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

Authors: Gao, Lan | Nguyen, Dieu | Moodie, Marj

Article Type: Research Article

Abstract: Background: The established link between cardiovascular disease (CVD) and dementia may provide new insights into dementia prevention. Objective: It aims to quantify the burden of dementia attributable to people with CVD. Methods: A Markov microsimulation model was developed to simulate the lifetime cost and quality-adjusted life-years (QALYs) related to people with and without CVD in Australia. A de-novo systematic review was undertaken to identify all evidence around the association between CVD [i.e., stroke, myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF)] and the risk of developing dementia. Incremental costs and QALY losses were …estimated for people by type of CVD compared to the general Australian population without CVD. Results: Of the comprehensive literature search, 19 observational studies were included in the qualitative synthesis. Patients who had CVD incurred both higher healthcare costs over their lifetime (ranging from $73,131 for patients with AF to $127,396 for patients with HF) and fewer QALYs gains (from –1.099 for patients with MI to –5.163 for patients with stroke), compared to people who did not have CVD. The total incremental economic burden of dementia from patients aged 65 years and over with CVD was $6.45 billion (stroke), $11.89 billion (AF), $17.57 billion (MI), or $7.95 billion (HF) over their remaining life expectancy. Conclusion: The results highlighted the importance of CVD prevention to reduce the CVD burden and decrease the prevalence of dementia. Interventions that target patients with dementia risk factors like CVD may prove to be effective and cost-effective strategies. Show more

Keywords: Burden of disease, cardiovascular disease, dementia, meta-analysis, systematic review

DOI: 10.3233/JAD-215368

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

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