/JAD-210665

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Suo, William Z.

Article Type: Research Article

Abstract: Prevention of Alzheimer’s disease (AD) is a high priority mission while searching for a disease modifying therapy for AD, a devastating major public health crisis. Clinical observations have identified a prodromal stage of AD for which the patients have mild cognitive impairment (MCI) though do not yet meet AD diagnostic criteria. As an identifiable transitional stage before the onset of AD, MCI should become the high priority target for AD prevention, assuming successful prevention of MCI and/or its conversion to AD also prevents the subsequent AD. By pulling this string, one demonstrated cause of amnestic MCI appears to be the …deficiency of G protein-coupled receptor-5 (GRK5). The most compelling evidence is that GRK5 knockout (GRK5KO) mice naturally develop into aMCI during aging. Moreover, GRK5 deficiency was reported to occur during prodromal stage of AD in CRND8 transgenic mice. When a GRK5KO mouse was crossbred with Tg2576 Swedish amyloid precursor protein transgenic mouse, the resulted double transgenic GAP mice displayed exaggerated behavioral and pathological changes across the spectrum of AD pathogenesis. Therefore, the GRK5 deficiency possesses unique features and advantage to serve as a prophylactic therapeutic target for MCI due to AD. Show more

Keywords: Alzheimer’s disease, amnestic, G protein, kinase, mild cognitive impairment, pathogenesis, receptor

DOI: 10.3233/JAD-215379

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Zhang, Heng | Lyu, Diyang | Jia, Jianping | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on …cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials. Show more

Keywords: Alzheimer’s disease, biomarker, growth-associated protein 43, synaptic dysfunction

DOI: 10.3233/JAD-215456

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Sun, Hao-Lun | Zhou, Fa-Ying | Chen, Dong-Wan | Tan, Cheng-Rong | Zeng, Gui-Hua | Liu, Yu-Hui | Wang, Jun | Bu, Xian-Le | Wang, Yan-Jiang | Li, Hui-Yun | Jin, Wang-Sheng

Article Type: Research Article

Abstract: Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD …patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ 42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain. Show more

Keywords: Alzheimer’s disease, monocytes, pathogenesis, tau

DOI: 10.3233/JAD-210692

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Gao, Zhaoyu | Zhang, Rui | Jiang, Lei | Zhou, Huimin | Wang, Qian | Ma, Yingxin | Zhang, Di | Qin, Yushi | Tian, Pei | Zhang, Nan | Shi, Zhongli | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction is an early feature of Alzheimer’s disease (AD) and miR-195 is involved in mitochondrial disorder through targeting MFN-2 protein in hippocampal neurons of AD. Objective: To clarify if administration of miR-195 inhibitor could enhance the memory deficits through improving hippocampal neuron mitochondrial dysfunction in SAMP8 mice. Methods: The expression of miR-195 was detected by RT-qPCR in primary hippocampal neurons and HT-22 cells treated with Aβ 1–42 . Morris water maze (MWM) was used to assess the learning and memory function in SAMP8 mice administrated with antagomir-195. Transmission electron microscopy was …employed to determine the morphological changes of synapses and mitochondria of hippocampus in SAMP8 mice. Mitochondrial respiration was measured using a high-resolution oxygraph. Results: The expression of miR-195 were upregulated in the primary hippocampal neurons and HT-22 cells induced by Aβ 1–42 . Inhibition of miR-195 ameliorated the mitochondrial dysfunction in HT-22 cells induced by Aβ 1–42 , including mitochondrial morphologic damages, mitochondrial membrane potential, respiration function, and ATP production. Administration of antagomir-195 by the third ventricle injection markedly ameliorated the cognitive function, postsynaptic density thickness, length of synaptic active area, mitochondrial aspect ratio, and area in hippocampus of SAMP8 mice. Finally, antagomir-195 was able to promote an increase in the activity of respiratory chain complex CI and II in SAMP8 mice. Conclusion: This study demonstrated that miR-195 inhibitor ameliorated the cognitive impairment of AD mice by improving mitochondrial structure damages and dysfunction in the hippocampal neurons, which provide an experimental basis for further exploring the treatment strategy of AD. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, microRNA-195, mitochondria, synaptic membranes

DOI: 10.3233/JAD-215301

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Yuen, Sze Chung | Lee, Simon Ming-Yuen | Leung, Siu-wai

Article Type: Research Article

Abstract: Background: Neuronal cell cycle re-entry (CCR) is a mechanism, along with amyloid-β (Aβ) oligomers and hyperphosphorylated tau proteins, contributing to toxicity in Alzheimer’s disease (AD). Objective: This study aimed to examine the putative factors in CCR based on evidence corroboration by combining meta-analysis and co-expression analysis of omic data. Methods: The differentially expressed genes (DEGs) and CCR-related modules were obtained through the differential analysis and co-expression of transcriptomic data, respectively. Differentially expressed microRNAs (DEmiRNAs) were extracted from the differential miRNA expression studies. The dysregulations of DEGs and DEmiRNAs as binary outcomes were independently …analyzed by meta-analysis based on a random-effects model. The CCR-related modules were mapped to human protein-protein interaction databases to construct a network. The importance score of each node within the network was determined by the PageRank algorithm, and nodes that fit the pre-defined criteria were treated as putative CCR-related factors. Results: The meta-analysis identified 18,261 DEGs and 36 DEmiRNAs, including genes in the ubiquitination proteasome system, mitochondrial homeostasis, and CCR, and miRNAs associated with AD pathologies. The co-expression analysis identified 156 CCR-related modules to construct a protein-protein interaction network. Five genes, UBC , ESR1 , EGFR , CUL3 , and KRAS , were selected as putative CCR-related factors. Their functions suggested that the combined effects of cellular dyshomeostasis and receptors mediating Aβ toxicity from impaired ubiquitination proteasome system are involved in CCR. Conclusion: This study identified five genes as putative factors and revealed the significance of cellular dyshomeostasis in the CCR of AD. Show more

Keywords: Alzheimer’s disease, cell cycle re-entry, co-expression analysis, meta-analysis, pagerank algorithm

DOI: 10.3233/JAD-215349

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2021

Authors: Malone, Joseph | Jung, Jeah | Tran, Linh | Zhao, Chen

Article Type: Research Article

Abstract: Background: Periodontal disease and hepatitis C virus (HCV) represent chronic infectious states that are common in elderly adults. Both conditions have independently been associated with an increased risk for dementia. Chronic infections are thought to lead to neurodegenerative changes in the central nervous system possibly by promoting a proinflammatory state. This is consistent with growing literature on the etiological role of infections in dementia. Few studies have previously evaluated the association of periodontal disease with dementia in HCV patients. Objective: To examine whether periodontal disease increases the risk of developing Alzheimer’s disease and related dementias (ADRD) among HCV …patients in Medicare claims data. Methods: We used Medicare claims data for HCV patients to assess the incidence rate of ADRD with and without exposure to periodontal disease between 2014 and 2017. Cox multivariate regression was used to estimate the association between periodontal disease and development of ADRD, controlling for age, gender, race, ZIP-level income and education, and medical comorbidities. Results: Of 439,760 HCV patients, the incidence rate of ADRD was higher in patients with periodontal diseases compared to those without (10.84% versus 9.26%, p  <  0.001), and those with periodontal disease developed ADRD earlier compared to those without periodontal disease (13.99 versus 21.60 months, p  <  0.001). The hazard of developing ADRD was 1.35 times higher in those with periodontal disease (95% CI, 1.30 to 1.40, p  <  0.001) after adjusting for all covariates, including age. Conclusion: Periodontal disease increased the risk of developing ADRD among HCV patients in a national Medicare claims dataset. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementias, dementia, Hepatitis C virus, infection, periodontal disease

DOI: 10.3233/JAD-210666

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Tropea, Maria Rosaria | Sanfilippo, Giulia | Giannino, Federico | Davì, Valentina | Gulisano, Walter | Puzzo, Daniela

Article Type: Research Article

Abstract: Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables. Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg. Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based …on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models. Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation. Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases. Show more

Keywords: Alzheimer’s mice, exploration, object preference, object recognition task

DOI: 10.3233/JAD-215209

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Chen, Jiu | Chen, Rong | Xue, Chen | Qi, Wenzhang | Hu, Guanjie | Xu, Wenwen | Chen, Shanshan | Rao, Jiang | Zhang, Fuquan | Zhang, Xiangrong

Article Type: Research Article

Abstract: Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated …with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, episodic memory, functional connectivity, grey matter, hippocampalsubregion, pattern classification, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210661

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Kwak, Seyul | Oh, Dae Jong | Jeon, Yeong-Ju | Oh, Da Young | Park, Su Mi | Kim, Hairin | Lee, Jun-Young

Article Type: Research Article

Abstract: Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status. Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied. Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n  = 285), mild cognitive impairment (n  = 1,057), and Alzheimer’s …disease (n  = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes. Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n  >  500), especially when the model training is allowed to exploit complex patterns of the dataset. Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia. Show more

Keywords: Dementia, functional status, machine learning, neuropsychological tests

DOI: 10.3233/JAD-215244

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Yang, Li | Xuan, Cheng | Yu, Caiyan | Zheng, Pinpin | Yan, Jing

Article Type: Research Article

Abstract: Background: With the accelerating aging process, the number of participants with Alzheimer’s disease (AD) is rising sharply, causing a huge economic burden. Objective: This study aimed to identify blood protein and metabolic biomarkers and explore the diagnostic model for AD among elderly in southeast China. Methods: We established a cohort among population with high risk AD in Zhejiang Province in 2018. Case and control groups each consisting of 45 subjects, matched for gender and age, were randomly selected from the cohort. Based on bioinformatics research, PRM/MRM technology was used to detect candidate biomarkers. Ensemble-based feature selection …and machine learning methods was used to screen important variables as risk indicators for AD. Based on the risk biomarkers, the risk diagnostic model of AD in the elderly was constructed and evaluated. Results: Cystine and CPB2 were evaluated as biomarkers. The diagnostic model is constructed using logistic regression algorithm with the best cutoff value, sensitivity, specificity, and accuracy of 0.554, 0.895, 0.976, and 0.938, respectively, which determined by Youden’s index. The results showed that the model with protein and metabolite had a high efficiency. Conclusion: It showed that the diagnostic model constructed by Cystine and CPB2 had a good performance on sample classification. This study was of great significance for the early screening and diagnosis of AD, timely intervention, control and delay the development of dementia in southeast China. Show more

Keywords: Alzheimer’s disease, biomarker, diagnostic model, elderly

DOI: 10.3233/JAD-215119

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Ramos, Claudia | Villalba, Camilo | García, Jenny | Lanata, Serggio | López, Hugo | Aguillón, David | Cordano, Christian | Madrigal, Lucía | Aguirre-Acevedo, Daniel C. | Lopera, Francisco

Article Type: Research Article

Abstract: Background: Cigarette smoking is a known risk factor for Alzheimer’s disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. Objective: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. Methods: …A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. Results: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. Conclusion: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, disease prevention, substance-related disorders

DOI: 10.3233/JAD-215169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: von Linstow, Christian Ulrich | Waider, Jonas | Bergh, Marianne Skov-Skov | Anzalone, Marco | Madsen, Cecilie | Nicolau, Aina Battle | Wirenfeldt, Martin | Lesch, Klaus-Peter | Finsen, Bente

Article Type: Research Article

Abstract: Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-4β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe /presenilin 1 (PS1) ΔE9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/– , …and wildtype mice. Survival and weight were recorded. Levels of Aβ 42/40/38 , soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ 42 and Aβ 40 in neocortex and hippocampus, and with only mild changes of soluble Aβ 42 /Aβ 40 . However, sAβPPα and sAβPPβ in hippocampus and Aβ 38 and Aβ 40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, APP/PS1, AβPP processing, cerebral amyloidosis, cerebrospinal fluid, 5-HT, neuroinflammation, tryptophan hydroxylase 2

DOI: 10.3233/JAD-210581

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Wang, Gang | Zhou, Wenju | Kong, Deping | Qu, Zongshuai | Ba, Maowen | Hao, Jinguang | Yao, Tao | Dong, Qunxi | Su, Yi | Reiman, Eric M. | Caselli, Richard J. | Chen, Kewei | Wang, Yalin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. Objective: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N  = 30), heterozygotes (HT, N  = 49) and …non-carriers (NC, N  = 61). Methods: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. Results: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. Conclusion: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals. Show more

Keywords: Effect size, magnetic resonance imaging, permutation t-test, radial distance, regions-of-interest, subspace decomposition

DOI: 10.3233/JAD-215149

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Salami, Alireza | Adolfsson, Rolf | Andersson, Micael | Blennow, Kaj | Lundquist, Anders | Adolfsson, Annelie Nordin | Schöll, Michael | Zetterberg, Henrik | Nyberg, Lars

Article Type: Research Article

Abstract: Background: The Apolipoprotein E (APOE ) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for AD progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers. Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to …AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity. Methods: Longitudinal population-based study. Plasma p-tau181 was analyzed in 142 clinically defined Alzheimer’s disease (AD) cases and 126 controls. The longitudinal analysis involved 87 non-demented individuals with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding. Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity. Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning. Show more

Keywords: Alzheimer’s disease, APOE, fMRI, hippocampus, longitudinal, magnetic resonance imaging, p-tau181, phosphorylated tau, population-based

DOI: 10.3233/JAD-210673

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Fan, Fangcheng | Liu, Hua | Shi, Xiaojie | Ai, Yangwen | Liu, Qingshan | Cheng, Yong

Article Type: Research Article

Abstract: Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer’s disease (AD) are sparse. Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. Results: …Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, anti-Aβ agents, systematic review, umbrella review

DOI: 10.3233/JAD-215423

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Teipel, Stefan J. | Dyrba, Martin | Ballarini, Tommaso | Brosseron, Frederic | Bruno, Davide | Buerger, Katharina | Cosma, Nicoleta-Carmen | Dechent, Peter | Dobisch, Laura | Düzel, Emrah | Ewers, Michael | Fliessbach, Klaus | Haynes, John D. | Janowitz, Daniel | Kilimann, Ingo | Laske, Christoph | Maier, Franziska | Metzger, Coraline D. | Munk, Matthias H. | Peters, Oliver | Pomara, Nunzio | Preis, Lukas | Priller, Josef | Ramírez, Alfredo | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Schott, Björn H. | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Jessen, Frank | Heneka, Michael T.

Article Type: Research Article

Abstract: Background: Inflammation has been described as a key pathogenic event In Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of …cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ 42 /ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ 42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cholinergic system, neuroinflammation, MRI, plasma, sTREM2

DOI: 10.3233/JAD-215196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Chaudhary, Shefali | Zhornitsky, Simon | Chao, Herta H. | van Dyck, Christopher H. | Li, Chiang-Shan R.

Article Type: Research Article

Abstract: Background: Affecting nearly half of the patients with Alzheimer’s disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. Objective: To identify neuroanatomical correlates of AD-associated apathy. Methods: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 …healthy controls evaluated with the Apathy Evaluation Scale. Results: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p  <  0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. Conclusion: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy. Show more

Keywords: Activation likelihood estimation, Alzheimer-type dementia, Alzheimer’s disease, emotional apathy, gray matter, inferior frontal gyrus, meta-analysis, middle temporal gyrus, striatum

DOI: 10.3233/JAD-215316

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Kimmel, Hannah J. | Levine, Deborah A. | Whitney, Rachael T. | Forman, Jane | Plassman, Brenda L. | Fagerlin, Angela | Welsh-Bohmer, Kathleen Anne | Reale, Bailey K. | Galecki, Andrzej T. | Blair, Emilie | Langa, Kenneth M. | Giordani, Bruno | Kollman, Colleen | Wang, Jing | Zahuranec, Darin B.

Article Type: Research Article

Abstract: Background: Older patients (≥65 years) with mild cognitive impairment (MCI) are undertreated for cardiovascular disease (CVD). One reason for this disparity could be that patients with MCI might underestimate the chances of CVD and overestimate dementia. Objective: To compare conceptions of health risk between older patients with MCI and normal cognition (NC) and their care partners. Methods: We conducted a multi-center mixed-methods study of patient-care partner dyads completing written quantitative surveys (73% response rate; 127 dyads: 66 MCI and 61 NC) or semi-structured interviews (20 dyads: 11 MCI, and 9 NC). Surveys assessed two-year patient risks …of dementia, heart attack, stroke, and fall. Interviews assessed similar health risks and reasons for risk perceptions. Results: On surveys, a similarly low proportion of MCI and NC patients felt they were at risk of stroke (5% versus 2% ; p  = 0.62) and heart attack (2% versus 0% ; p  = 0.99). More MCI than NC patients perceived dementia risk (26% versus 2% ; p  <  0.001). Care partners’ survey findings were similar. Interviews generally confirmed these patterns and also identified reasons for future health concerns. For both MCI and NC dyads, personal experience with cognitive decline or CVD (personal or family history) increased concerns about each disease. Additionally, perceptions of irreversibility and lack of treatment for cognitive decline increased concern about dementia. Conclusion: Less use of CVD treatments in MCI seems unlikely to be driven by differential perceptions of CVD risk. Future work to improve awareness of CVD risks in older patients and dementia risk in patients with MCI are warranted. Show more

Keywords: Dementia, family caregivers, heart disease risk factors, mild cognitive impairment, risk assessment

DOI: 10.3233/JAD-215155

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Zhou, Andrew L. | Sharda, Nidhi | Sarma, Vidur V. | Ahlschwede, Kristen M. | Curran, Geoffry L. | Tang, Xiaojia | Poduslo, Joseph F. | Kalari, Krishna R. | Lowe, Val J. | Kandimalla, Karunya K.

Article Type: Research Article

Abstract: Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125 I-Aβ 40 , 125 I-Aβ 42 , or 125 I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. …Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125 I-Aβ 40 , estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125 I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125 I-Aβ 40 , the brain influx of 125 I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk. Show more

Keywords: Aging, amyloid-β, blood-brain barrier, insulin, pharmacokinetics

DOI: 10.3233/JAD-215128

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Tadokoro, Koh | Yamashita, Toru | Sato, Junko | Omote, Yoshio | Takemoto, Mami | Morihara, Ryuta | Nishiura, Koichiro | Tani, Tomiko | Abe, Koji

Article Type: Research Article

Abstract: Background: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. Objective: To evaluate the therapeutic effect of makeup therapy. Methods: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n  = 16) or skin care plus makeup therapy (makeup therapy group, n  = 18) once every 2 weeks for 3 months were assessed. Results: Three months of makeup therapy significantly improved the Mini-Mental State …Examination (MMSE) score compared with control patients ( * p  <  0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression ( * p  <  0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r  = 0.43,  * p  <  0.05). Conclusion: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software. Show more

Keywords: Artificial intelligence, dementia, facial appearance, makeup therapy

DOI: 10.3233/JAD-215385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Haverkamp, Rinske A. | Melis, René J.F. | Claassen, Jurgen A.H.R. | de Heus, Rianne A.A.

Article Type: Research Article

Abstract: Background: High day-to-day blood pressure variability (BPV) has been associated with an increased risk for cognitive decline and mortality in the general population. Whether BPV is associated with increased all-cause mortality in older people with cognitive impairment is unknown. Objective: To investigate the association between day-to-day home BPV and all-cause mortality in older patients attending a memory clinic. Methods: We included 279 patients attending a memory clinic, who measured home blood pressure (BP) for 7 consecutive days in the morning and evening. Within-subject BPV was defined as the variation independent of the mean (VIM). Time-to-death was …verified through the Dutch population registry. Cox proportional hazard regression was used. Separate analyses were performed for morning-to-morning and evening-to-evening BPV. Results: Mean age was 73±9 years, dementia and mild cognitive impairment were diagnosed in 35% and 34% respectively, and mean home BP was 139/79 mmHg. After a mean follow-up of 3.2 years, 52 patients had died. Neither day-to-day systolic nor diastolic VIM were associated with mortality (adjusted hazard ratio [HR] systolic VIM: 0.99, 95% -CI 0.92–1.06, p  = 0.770, HR diastolic VIM: 1.04, 95% -CI 0.93–1.17, p  = 0.517). When morning and evening measurements were analyzed separately, systolic morning-to-morning VIM was associated with mortality (adjusted HR: 1.09, 95% -CI 1.01–1.18, p  = 0.033). Conclusion: In this study, day-to-day BPV was not associated with all-cause mortality in patients attending a memory clinic. However, morning-to-morning BPV was. Due to the short assessment window, there is still a lack of clarity; hence future research is warranted to clarify the role of all BPV components in aging. Show more

Keywords: Alzheimer, cardiovascular risk management, dementia, geriatrics, home blood pressure monitoring, hypertension

DOI: 10.3233/JAD-215002

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Smith, C. Aaron | Smith, Haddon | Roberts, Lisa | Coward, Lori | Gorman, Gregory | Verma, Amrisha | Li, Qiuhong | Buford, Thomas W. | Carter, Christy S. | Jumbo-Lucioni, Patricia

Article Type: Research Article

Abstract: Background: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer’s disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Objective: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral …supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Methods: Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Results: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. Conclusion: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response. Show more

Keywords: Alzheimer’s disease, angiotensin (1-7), probiotic, Lactobacillus, tryptophan

DOI: 10.3233/JAD-210464

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Lutski, Miri | Rasooli, Iris | Sternberg, Shelley | Lemberger, John | Mery, Nisim | Shohat, Tamy | Zucker, Inbar

Article Type: Research Article

Abstract: Background: Data on the rate of dementia is essential for planning and developing appropriate services at the national level. Objective: We report the prevalence and incidence of dementia, based on electronic health records available for the whole population. Methods: This national dementia dataset was established as a part of the National Program to Address Alzheimer’s and Other Types of Dementia. Data from medical health records for all persons aged 45+ in Israel, for 2016, were extracted from the databases of the four health maintenance organizations. Dementia cases were identified based on either recorded dementia diagnosis, through …International Classification of Diseases (ICD-9 and ICD-10) or dispensation of anti-dementia drugs. The date of first diagnosis was determined by the earliest recording. Results: A total of 65,951 persons with dementia, aged 45+, were identified from electronic health data. Based on both ICD codes and anti-dementia drugs, the prevalence rates of dementia among individuals aged 45+ and 65+ in 2016 were 2.5%and 6.4%, respectively, and the incidence rates were 0.49%and 1.3%, respectively. Based on ICD codes alone, the prevalence rates of dementia among individuals aged 45+ and 65+ in 2016 were 2.1%and 5.4%respectively, and the incidence rates were 0.36%and 0.96%respectively. The rates were higher among females compared to males and paradoxically lower in lower socioeconomic status compared to higher statuses. Conclusion: This data collection reflects the present access of dementia patients to medical care resources and provides the basis for service planning and future dementia policies. Show more

Keywords: Dementia, early-onset dementia, electronic health data, incidence, national dataset, prevalence

DOI: 10.3233/JAD-215048

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Schubert, Carla R. | Paulsen, Adam J. | Pinto, A. Alex | Merten, Natascha | Cruickshanks, Karen J.

Article Type: Research Article

Abstract: Background: Stored blood samples from longitudinal cohort studies may be useful for studying biomarkers of preclinical Alzheimer’s disease. Objective: This study aimed to determine the reliability of amyloid-β 40 and amyloid-β 42 (Aβ 40 , Aβ 42 ), total tau (TTau), and neurofilament light (NfL) concentrations measured in blood samples stored long-term at -80°C. Methods: Aβ 40 , Aβ 42 , TTau, and NfL were measured in serum and plasma samples from two longitudinal cohort studies. Serum samples had been stored at -80°C for 5 (n  = 24), 14 (n  = 24), and …20 years (N  = 78) and plasma samples had been stored for 16 years (N  = 78). Biomarker concentrations were measured in duplicate using a single molecule array assay (Simoa; Quanterix, Billerica, MA). Replicate samples for each sample type and storage length were included. Results: The concentrations of Aβ 40 , Aβ 42 , TTau, and NfL were within expected ranges. Some serum TTau concentrations were below the limit of detection. The average intra-assay coefficients of variation (CV) for duplicate measures were 2–7% for all assays except for serum TTau, which were higher (CVs 13% and 17%). Mean differences in original replicate pair Aβ 40 , Aβ 42 , and NfL concentrations were slightly greater in samples stored for longer versus shorter time periods. Conclusion: Aβ 40 , Aβ 42 , TTau, and NfL can be measured in serum and plasma samples that have been stored up to 20 years at -80°C. Long-term storage may be associated with small increases in the variability of concentrations in samples stored 14 or more years. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood biomarkers, epidemiology, neurofilament light, plasma, serum, single molecule array, total tau

DOI: 10.3233/JAD-215096

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Wen, Chen | Bi, Yan-Lin | Hu, Hao | Huang, Shu-Yi | Ma, Ya-Hui | Hu, He-Ying | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia. Objective: We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology in cognitively normal individuals. Methods: A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aβ 42 , P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD …status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology. Results: After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aβ 42 (SCD: β= –0.0003, p  = 0.0263; SCD severity: β= –0.0004, p  = 0.0046), CSF T-tau/Aβ 42 ratio (SCD: β= 0.1080, p  = 0.1080; SCD severity: β= 0.1129, p  = 0.0009) and CSF P-tau/Aβ 42 ratio (SCD: β= 0.0167, p  = 0.0103; SCD severity: β= 0.0193, p  = 0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aβ 42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN. Conclusion: The results indicated that pathophysiological changes in CSF Aβ pathology occurred in individuals with SCD, which provide new insights into early intervention of AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarker, subjective cognitive decline

DOI: 10.3233/JAD-215178

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Mayà, Gerard | Sarto, Jordi | Compta, Yaroslau | Balasa, Mircea | Ximelis, Teresa | Aldecoa, Iban | Gelpi, Ellen | Sánchez-Valle, Raquel | Molina-Porcel, Laura

Article Type: Research Article

Abstract: Background: For neuroscience research, the study of brain tissue of neurologically unimpaired subjects is crucial to interpret findings in neurodegenerative diseases. Sub-optimal neurological follow-up and the presence of neuropathological lesions in supposedly asymptomatic subjects casts doubt as to whether these subjects present an undetected underlying neurodegenerative disease or are resilient to neurodegeneration. Objective: We aimed to assess whether the control donors registered in the Neurological Tissue Bank-Hospital Clínic-IDIBAPS (NTB-HCI) are still free of cognitive symptoms at follow-up and to evaluate the feasibility and utility of a telephone-based screening. Methods: All control subjects older …than 65 years registered at the NTB-HCI database were selected for the study. After a structured telephone interview, those subjects already diagnosed with a neurological disease were excluded. Then, a cognitive screening was performed, including the telephone version of the Mini-Mental State Examination (t-MMSE) and the eight-item interview (AD-8) to the subject and to one informant. Results: In total, 73.8% of the registered donors collaborated in the study. Only 21.4% had at least one of the three cognitive screening tools impaired, and 2.7% had a profile highly suggestive of cognitive impairment. AD-8i correlated moderately with t-MMSE. Conclusion: Telephone-based neurologic screening in control donors is feasible and was within the normal range in most of the subjects in our cohort. Albeit, the involvement of neurologists and periodic neurological screenings are desirable in a control subjects brain donor program, AD8-i could be used to screen the control’s neurological status in the absence of accurate clinical data at the time of the death. Show more

Keywords: AD-8, brain bank, cognitive symptoms, neurological healthy controls, neurological screening, telephone-based screening, telephone MMSE

DOI: 10.3233/JAD-215444

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Sun, Xiaoru | Zhang, Hui | Yao, Dongdong | Xu, Yaru | Jing, Qi | Cao, Silu | Tian, Li | Li, Cheng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease, the etiology of which is unclear. Previous studies have suggested that some viruses are neurotropic and associated with AD. Objective: By using bioinformatics analysis, we investigated the potential association between viral infection and AD. Methods: A total of 5,066 differentially expressed genes (DEGs) in the temporal cortex between AD and control samples were identified. These DEGs were then examined via weighted gene co-expression network analysis (WGCNA) and clustered into modules of genes with similar expression patterns. Of identified modules, module turquoise had the highest …correlation with AD. The module turquoise was further characterized using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. Results: Our results showed that the KEGG pathways of the module turquoise were mainly associated with viral infection signaling, specifically Herpes simplex virus, Human papillomavirus, and Epstein-Barr virus infections. A total of 126 genes were enriched in viral infection signaling pathways. In addition, based on values of module membership and gene significance, a total of 508 genes within the module were selected for further analysis. By intersecting these 508 genes with those 126 genes enriched in viral infection pathways, we identified 4 hub genes that were associated with both viral infection and AD: TLR2, COL1A2, NOTCH3, and ZNF132. Conclusion: Through bioinformatics analysis, we demonstrated a potential link between viral infection and AD. These findings may provide a platform to further our understanding of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, anti-viral, bioinformatics analysis, hub genes, viral infection

DOI: 10.3233/JAD-215232

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Smith, Lee | Shin, Jae Il | Oh, Hans | Carmichael, Christina | Jacob, Louis | Stefanac, Sinisa | Lindsay, Rosie K. | Soysal, Pinar | Veronese, Nicola | Tully, Mark A. | Butler, Laurie | Barnett, Yvonne | Koyanagi, Ai

Article Type: Research Article

Abstract: Background: The effect of weight modification on future dementia risk is currently a subject of debate and may be modified by age. Objective: The aim of the present study was to investigate the association between body mass index (BMI) status with mild cognitive impairment (MCI) (a preclinical stage of dementia) in middle-aged and older adults residing in six low- and middle-income countries using nationally representative data. Methods: Cross-sectional data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer’s Association criteria. BMI …(kg/m2 ) was based on measured weight and height and categorized as: underweight (<18.5), normal (18.5–24.9), overweight (25.0–29.9), and obese (≥30.0). Multivariable logistic regression analysis and meta-analysis were conducted to assess associations. Results: Data on 32,715 individuals aged ≥50 years with preservation in functional abilities were analyzed [mean (SD) age 62.1 (15.6) years; 51.7% females]. Among those aged 50–64 years, compared to normal weight, underweight (OR = 1.44; 95% CI = 1.14–1.81), overweight (OR = 1.17; 95% CI = 1.002–1.37), and obesity (OR = 1.46; 95% CI = 1.09–1.94) were all significantly associated with higher odds for MCI. In those aged ≥65 years, underweight (OR = 0.71; 95% CI = 0.54–0.95) and overweight (OR = 0.72; 95% CI = 0.55–0.94) were associated with significantly lower odds for MCI, while obesity was not significantly associated with MCI. Conclusion: The results of the study suggest that the association between BMI and MCI is likely moderated by age. Future longitudinal studies are required to confirm or refute the present findings before recommendations for policy and practice can be made. Show more

Keywords: Aged, body mass index, cognitive dysfunction, obesity

DOI: 10.3233/JAD-215345

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Li, Weihua | Zhao, Zhilian | Liu, Min | Yan, Shaozhen | An, Yanhong | Qiao, Liyan | Wang, Guihong | Qi, Zhigang | Lu, Jie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory impairment. Amnestic mild cognitive impairment (aMCI) is the intermediate stage between normal cognitive aging and early dementia caused by AD. It can be challenging to differentiate aMCI patients from healthy controls (HC) and mild AD patients. Objective: To validate whether the combination of 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) and diffusion tensor imaging (DTI) will improve classification performance compared with that based on a single modality. Methods: A total of thirty patients with AD, sixty patients …with aMCI, and fifty healthy controls were included. AD was diagnosed according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable. aMCI diagnosis was based on Petersen’s criteria. The 18 F-FDG PET and DTI measures were each used separately or in combination to evaluate sensitivity, specificity, and accuracy for differentiating HC, aMCI, and AD using receiver operating characteristic analysis together with binary logistic regression. The rate of accuracy was based on the area under the curve (AUC). Results: For classifying AD from HC, we achieve an AUC of 0.96 when combining two modalities of biomarkers and 0.93 when using 18 F-FDG PET individually. For classifying aMCI from HC, we achieve an AUC of 0.79 and 0.76 using the best individual modality of biomarkers. Conclusion: Our results show that the combination of two modalities improves classification performance, compared with that using any individual modality. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, 18F-FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-215338

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021