Journal of Alzheimer's Disease - Volume 58, issue 1

Authors: Jiang, Chunmei | Li, Guangning | Huang, Pengru | Liu, Zhou | Zhao, Bin

Article Type: Review Article

Abstract: The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer’s disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest …a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, amyloid beta-peptides, blood-brain barrier, dysbiosis, gut microbiota, lipopolysaccharides, obesity, type 2 diabetes mellitus

DOI: 10.3233/JAD-161141

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 1-15, 2017

Authors: Shellington, Erin M. | Heath, Matthew | Gill, Dawn P. | Petrella, Robert J.

Article Type: Short Communication

Abstract: Adults (≥55 years) with self-reported cognitive complaints (sCC) were randomized to: multiple-modality exercise (M2), or multiple-modality plus mind-motor exercise (M4), for 24-weeks. Participants (n  = 58) were assessed on antisaccade reaction time (RT) to examine executive-related oculomotor control and self-reported physical activity (PA) at pre-intervention (V0), post-intervention (V1), and 52-weeks follow-up (V2). We previously reported significant improvements in antisaccade RT of 23 ms at V1, in both groups. We now report maintenance of antisaccade RT improvement from V1 to V2, t(57) = 0.8, p  = 0.45, and improved PA from V1 to V2, t(56) = –2.4, p  = 0.02. Improvements in executive-related oculomotor control attained at V1 were …maintained at V2. Show more

Keywords: Adults, cognition, executive function, exercise, resistance training, saccades

DOI: 10.3233/JAD-161190

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 17-22, 2017

Authors: Williams, Stephanie M. | Schulz, Philip | Rosenberry, Terrone L. | Caselli, Richard J. | Sierks, Michael R.

Article Type: Research Article

Abstract: Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer’s disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis. While the subsequent diagnoses for the cases covered …several different conditions, all samples had elevated protein variant levels relative to the plasma controls although with different individual biomarker profiles. We then analyzed a set of longitudinal human plasma samples from four AD (encompassing time points prior to MCI diagnosis and continuing until after conversion to AD) and two control cases. Pre-MCI samples were characterized by high TDP-43 variant levels, MCI samples by high Aβ variant levels, and AD samples by high Aβ and tau variant levels. Sample time points ranged from ∼7 years pre-MCI to ∼9 years after AD conversion. Bivariate correlations showed a negative correlation with TDP-43 levels and positive correlations with cumulative Aβ and oligomeric tau levels indicating an increase in neurodegenerative processes with time in AD. Detection of disease related protein variants not only readily selects AD cases from controls, but also stages progression of AD and holds promise for a pre-symptomatic blood-based biomarker profile for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, longitudinal, oligomers, plasma, sera, tau, TDP-43

DOI: 10.3233/JAD-161116

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 23-35, 2017

Authors: Bohlken, Jens | Jacob, Louis | Kostev, Karel

Article Type: Research Article

Abstract: Background: High adherence and persistence are important for the efficacy of anti-dementia treatments. Objective: The goal of this study was to analyze the association between anti-dementia treatment persistence and daily dosage of the first prescription in patients treated in neuropsychiatric practices in Germany. Methods: This study included patients aged 60 years or over who were diagnosed with Alzheimer’s disease and received anti-dementia prescriptions (galantamine, donepezil, memantine, and rivastigmine) for the first time between 2005 and 2014. The main outcome measure was the treatment persistence rate within 12 months after the index date as a function …of the first dose. Cox proportional hazards regression models were used to estimate the relation between persistence and daily dosages after adjusting for age, gender, and residence in nursing homes. Results: In this study, 2,442, 5,669, 4,416, 642, and 2,334 patients received galantamine, donepezil, memantine, oral rivastigmine, and patch rivastigmine, respectively. After 12 months of follow-up, continuation rates were similar for individuals using different doses of galantamine, donepezil, oral rivastigmine, and patch rivastigmine, but were significantly different for those taking memantine. Patients using 20 mg of memantine were less likely to discontinue their treatment than patients using 10 mg (HR = 0.88, 95% CI: 0.80–0.96). There was no significant association between daily dosages and persistence for the other drugs (HRs ranging from 0.86 to 1.15). Conclusions: There was no significant association between treatment persistence and daily dosages in patients with Alzheimer’s disease in Germany who were treated with galantamine, donepezil, or rivastigmine. Show more

Keywords: Alzheimer’s disease, daily dosage, dementia, Germany, treatment persistence

DOI: 10.3233/JAD-170091

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 37-44, 2017

Authors: Mukadam, Naaheed | Sommerlad, Andrew | Livingston, Gill

Article Type: Research Article

Abstract: Background: Bilingualism may contribute to cognitive reserve, protect against cognitive decline, and delay the onset of dementia. Objective: We systematically reviewed evidence about the effect of bilingualism on subsequent cognitive decline or dementia. Methods: We searched electronic databases and references for longitudinal studies comparing cognitive decline in people who were bilingual with those who were monolingual and evaluated study quality. We conducted meta-analyses using random effects models to calculate pooled odds ratio of incident dementia. Results: We included 13/1,156 eligible articles. Meta-analysis of prospective studies of the effects of bilingualism on future dementia …gave a combined Odds Ratio of dementia of 0.96 (95% CI 0.74–1.23) in bilingual participants (n  = 5,527) compared to monolinguals. Most retrospective studies found that bilingual people were reported to develop symptoms of cognitive decline at a later age than monolingual participants. Conclusion: We did not find that bilingualism protects from cognitive decline or dementia from prospective studies. Retrospective studies are more prone to confounding by education, or cultural differences in presentation to dementia services and are therefore not suited to establishing causative links between risk factors and outcomes. Show more

Keywords: Bilingualism, cognitive decline, dementia, prospective cohort studies

DOI: 10.3233/JAD-170131

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 45-54, 2017

Authors: Alonso, Ruth | Pisa, Diana | Aguado, Begoña | Carrasco, Luis

Article Type: Research Article

Abstract: The possibility that patients diagnosed with Alzheimer’s disease (AD) have disseminated fungal infection has been recently advanced by the demonstration of fungal proteins and DNA in nervous tissue from AD patients. In the present study, next-generation sequencing (NGS) was used to identify fungal species present in the central nervous system (CNS) of AD patients. Initially, DNA was extracted from frozen tissue from four different CNS regions of one AD patient and the fungi in each region were identified by NGS. Notably, whereas a great variety of species were identified using the Illumina platform, Botrytis cinerea and Cryptococcus curvatus …were common to all four CNS regions analyzed. Further analysis of entorhinal/cortex hippocampus samples from an additional eight AD patients revealed a variety of fungal species, although some were more prominent than others. Five genera were common to all nine patients: Alternaria , Botrytis , Candida , Cladosporium , and Malassezia . These observations could be used to guide targeted antifungal therapy for AD patients. Moreover, the differences found between the fungal species in each patient may constitute a basis to understand the evolution and severity of clinical symptoms in AD. Show more

Keywords: Disseminated mycoses, fungal infection, massive sequencing, neurodegenerative disease, next-generation sequencing

DOI: 10.3233/JAD-170058

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 55-67, 2017

Authors: Robb, Catherine | Udeh-Momoh, Chinedu | Wagenpfeil, Stefan | Schöpe, Jakob | Alexopoulos, Panagiotis | Perneczky, Robert | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Little is known of possible associations between Alzheimer’s disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time. Objective: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Methods: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients. Results: A significant correlation …was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted. Discussion: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers. Show more

Keywords: Activities of daily living, Alzheimer’s disease, biomarker, cerebrospinal fluid, early diagnosis, magnetic resonance imaging, positron emission tomography, prediction

DOI: 10.3233/JAD-161162

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 69-78, 2017

Authors: Wang, Tong | Wu, Yili | Sun, Yongye | Zhai, Long | Zhang, Dongfeng

Article Type: Research Article

Abstract: Background: Uric acid (UA) is a powerful antioxidant that may have neuroprotective properties, yet it is also a risk factor of vascular disease that predisposes individuals to cognitive impairment. Results from longitudinal studies on UA and cognitive decline remain controversial. Objective: We examined the associations of baseline plasma UA level with follow-up cognitive function as well as cognitive decline over time among a large sample of middle-aged and older Chinese. Methods: Data from China Health and Retirement Longitudinal Study (CHARLS) were used. Cognitive function, including episodic memory, mental intactness, and global cognition, were tested twice …with 2-year interval. Plasma UA was measured at baseline. Basic demographics, life habits, and health status were considered as potential confounders. Multiple linear regression models and mixed-effects regression models were fitted. Results: A total of 12,798 individuals aged above 45 years were eligible with the follow-up time ranging from 1.33 to 2.42 years. Both global cognitive function and mental intactness declined, while episodic memory remained stable over time. In multiple linear regression models, compared with the lowest baseline UA level, 3rd baseline UA quartile was associated with better follow-up global cognitive function (b = 0.425, p  = 0.041) and episodic memory (b = 0.413, p  = 0.004), and highest baseline UA quartile was associated with better follow-up mental intactness (b = 0.253, p  = 0.041) in males; highest baseline UA level was associated with better follow-up cognition for each measure (b = 0.281∼0.768, p ≤0.046) in females. Mixed-effects regression models suggested no significant baseline UA-by-time interactions on any cognitive measure. Conclusion: Higher baseline UA level was associated with better cognition in later life but not with rates of cognitive decline among middle-aged and older Chinese. Show more

Keywords: Aged, cognition, episodic memory, mental intactness, uric acid

DOI: 10.3233/JAD-161243

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 79-86, 2017

Authors: Bennys, Karim | Gabelle, Audrey | Berr, Claudine | De Verbizier, Delphine | Andrieu, Sandrine | Vellas, Bruno | Touchon, Jacques | MAPT-DSA Study group

Article Type: Research Article

Abstract: Background: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer’s disease (AD) diagnosis. Objective: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. Methods: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. Results: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n  = 15) and PET-Aβ negative (n  = 21). In the amyloid positive group, we …observed a highly significant increase in P3b latency in parietal brain regions (p  = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group. Conclusions: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, frail elderly, P300 event-related potentials

DOI: 10.3233/JAD-161012

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 87-97, 2017

Authors: Khondoker, Mizanur | Rafnsson, Snorri Bjorn | Morris, Stephen | Orrell, Martin | Steptoe, Andrew

Article Type: Research Article

Abstract: Background: Having a network of close relationships may reduce the risk of developing dementia. However, social exchange theory suggests that social interaction entails both rewards and costs. The effects of quality of close social relationships in later life on the risk of developing dementia are not well understood. Objective: To investigate the effects of positive and negative experiences of social support within key relationships (spouse or partner, children, other immediate family, and friends) on the risk of developing dementia in later life. Methods: We analyzed 10-year follow up data (2003/4 to 2012/13) in a cohort …of 10,055 dementia free (at baseline) core participants aged 50 years and over from the English Longitudinal Study of Ageing (ELSA). Incidence of dementia was identified from participant or informant reported physician diagnosed dementia or overall score of informant-completed IQCODE questionnaire. Effects of positive and negative experiences of social support measured at baseline on risk of developing dementia were investigated using proportional hazards regression accommodating interval censoring of time-to-dementia. Results: There were 340 (3.4%) incident dementia cases during the follow-up. Positive social support from children significantly reduced the risk of dementia (hazard ratio, HR = 0.83, p  = 0.042, 95% CI: 0.69 to 0.99). Negative support from other immediate family (HR = 1.26, p  = 0.011, CI: 1.05 to 1.50); combined negative scores from spouse and children (HR = 1.23, p  = 0.046, CI: 1.004 to 1.51); spouse, children, and other family (HR = 1.27, p  = 0.021, CI = 1.04 to 1.56); other family & friends (HR = 1.25, p  = 0.033, CI: 1.02 to 1.55); and the overall negative scores (HR = 1.31, p  = 0.019, CI: 1.05 to 1.64) all were significantly associated with increased risk of dementia. Conclusion: Positive social support from children is associated with reduced risk of developing dementia whereas experiences of negative social support from children and other immediate family increase the risk. Further research is needed to better understand the causal mechanisms that drive these associations. Show more

Keywords: Dementia, interval censoring, positive/negative social support, proportional hazards

DOI: 10.3233/JAD-161160

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 99-108, 2017