Journal of Alzheimer's Disease - Volume 77, issue 2

Authors: Lamballais, Sander | Zijlmans, Jendé L. | Vernooij, Meike W. | Ikram, M. Kamran | Luik, Annemarie I. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Individual differences in the risk to develop dementia remain poorly understood. These differences may partly be explained through reserve, which is the ability to buffer cognitive decline due to neuropathology and age. Objective: To determine how much early and late–life cognitive reserve (CR) and brain reserve (BR) contribute to the risk of dementia. Methods: 4,112 dementia-free participants (mean age = 66.3 years) from the Rotterdam Study were followed up for on average 6.0 years. Early-life CR and BR were defined as attained education and intracranial volume, respectively. Late-life CR was derived through variance decomposition based on cognition. …Late-life BR was set as the total non-lesioned brain volume divided by intracranial volume. Results: Higher early-life CR (hazard ratio = 0.48, 95% CI = [0.21; 1.06]) but not early-life BR associated with a lower risk of incident dementia. Higher late-life CR (hazard ratio = 0.57, 95% CI = [0.48; 0.68]) and late-life BR (hazard ratio = 0.54, 95% CI = [0.43; 0.68]) also showed lower levels of dementia. Combining all proxies into one model attenuated the association between early-life CR and dementia (hazard ratio = 0.56, 95% CI = [0.25; 1.25]) whereas the other associations were unaffected. These findings were stable upon stratification for sex, age, and APOE ɛ 4. Finally, high levels of late-life CR and BR provided additive protection against dementia. Conclusion: The findings illustrate the importance of late-life over early-life reserve in understanding the risk of dementia, and show the need to study CR and BR conjointly. Show more

Keywords: Cognition, cognitive reserve, dementia, education, neuroimaging

DOI: 10.3233/JAD-200264

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 607-618, 2020

Authors: de Leeuw, Francisca A. | Honer, William G. | Schneider, Julie A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. Methods: We examined associations of α - and γ -tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a …SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. Results: Higher brain γ -tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p  < 0.001 to 0.003). When additionally adjusted for global Alzheimer’s disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α -tocopherol and presynaptic protein levels. Conclusion: In this cross-sectional study, we found higher brain γ -tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels. Show more

Keywords: Antioxidants, SNARE protein, tocopherols, vitamin E

DOI: 10.3233/JAD-200166

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 619-627, 2020

Authors: Hu, Li | Zhu, Shaoping | Peng, Xiaoping | Li, Kanglan | Peng, Wanjuan | Zhong, Yu | Kang, Chenyao | Cao, Xingxing | Liu, Zhou | Zhao, Bin

Article Type: Research Article

Abstract: Background: Excessive salt intake is considered as an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. Objective: To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Methods: Adult female C57BL/6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. …Results: The mice fed a HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β , IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. Conclusion: The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production. Show more

Keywords: Blood-brain barrier, cognition, gut microbiota, high-salt diet, microglia, short-chain fatty acids

DOI: 10.3233/JAD-200035

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 629-640, 2020

Authors: Junquera, Almudena | García-Zamora, Estefanía | Olazarán, Javier | Parra, Mario A. | Fernández-Guinea, Sara

Article Type: Research Article

Abstract: Background: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI) to dementia in Alzheimer’s clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). Objective: The present study analyzes the contributions of executive functions to predict MCI–dementia progression in ACS. Methods: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at …1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. Results: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI–dementia conversion, even after controlling for the severity of MCI at baseline (F (1, 68) = 116.25, p  = 0.000, R2  = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F (1, 68) = 5.09, p  = 0.955, R2  = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. Conclusion: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive dysfunction, executive function, longitudinal studies

DOI: 10.3233/JAD-200586

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 641-653, 2020

Authors: Caruso, Giulia | Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall , performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two …tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance. Objective: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia. Methods: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer’s disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs). Results: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance. Conclusion: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks. Show more

Keywords: Alzheimer’s disease, familiarity, frontotemporal dementia, recall, recognition, recollection

DOI: 10.3233/JAD-200126

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 655-666, 2020

Authors: Tan, Ji-Ping | Wang, Xiaoxiao | Lan, Xiaoyang | Li, Nan | Zhang, Shimin | Zhao, Yiming | Wang, Lu-Ning

Article Type: Research Article

Abstract: Background: Over time, improved cognitive abilities in elderly individuals lead to an overall increase in performance on widely used cognitive screening tests (e.g., Mini-Mental State Examination, MMSE) and impact screening efficacy. Objective: We aimed to examine the epoch effect on cognitive function measured using MMSE, in addition to the influence of demographic characteristics on MMSE. We also evaluated the ability of the MMSE in detecting dementia and examined the discrimination ability and measurement precision of the MMSE. Methods: In a cross-sectional survey, Chinese veterans aged ≥60 years were interviewed. Multiple linear regression analysis was applied to …explore the factors affecting the MMSE. The expected MMSE score was calculated to examine the epoch effect. The diagnostic accuracy of the MMSE was determined via receiver operating characteristic curve analyses. Item response theory methods were implemented using Stata 16.0. Results: The MMSE score increased with higher education and decreased with advancing age. The observed MMSE score in this study (26.9) was higher than the expected MMSE score (24.9). It demonstrated 78.3% /84.1% /89.9% sensitivity and 85.8% /79.5% /66.8% specificity in detecting dementia using the cut-off score 25/26/27. The MMSE showed reduced discrimination and provided little information for ability level of −1 and above. Conclusion: Improved cognitive ability over time may increase the performance on cognitive screening tests (e.g., MMSE). This impact of epoch in cognitive function emphasizes the importance of regularly updating cognitive screening tests. Show more

Keywords: Dementia, epoch effect, item response theory, Mini-Mental State Examination

DOI: 10.3233/JAD-200112

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 667-674, 2020

Authors: Fung, Susan | Smith, Carole L. | Prater, Katherine E. | Case, Amanda | Green, Kevin | Osnis, Leah | Winston, Chloe | Kinoshita, Yoshito | Sopher, Bryce | Morrison, Richard S. | Garden, Gwenn A. | Jayadev, Suman

Article Type: Research Article

Abstract: Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1 ), presenilin 2 (PSEN 2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: …Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ -secretase activity as well as exaggerated inflammatory cytokine release, NFκ B activity, and Aβ internalization. In vivo , PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production. Show more

Keywords: Alzheimer’s disease, cytokine, glia, inflammation, microglia, phagocytosis, presenilin

DOI: 10.3233/JAD-200492

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 675-688, 2020

Authors: Gallucci, Maurizio | Mazzarolo, Anna Paola | Focella, Lucia | Piovesan, Cinzia | Mazzetto, Manuela | Ramigni, Mauro | Marzetti, Emanuele

Article Type: Research Article

Abstract: Background: Frailty is a condition of increased vulnerability to exogenous and endogenous stressors, which is correlated with aging, functional decline, institutionalization, hospitalization, and mortality. Given the multifaceted nature of frailty, programs aimed at its prevention are recommended to act on multiple domains. Objective: The present intervention program aimed at assessing the effects of combined physical and cognitive training in older people with mild cognitive impairment (MCI) and at investigating how their frailty status changed over one year of follow-up. Methods: Two-hundred and seven participants were recruited among outpatients of the Cognitive Impairment Center who agreed to …receive a comprehensive assessment. Forty-six participants, who joined a structured program of physical activity and group readings for a period of one year, were defined as active. The remaining 161, who decided not to engage in those activities, were considered controls. In both groups, frailty status was assessed at baseline and over one year of follow-up. Results: Control participants showed twice the risk of becoming frail at 12 months compared with those in the active group. Participants in the active group had more than three times the probability of improving their frailty status compared with the control group from T0 to T12. Age and NPI scores were significantly associated with worsening frailty status. When analyses were restricted to participants who were robust at baseline, the frailty status varied significantly between groups over time. Conclusion: Findings of the present study confirm the beneficial effects of physical activity and reading to prevent frailty in older people with MCI. Show more

Keywords: Cognitive frailty, community, multi-domain intervention, neuroimaging, TREDEM registry

DOI: 10.3233/JAD-200542

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 689-699, 2020

Authors: Fu, Pengfei | Yung, Ken Kin Lam

Article Type: Research Article

Abstract: Background: Ambient air pollution has been associated with Alzheimer’s disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively. Objective: We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence. Methods: We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM10 ), PM2.5 , ozone (O3 ), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and carbon monoxide (CO). The subgroup analysis was conducted based on …the pollution levels. Results: Nine studies were included in the meta-analysis and review. The OR per 10μ g/m3 increase of PM2.5 was 1.95 (95% CI: 0.88–4.30). The corresponding values per 10μ g/m3 increment of other pollutants were 1.03 (95% CI: 0.68–1.57) for O3 , 1.00 (95% CI: 0.89–1.13) for NO2 , and 0.95 (95% CI: 0.91–0.99) for PM10 (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09–1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO2 or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO2 or CO exposure increased risks of dementia, implying that SO2 or CO might have a potential impact on AD. Conclusion: Air pollution exposure may exacerbate AD development. Show more

Keywords: Air pollution, Alzheimer’s disease, meta-analysis, systematic review

DOI: 10.3233/JAD-200483

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 701-714, 2020

Authors: Poptsi, Eleni | Moraitou, Despina | Tsardoulias, Emmanouil | Symeonidisd, Andreas L. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The early diagnosis of neurocognitive disorders before the symptoms’ onset is the ultimate goal of the scientific community. REMEDES for Alzheimer (R4Alz) is a battery, designed for assessing cognitive control abilities in people with minor and major neurocognitive disorders. Objective: To investigate whether the R4Alz battery’s tasks differentiate subjective cognitive decline (SCD) from cognitively healthy adults (CHA) and mild cognitive impairment (MCI). Methods: The R4Alz battery was administered to 175 Greek adults, categorized in five groups a) healthy young adults (HYA; n  = 42), b) healthy middle-aged adults (HMaA; n  = 33), c) healthy older adults (HOA; …n  = 14), d) community-dwelling older adults with SCD (n  = 34), and e) people with MCI (n  = 52). Results: Between the seven R4Alz subtasks, four showcased the best results for differentiating HOA from SCD: the working memory updating (WMCUT-S3), the inhibition and switching subtask (ICT/RST-S1&S2), the failure sets (FS) of the ICT/RST-S1&S2, and the cognitive flexibility subtask (ICT/RST-S3). The total score of the four R4Alz subtasks (R4AlzTot4) leads to an excellent discrimination among SCD and healthy adulthood, and to fare discrimination among SCD and MCI. Conclusion: The R4Alz battery is a novel approach regarding the neuropsychological assessment of people with SCD, since it can very well assist toward discriminating SCD from HOA. The R4Alz is able to measure decline of specific cognitive control abilities - namely of working memory updating, and complex executive functions - which seem to be the neuropsychological substrate of cognitive complaints in community dwelling adults of advancing age. Show more

Keywords: Cognitive control assessment battery, cognitively healthy adults, mild cognitive impairment, normative data, subjective cognitive decline

DOI: 10.3233/JAD-200562

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 715-732, 2020

Authors: Pedrini, Steve | Hone, Eugene | Gupta, Veer B. | James, Ian | Teimouri, Elham | Bush, Ashley I. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Masters, Colin L. | Rainey-Smith, Stephanie | Verdile, Giuseppe | Sohrabi, Hamid R. | Raida, Manfred R. | Wenk, Markus R. | Taddei, Kevin | Chatterjee, Pratishtha | Martins, Ian | Laws, Simon M. | Martins, Ralph N. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: The link between cholesterol and Alzheimer’s disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a “good” lipid complex due to its ability to enable clearance of excess cholesterol via ‘cholesterol reverse transport’, although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly …formed small HDL, to much larger HDL. Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1–42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances. Show more

Keywords: Amyloid-β, apolipoprotein, blood, cholesterol, lipid transport

DOI: 10.3233/JAD-200291

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 733-744, 2020

Authors: Keleman, Audrey | Wisch, Julie K. | Bollinger, Rebecca M. | Grant, Elizabeth A. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n  = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, …and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p  = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = –0.75, p  = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p  = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD. Show more

Keywords: Alzheimer’s disease, biomarkers, falls, resting state functional connectivity, volumetrics

DOI: 10.3233/JAD-200192

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 745-752, 2020

Authors: Rao, Shalini S. | Portbury, Stuart. D. | Lago, Larissa | Bush, Ashley I. | Adlard, Paul A.

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked “RETRACTED”. A retraction notice is available at DOI: https://dx.doi.org/10.3233/JAD-239009 .

DOI: 10.3233/JAD-200551

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 753-771, 2020

Authors: Hasegawa, Tohru | Kosoku, Yoshinori | Sano, Yuka | Yoshida, Hiroshi | Kudoh, Chiaki | Tabira, Takeshi

Article Type: Research Article

Abstract: Background: In the treatment of Alzheimer’s disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD. Objective: Homocysteic acid (HCA) is useful as an …early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. Methods: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients’ plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. Results: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μ M was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. Conclusion: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD. Show more

Keywords: Alzheimer disease, homocysteic acid, mild cognitive impairment, plasma

DOI: 10.3233/JAD-200234

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 773-780, 2020

Authors: Zhang, Chenbo | Luo, Jianfeng | Yuan, Changzheng | Ding, Ding

Article Type: Research Article

Abstract: Background: Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. Objective: To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. Methods: Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake …levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. Results: Twenty-one observational studies with sample sizes ranging from 155–7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61–0.97) and folate concentration (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. Conclusion: The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, folate, nutrition, vitamin B6, vitamin B12

DOI: 10.3233/JAD-200534

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 781-794, 2020

Authors: Furtado, André | Astaburuaga, Rosario | Costa, Ana | Duarte, Ana C. | Gonçalves, Isabel | Cipolla-Neto, José | Lemos, Manuel C. | Carro, Eva | Relógio, Angela | Santos, Cecília R.A. | Quintela, Telma

Article Type: Research Article

Abstract: Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before …amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2 ) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood-cerebrospinal fluid barrier, choroid plexus, circadian clock, melatonin

DOI: 10.3233/JAD-200331

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 795-806, 2020

Authors: Wang, Yan-Juan | Gong, Wei-Gang | Ren, Qing-Guo | Zhang, Zhi-Jun

Article Type: Research Article

Abstract: Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro . Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. …Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway. Show more

Keywords: Alzheimer’s disease, selective serotonin reuptake inhibitor, synapse, tau hyperphosphorylation, transgenic mice

DOI: 10.3233/JAD-200401

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 807-819, 2020

Authors: Silverman, Hannah E. | Gazes, Yunglin | Barker, Megan S. | Manoochehri, Masood | Goldman, Jill S. | Wassermann, Eric M. | Tierney, Michael C. | Cosentino, Stephanie | Grafman, Jordan | Huey, Edward D.

Article Type: Research Article

Abstract: Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography …(18 FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p  = 0.009] and NC [p  < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p  = 0.026] and NC [p  < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p  < 0.01. Hypometabolism in Brodmann’s Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p (FWE-corr) <0.05, k  = 44]. No anatomical associations were found with other sexual changes. Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction. Show more

Keywords: Frontal lobe, frontotemporal dementia, neurodegenerative disorders, prefrontal cortex, sexual behavior

DOI: 10.3233/JAD-200346

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 821-830, 2020

Authors: Aksnes, Mari | Müller, Ebba Glersen | Tiiman, Ann | Edwin, Trine Holt | Terenius, Lars | Revheim, Mona-Elisabeth | Vukojević, Vladana | Bogdanović, Nenad | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18 F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory …clinic patients were compared between sub-groups classified by 18 F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptides, amyloidogenic proteins, biomarkers, cerebrospinal fluid, fluorescence spectrometry, positron-emission tomography, Thioflavin T

DOI: 10.3233/JAD-200237

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 831-842, 2020

Authors: Trammell, Antoine R. | McDaniel, Darius J. | Obideen, Malik | Okafor, Maureen | Thomas, Tiffany L. | Goldstein, Felicia C. | Shaw, Leslie M. | Hajjar, Ihab M.

Article Type: Research Article

Abstract: Background: African Americans (AA) have a higher Alzheimer’s disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. Objective: Establish biomarker evidence for the observed association between stress and AD, especially in AA. Methods: A cross-sectional study (n  = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n  = 309) provided cerebrospinal fluid for measurement of Aβ42 , Tau, Ptau, Tau/Aβ42 (TAR), and Ptau/Aβ42 (PTAR). …Multivariate linear regression, including factors that confound racial differences in AD, was performed. Results: Higher PSS scores were associated with higher Ptau (β= 0.43, p  = 0.01) and PTAR (β= 0.005, p  = 0.03) in AA with impaired cognition (mild cognitive impairment). Conclusion: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity. Show more

Keywords: African Americans, Alzheimer’s disease, tauopathy, amyloid-β peptides, cognitive function, mild cognitive impairment, neurocognitive tests, psychological stress

DOI: 10.3233/JAD-200089

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 843-853, 2020

Authors: Mar, Javier | Gorostiza, Ania | Ibarrondo, Oliver | Cernuda, Carlos | Arrospide, Arantzazu | Iruin, Álvaro | Larrañaga, Igor | Tainta, Mikel | Ezpeleta, Enaitz | Alberdi, Ane

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are the leading cause of the social burden of dementia but their role is underestimated. Objective: The objective of the study was to validate predictive models to separately identify psychotic and depressive symptoms in patients diagnosed with dementia using clinical databases representing the whole population to inform decision-makers. Methods: First, we searched the electronic health records of 4,003 patients with dementia to identify NPS. Second, machine learning (random forest) algorithms were applied to build separate predictive models for psychotic and depressive symptom clusters in the training set (N = 3,003). Third, calibration and discrimination …were assessed in the test set (N = 1,000) to assess the performance of the models. Results: Neuropsychiatric symptoms were noted in the electronic health record of 58% of patients. The area under the receiver operating curve reached 0.80 for the psychotic cluster model and 0.74 for the depressive cluster model. The Kappa index and accuracy also showed better discrimination in the psychotic model. Calibration plots indicated that both types of model had less predictive accuracy when the probability of neuropsychiatric symptoms was <25%. The most important variables in the psychotic cluster model were use of risperidone, level of sedation, use of quetiapine and haloperidol and the number of antipsychotics prescribed. In the depressive cluster model, the most important variables were number of antidepressants prescribed, escitalopram use, level of sedation, and age. Conclusion: Given their relatively good performance, the predictive models can be used to estimate prevalence of NPS in population databases. Show more

Keywords: Dementia, depressive symptoms, machine learning, neuropsychiatric symptoms, predictive model\sep prevalence, psychotic symptoms, real-world data

DOI: 10.3233/JAD-200345

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 855-864, 2020

Authors: Monsees, Jessica | Schmachtenberg, Tim | Hoffmann, Wolfgang | Kind, Amy | Gilmore-Bykovskyi, Andrea | Kim, Alice J. | Thyrian, Jochen René

Article Type: Research Article

Abstract: Background: As the proportion of older people with migration background (PwM) increases, the proportion of older PwM with dementia might also increase. Dementia is underdiagnosed in this group and a large proportion of PwM with dementia and family caregivers are not properly supported. Healthcare utilization is lower among older migrant populations. Thus, a better understanding of how PwM and family caregivers perceive their situation and how they experience healthcare services is needed to improve utilization of the healthcare system. Objective: Analyze how family caregivers of PwM with dementia experience their situation, why healthcare services are utilized less often, …and what can be done to reverse this. Methods: Eight semi-structured interviews were conducted with people with Turkish migration background caring for PwM with dementia. Qualitative content analysis was used for data analysis. Results: Daily care was performed by one family member with the support of others. Healthcare services were used by most participants. Participants identified a need for better access to relevant information and incorporation of Turkish culture into healthcare services. Conclusion: PwM face similar challenges in taking care of persons with dementia as those without migration background. There is a willingness to use services, and services embracing Turkish culture would help to reduce hesitance and make affected people feel more comfortable, thereby increasing utilization and satisfaction. A limitation of this study is that participants were already connected to health services, which may not reflect the help-seeking behavior of those in the Turkish community who are not involved in healthcare. Show more

Keywords: Dementia, healthcare, healthcare services, migration, Turkish migration background, utilization

DOI: 10.3233/JAD-200184

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 865-875, 2020

Authors: González, Andrea | Guzmán-Martínez, Leonardo | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Background: A major drawback in Alzheimer’s disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau® , based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. Objective: To analyze a potential novel source of antigen for Alz-tau® , plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. Methods: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by …western blot with this novel monoclonal antibody. Results: The HMW/LMWtau ratio was statistically different between AD patients and controls. Conclusions: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD. Show more

Keywords: Alz-tau®, Alzheimer’s disease, HMW/LMWtau ratio, monoclonal antibodies, peripheral biomarkers, tau protein in the human plasma

DOI: 10.3233/JAD-200386

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 877-883, 2020

Authors: Lepper, Simon | Rädke, Anika | Wehrmann, Hannah | Michalowsky, Bernhard | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Treatment decisions based on guidelines rather than patients’ preferences determine adherence to and compliance with treatment, which, in turn, could improve health-related outcomes. Objectives: To summarize the stated treatment and care preferences of people with dementia (PwD). Methods: A systematic review was conducted to assess the stated preferences of PwD. The inclusion criterion was the use of quantitative methods to elicit stated preferences, enabling a ranking of preferences. Results: Eleven studies revealed preferences for diagnostics, treatment decisions, patient-related outcomes, care services, end-of-life care, leisure activities, and digital life story work. PwDs prefer accurate, …pain-free, and comfortable diagnostic procedures without radioactive markers as well as being accompanied by a caregiver. PwD’s quality of life (QoL), self-efficacy, and depression were equally most important for PwD and caregivers. However, PwD memory was only important for caregivers but not for PwD, and caregiver QoL was moderately important for PwD but least important for caregivers. Additionally, comfort and family involvement were most important for patients’ end-of-life care, whereas caregivers most preferred good communication and pain management. Also, preferences depend on the living situation: Patients living not alone prefer a regular care provider most, whereas those living alone only want to live nearby the caregiver. Preferences for leisure activities did not differ between past and present ratings, indicating that PwD prefer activities that have always been carried out. Conclusion: Only a few studies have applied quantitative methods to elicit the preferences of PwD. More research is needed to capture the stated preferences for the treatment, care, and support of PwD to improve health-related outcomes and the allocation of healthcare resources. Show more

Keywords: Dementia, decision making, patient outcome assessment, patient preference

DOI: 10.3233/JAD-191299

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 885-901, 2020

Authors: Sheng, Can | Yang, Kun | Wang, Xiaoni | Li, Hongyan | Li, Taoran | Lin, Li | Liu, Yi | Yang, Qin | Wang, Xiaoqi | Wang, Xue | Sun, Yu | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Currently, given the lack of effective and curable pharmacological treatments for AD, non-pharmacological interventions (NPIs) for individuals with SCD may provide a valuable opportunity for the secondary prevention of AD. Objective: This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to investigate the benefits of current NPIs in the population with SCD. Methods: The online electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, PsycInfo, and CINAHL, were searched to identify randomized controlled trials …of NPIs for SCD. Intervention strategies were psychological and health-related education interventions, mind-body therapy, lifestyle modification, cognitive training, and multidomain interventions. Outcomes included subjective memory, objective memory, global cognitive function, psychological well-being, and mood. Study quality was determined using the criteria of the Cochrane collaboration’s tool. The Hedges’ g of change was analyzed. Results: Eighteen studies were included in this review and meta-analysis. Overall, psychological and health-related education interventions exhibited a medium effect on objective memory function (Hedges’ g  = 0.53, p  = 0.01). Cognitive training led to a small effect on objective memory, which was marginal statistically (Hedges’ g  = 0.19, p  = 0.05). In addition, cognitive training also significantly improved subjective memory performance (Hedges’ g  = 0.49, p  = 0.0003) and psychological well-being (Hedges’ g  = 0.27, p  = 0.03). Conclusion: Overall, the psychological intervention and cognitive training may be beneficial to cognitive function and psychological well-being. NPIs may be effectively implemented in older adults with SCD. Show more

Keywords: Alzheimer’s disease, cognitive training, intervention, lifestyle, non-pharmacological, psychological, subjective cognitive decline

DOI: 10.3233/JAD-191295

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 903-920, 2020

Article Type: Book Review

DOI: 10.3233/JAD-201012

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 921-921, 2020