Journal of Alzheimer's Disease - Volume 73, issue 3

Authors: Wang, Xiaoni | Sun, Yu | Li, Taoran | Cai, Yanning | Han, Ying

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the main cause of dementia, is characterized by the aggregation of amyloid-β (Aβ). This pathophysiological process starts many years to decades before the onset of clinical symptoms. Cerebrospinal fluid analysis and amyloid positron emission tomography scans are two standard methods to measure brain Aβ, but their invasive nature and expense limit their usage as screening tools. Therefore, peripheral Aβ studies have grown exponentially during the past few years. In this review, we discuss recent studies on plasma Aβ and its potential as a reliable biomarker of AD.

Keywords: Alzheimer’s disease, biomarker, cognitive decline, plasma amyloid-beta

DOI: 10.3233/JAD-190714

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 819-832, 2020

Authors: Musa, Gada | Slachevsky, Andrea | Muñoz-Neira, Carlos | Méndez-Orellana, Carolina | Villagra, Roque | González-Billault, Christian | Ibáñez, Agustín | Hornberger, Michael | Lillo, Patricia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intends to summarize briefly the main differences at the clinical, neuropsychological, and behavioral levels, in an attempt to suggest which aspects would facilitate an adequate diagnosis in a clinical setting, especially in Latin American and low- and middle-income countries, where the resources needed for a differential diagnosis (such as MRI or …biomarkers) are not always available. A timely diagnosis of AD and FTD have significant implications for the medical management and quality of life of patients and careers. Show more

Keywords: Alzheimer’s disease, neuropsychology, differential diagnosis, frontotemporal dementia, young onset dementia

DOI: 10.3233/JAD-190924

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 833-848, 2020

Authors: Sun, Miao | Ma, Kai | Wen, Jie | Wang, Guangxian | Zhang, Changliang | Li, Qi | Bao, Xiaofeng | Wang, Hui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of “senile” plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to …as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a “lost link” in understanding and treating AD and call for future work. Show more

Keywords: Alzheimer’s disease, dementia, gut microbiome, neurodegenerative disorders

DOI: 10.3233/JAD-190872

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 849-865, 2020

Authors: Fowler-Davis, Sally | Barnett, Deborah | Kelley, John | Curtis, David

Article Type: Short Communication

Abstract: Digital technologies have the potential to assist people with dementia to monitor day to day activities and mitigate the risks of living independently. This purposive pilot study surveyed participants for frailty, wellbeing, and perceived carer burden using the 3Rings™ digital plug. 30 paired participants used the digital device for four months. People with dementia reported a decline in wellbeing and increased frailty. Family carers reported a decline in wellbeing but 18 reported a reduction in burden. The use of digital monitoring by family carers demonstrated a reduction in their perceived burden and the device was acceptable to people with mild …dementia living alone. Show more

Keywords: Assistive technology, burden, dementia, digital monitoring, family carers, frailty, wellbeing

DOI: 10.3233/JAD-190844

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 867-872, 2020

Authors: Chung, Seok Jong | Jeon, Seun | Yoo, Han Soo | Lee, Yang Hyun | Yun, Mijin | Lee, Seung-Koo | Lee, Phil Hyu | Sohn, Young Ho | Evans, Alan C. | Ye, Byoung Seok

Article Type: Research Article

Abstract: Background: Clinicopathological studies have demonstrated that the neuropsychological profiles and outcomes are different between two dementia subtypes, namely Alzheimer’s disease (AD) and Lewy bodies-related disease. Objective: We investigated the neural correlates of cognitive dysfunction in patients with AD-related cognitive impairment (ADCI) and those with Lewy bodies-related cognitive impairment (LBCI). Methods: We enrolled 216 ADCI patients, 183 LBCI patients, and 30 controls. Cortical thickness and diffusion tensor imaging analyses were performed to correlate gray matter and white matter (WM) abnormalities to cognitive composite scores for memory, visuospatial, and attention/executive domains in the ADCI spectrum (ADCI patients and …controls) and the LBCI spectrum (LBCI patients and controls) separately. Results: Memory dysfunction correlated with cortical thinning and increased mean diffusivity in the AD-prone regions, particularly the medial temporal region, in ADCI. Meanwhile, it only correlated with increased mean diffusivity in the WM adjacent to the anteromedial temporal, insula, and basal frontal cortices in LBCI. Visuospatial dysfunction correlated with cortical thinning in posterior brain regions in ADCI, while it correlated with decreased fractional anisotropy in the corpus callosum and widespread WM regions in LBCI. Attention/executive dysfunction correlated with cortical thinning and WM abnormalities in widespread brain regions in both disease spectra; however, ADCI had more prominent correlation with cortical thickness and LBCI did with fractional anisotropy values. Conclusions: Our study demonstrated that ADCI and LBCI have different neural correlates with respect to cognitive dysfunction. Cortical thinning had greater effects on cognitive dysfunction in the ADCI, while WM disruption did in the LBCI. Show more

Keywords: Alzheimer’s disease, cognition, Lewy body, neural correlate

DOI: 10.3233/JAD-190814

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 873-885, 2020

Authors: Waki, Takashi | Tanaka-Mizuno, Sachiko | Takashima, Naoyuki | Takechi, Hajime | Hayakawa, Takehito | Miura, Katsuyuki | Ueshima, Hirotsugu | Kita, Yoshikuni | Dodge, Hiroko H.

Article Type: Research Article

Abstract: Background: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the “obesity paradox”, but the underlying reasons and potential sex difference have not been well understood. Objective: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men …and women separately. Methods: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85 + years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension. Results: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men. Conclusion: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84), larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups. Show more

Keywords: Acquisition, attention, healthy aging, learning, sex differences, working memory

DOI: 10.3233/JAD-190395

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 887-896, 2020

Authors: Yassi, Nawaf | Hilal, Saima | Xia, Ying | Lim, Yen Ying | Watson, Rosie | Kuijf, Hugo | Fowler, Christopher | Yates, Paul | Maruff, Paul | Martins, Ralph | Ames, David | Chen, Christopher | Rowe, Christopher C. | Villemagne, Victor L. | Salvado, Olivier | Desmond, Patricia M. | Masters, Colin L.

Article Type: Research Article

Abstract: Background: Quantifying the contribution of cerebrovascular disease to the clinical and pathological profile of Alzheimer’s disease is challenging. Objective: We aimed to determine the influence of cerebrovascular disease, amyloid-β (Aβ), and their comorbidity on cognitive decline, hippocampal atrophy, and Aβ deposition, by evaluating data from the Australian Imaging, Biomarker and Lifestyle Study of Ageing. Methods: Two-hundred and eighteen participants underwent Aβ PET, MRI, and cognitive assessment at 18-month intervals for up to 90 months. Aβ status was determined on baseline PET. Participants were also classified as V+ on baseline MRI if they had≥1 large cortical infarcts, …subcortical infarcts, or cortical cerebral microinfarcts; or white matter hyperintensity volume greater than the 90th percentile of healthy controls. Linear mixed models were conducted comparing slopes of change in cognition, hippocampal volume, and Aβ load between the four resultant groups. Results: Mean age at baseline was 74 years (range 59–96). One-hundred and fifteen participants were cognitively normal, 54 had mild cognitive impairment, and 49 had Alzheimer’s disease. Compared to the Aβ-/V- group, the Aβ+/V- and Aβ+/V+ groups showed significantly faster cognitive decline and hippocampal atrophy over 90 months. V + status was associated with greater cognitive decline (Cohen’s d  = 0.85, p  < 0.001) and hippocampal atrophy (d  = 2.05, p  < 0.001) in the Aβ+ group but not in the Aβ- group. V+ status was not associated with Aβ accumulation in any group. Conclusion: Comorbidity of cerebrovascular disease and Aβ was associated with cognitive decline and neurodegeneration. Cerebrovascular disease was not associated with the rate of Aβ accumulation. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, magnetic resonance imaging, mild cognitive impairment, positron emission tomography, stroke

DOI: 10.3233/JAD-191028

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 897-907, 2020

Authors: Sun, Ruihua | Wang, Huayuan | Shi, Yingying | Sun, Zhikun | Jiang, Haisong | Zhang, Jiewen

Article Type: Research Article

Abstract:  Exosomes are nano-sized extracellular vesicles that are secreted by cells and usually found in body fluids. Since they freely cross the blood-brain barrier, neuronal exosomes respond directly to changes in the brain’s environment. Recent studies have shown that exosomes contain both amyloid-β (Aβ) and tau proteins and have a controversial role in the Alzheimer’s disease (AD) process. In this study, enzyme-linked immunosorbent assay was used to detect the levels of P-S396-tau and Aβ1–42 in plasma exosomes. We found that levels of P-S396-tau and Aβ1–42 in plasma exosomes of AD patients were significantly higher compared to those in matched …healthy controls. The difference between plasma exosomes of AD patients and those of matched healthy controls was determined using transmission electron microscopy and nanoparticle tracking analysis. Exosomes from AD patients were smaller and lower in quantity. These data together may provide a basis for early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, exosomes, nanoparticle tracking analysis, pathological protein, plasma, transmission electron microscopy

DOI: 10.3233/JAD-190497

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 909-917, 2020

Authors: Liu, Yanying | Wang, Hongmin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, neuropathologically characterized by hyperphosphorylation of tau and formation of amyloid plaques. Most AD cases are sporadic with no clear cause. Cell models play an important role in understanding the pathogenesis of sporadic AD, and the cell reprogramming and epigenetic techniques have provided new avenue to model the disorder. However, since most sporadic AD patients are late-onset, it poses a challenge to reprogram elderly somatic cells into stem cells. Here, we report that combination of overexpressing a single transcription factor, hSOX, with nine small molecules, was able to directly reprogram elderly (55–75 years …of age) sporadic AD and the age-matched healthy individual dermal fibroblasts into the induced neural stem cells (iNSCs). These cells possessed the typical neural stem cell properties and were able to be further differentiated into neurons and glia in vitro and in vivo . More importantly, AD iNSC-derived neurons showed hyperphosphorylation at several sites of tau and increased release of Aβ into culture medium, indicating the replication of the major neuropathological hallmarks. Thus, we described a new technique to directly convert elderly AD dermal fibroblasts into iNSCs that may serve as a useful tool for studying the pathogenesis of sporadic AD and for drug discovery to treat the disorder. Show more

Keywords: Alzheimer’s disease, amyloid-β , hyperphosphorylation, induced neural stem cell, modeling, sporadic, tau

DOI: 10.3233/JAD-190614

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 919-933, 2020

Authors: Khatib, Thabat | Chisholm, David R. | Whiting, Andrew | Platt, Bettina | McCaffery, Peter

Article Type: Research Article

Abstract: Retinoic acid has been previously proposed in the treatment of Alzheimer’s disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP , PLB2TAU , PLB1Double , PLB1Triple , and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent …decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics. Show more

Keywords: Aldh1a2, amyloid, chemokines, cholesterol, cyp26a1, cyp26b1, growth factor, Nos2, stra6, Tnf

DOI: 10.3233/JAD-190931

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 935-954, 2020