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