Journal of Alzheimer's Disease - Volume 78, issue 1

Authors: Wang, Wei | Wei, Cuibai | Quan, Meina | Li, Tingting | Jia, Jianping

Article Type: Research Article

Abstract: Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, …was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, depression, neuroinflammation, oxidative stress, sulforaphane

DOI: 10.3233/JAD-200397

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 127-137, 2020

Authors: Mold, Matthew John | O’Farrell, Adam | Morris, Benjamin | Exley, Christopher

Article Type: Research Article

Abstract: Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high …level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease. Show more

Keywords: α-synuclein, aluminum in human brain tissue, amyloid-β , epilepsy, familial Alzheimer’s disease, Parkinson’s disease, tau

DOI: 10.3233/JAD-200838

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 139-149, 2020

Authors: Liu, Yi-Hsuan | Gao, Xiang | Na, Muzi | Kris-Etherton, Penny M. | Mitchell, Diane C. | Jensen, Gordon L.

Article Type: Research Article

Abstract: Background: Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia. Objective: In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori , and risk of dementia. Methods: We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in …English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results: Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratio = 0.82; 95% CI: 0.70, 0.95; n  = 12) and Alzheimer’s disease (pooled risk ratio = 0.61; 95% CI: 0.47, 0.79; n  = 6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results. Conclusion: Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia. Show more

Keywords: Alzheimer’s disease, dementia, diet quality, dietary pattern

DOI: 10.3233/JAD-200499

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 151-168, 2020

Authors: Alipour, Abolfazl | Mozhdehfarahbakhsh, Azadeh | Nouri, Saba | Petramfar, Peyman | Tahamtan, Mahshid | Kamali, Ali-Mohammad | Rao, K. S. | Nami, Mohammad

Article Type: Research Article

Abstract: Background: A proper explanation for perceptual symptoms in neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease (PD) is still lacking. Objective: This study aimed at investigating the imbalance between ‘bottom-up’ and ‘top-down’ information flow (IF) and processing in PD in relation with visual hallucination symptoms. Methods: Here, we looked at bottom-up and top-down IF markers using resting state electroencephalographic (EEG) data from PD patients analyzed through three different IF measures (direct Directed Transfer Function (dDTF), full frequency Directed Transfer Function (ff-DTF), and renormalized Partial Directed Coherence (rPDC). Results: We observed an increased gamma band …IF and a reduced beta band IF in PD patients compared to healthy controls. Additionally, we noticed a reduced theta band IF in PD patients using dDTF as a measure of IF. By source localizing the EEG activity of the PD patients and healthy controls, we looked at the alterations of IF in the prefrontal cortex of PD patients as well. Conclusion: In line with previous studies, our results suggest that the delicate balance between bottom-up and top-down IF is disrupted in Parkinson’s disease potentially contributing to the cognitive symptoms of PD patients. Show more

Keywords: Alzheimer’s disease, direct directed transfer function, EEG, full frequency directed transfer function, information flow, Parkinson’s disease, renormalized partial directed coherence, visual hallucinations

DOI: 10.3233/JAD-200590

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 169-183, 2020

Authors: Watermeyer, Tam | Marroig, Alejandra | Ritchie, Craig W. | Ritchie, Karen | Blennow, Kaj | Muniz-Terrera, Graciela | on behalf of the EPAD Consortium

Article Type: Research Article

Abstract: Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42 ), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older …adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42 , t-tau, and p-tau and amyloid positivity (Aβ42  < 1000 pg/ml). Relationships between sociodemographics, APOE ɛ 4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β= –0.007, SE = 0.002, p  = 0.001) and less educated (β= –0.009, SE = 0.003, p  = 0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognition, risk factors, tau

DOI: 10.3233/JAD-200514

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 185-194, 2020

Authors: Yun, Yejin | Lee, Sang-Yeon | Choi, Won Hoon | Park, Jong-Chan | Lee, Dong Han | Kim, Yun Kyung | Lee, Jung Hoon | Lee, Jun-Young | Lee, Min Jae | Kim, Young Ho

Article Type: Research Article

Abstract: Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive …Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42 , and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p  = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis. Show more

Keywords: Amyloid-β , biomarker, mild cognitive impairment, plasma, proteasome, tinnitus

DOI: 10.3233/JAD-200728

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 195-205, 2020

Authors: Henkel, Rebecca | Brendel, Matthias | Paolini, Marco | Brendel, Eva | Beyer, Leonie | Gutzeit, Andreas | Pogarell, Oliver | Rominger, Axel | Blautzik, Janusch

Article Type: Research Article

Abstract: Background: Various reasons may lead to cognitive symptoms in elderly, including the development of cognitive decline and dementia. Often, mixed pathologies such as neurodegeneration and cerebrovascular disease co-exist in these patients. Diagnostic work-up commonly includes imaging modalities such as FDG PET, MRI, and CT, each delivering specific information. Objective: To study the informative value of neuroimaging-based data supposed to reflect neurodegeneration (FDG PET), cerebral small vessel disease (MRI), and cerebral large vessel atherosclerosis (CT) with regard to cognitive performance in patients presenting to our memory clinic. Methods: Non-parametric partial correlations and an ordinal logistic regression model …were run to determine relationships between scores for cortical hypometabolism, white matter hyperintensities, calcified plaque burden, and results from Mini-Mental State Examination (MMSE). The final study group consisted of 162 patients (female: 94; MMSE: 6–30). Results: Only FDG PET data was linked to and predicted cognitive performance (r(157) = –0.388, p  < 0.001). Overall, parameters linked to cerebral small and large vessel disease showed no significant association with cognition. Further findings demonstrated a relationship between white matter hyperintensities and FDG PET data (r(157) = 0.230, p  = 0.004). Conclusion: Only FDG PET imaging mirrors cognitive performance, presumably due to the examination’s ability to reflect neurodegeneration and vascular dysfunction, thus capturing a broader spectrum of pathologies. This makes the examination a useful imaging-based diagnostic tool in the work-up of patients presenting to a memory clinic. Parameters of vascular dysfunction alone as depicted by conventional MRI and CT are less adequate in such a situation, most likely because they reflect one pathology complex only. Show more

Keywords: Atherosclerosis, cognitive performance, computed tomography, FDG PET, magnetic resonance imaging, neurodegeneration, small vessel disease

DOI: 10.3233/JAD-200826

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 207-216, 2020

Authors: Huang, Liang-Yu | Hu, He-Ying | Wang, Zuo-Teng | Ma, Ya-Hui | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. Objective: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). Methods: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. Results: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, …and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI = 0.34–0.94, I² = 85.00%, p  < 0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI = 0.91–1.00, I² = 57.00%, p  < 0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI = 1.05–1.39 I² = 62.00%, p  < 0.05; 95% CI = 1.05–1.26 I² = 31.00%, p  = 0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI = 1.01–1.57, I² = 69.00%, p  < 0.01) for dementia. Conclusion: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI. Show more

Keywords: Dementia, job strain, meta-analysis, occupation, occupational exposure, work complexity

DOI: 10.3233/JAD-200605

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 217-227, 2020

Authors: Squarzoni, Paula | Faria, Daniele de Paula | Yassuda, Mônica Sanches | Porto, Fábio Henrique de Gobbi | Coutinho, Artur Martins | Costa, Naomi Antunes da | Nitrini, Ricardo | Forlenza, Orestes Vicente | Duran, Fabio Luiz de Souza | Brucki, Sonia Maria Dozzi | Buchpiguel, Carlos Alberto | Busatto, Geraldo F.

Article Type: Research Article

Abstract: Background: Studies of elderly subjects using biomarkers that are proxies for Alzheimer’s disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. Objective: To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration. Methods: Patients with mild dementia compatible with AD (n  = 38) or amnestic mild cognitive impairment (aMCI; n  = 43) and a cognitively unimpaired group (n  = 27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18 F]FDG-PET assessing neurodegeneration …((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. Results: The A+(N)+ subgroup (n  = 32) showed decreased (p  < 0.001) cognitive test scores compared to both A+(N)–(n  = 18) and A–(N)–(n  = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n  = 9), the A–(N)+ subgroup showed lower (p  < 0.043) verbal memory scores relative to A–(N)–subjects, and trend lower (p  = 0.096) scores relative to A+(N)–subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)–groups. Conclusion: These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)–and A–(N)–subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cognition, cognitively unimpaired, 18-fluorode oxyglucose positron emission tomographic, Pittsburgh compound-B

DOI: 10.3233/JAD-200758

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 229-244, 2020

Authors: Sandau, Ursula S. | Wiedrick, Jack T. | Smith, Sierra J. | McFarland, Trevor J. | Lusardi, Theresa A. | Lind, Babett | Harrington, Christina A. | Lapidus, Jodi A. | Galasko, Douglas R. | Quinn, Joseph F. | Saugstad, Julie A.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group …and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ 4 allele (APOE ɛ 4) genotype and amyloid-β42 to total tau ratio (Aβ42 :T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42 :T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p  = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42 :T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ42 :T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42 :T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, biomarkers, cerebrospinal fluid, microRNA, mild cognitive impairment, tau proteins

DOI: 10.3233/JAD-200396

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 245-263, 2020