Journal of Alzheimer's Disease - Volume 82, issue 3

Authors: Klooster, Nathaniel | Humphries, Stacey | Cardillo, Eileen | Hartung, Franziska | Xie, Long | Das, Sandhitsu | Yushkevich, Paul | Pilania, Arun | Wang, Jieqiong | Wolk, David A. | Chatterjee, Anjan

Article Type: Research Article

Abstract: Background: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer’s disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. Objective: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. …Methods: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. Results: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. Conclusion: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention. Show more

Keywords: Alzheimer’s disease, figurative language, medial temporal lobe, mild cognitive impairment, perirhinal cortex, semantic memory

DOI: 10.3233/JAD-201280

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1123-1136, 2021

Authors: Ni, Lianghui | Zhao, Mingyan | Hu, Zhishan | Yang, Kun | Zhao, Xing | Niu, Haijing | Lin, Hua

Article Type: Research Article

Abstract: Background: A growing awareness about non-pharmacological intervention for cognitively impaired individuals may represent an alternative therapeutic approach that is actively accepted by patients with very early stage of Alzheimer’s disease. Understanding the neural basis of non-pharmacological intervention is a crucial step toward wide use for patients with cognitive disorders. Objective: To investigate the underlying neural mechanism of shentai tea polyphenols in subjects with subjective cognitive decline (SCD) using functional near-infrared spectroscopy (fNIRS). Methods: A total number of 36 patients with SCD participated in the study and received supplementation with shentai tea polyphenols for three months. All …participants underwent a series of tests on neuropsychological function and fNIRS assessment during n-back tasks at baseline and follow-up. Results: After intervention with shentai tea polyphenols in SCD, increased cerebral activity was observed in left dorsolateral prefrontal cortex (DLPFC), left premotor cortex (PMC), left primary somatosensory cortex (PSC), right inferior frontal gyrus (IFG), and premotor cortex (PMC). Moreover, shentai tea polyphenols intervention of three months significantly improved SCD subjects’ cognitive functions (memory, language, and subjective cognitive ability) and depression condition. We further found that the improvement of Hamilton Depression Rating Scale and Auditory Verbal Learning Test-recognition scores had positive correlations with increased brain activity in right IFG and left DLPFC, respectively. Conclusion: This study provides new evidence that the frontal cortex was found to be specifically activated after non-pharmacological intervention of shentai tea polyphenols in SCD, which may be associated with cognitive enhancement and mental wellbeing. These findings provide important implications for the selection of shentai tea polyphenols interventions for SCD. Show more

Keywords: Functional near-infrared spectroscopy, non-pharmacological intervention, shentai tea polyphenols, subjective cognitive decline

DOI: 10.3233/JAD-210469

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1137-1145, 2021

Authors: Chang, Yu-Ling | Zhuo, Yi-Yuan | Luo, Di-Hua

Article Type: Research Article

Abstract: Background: Studies have reported that apolipoprotein E epsilon 4 (APOE ɛ4) has adverse effects on executive functions (EFs) in late adulthood. However, the results have been inconsistent. Insufficient measurements of executive functioning, uncontrolled clinical and demographic confounders, and moderation effects from other environmental factors are suspected to account for the inconsistency. Objective: This study used aggregate measures to examine the effects of APOE ɛ4 on four components of EFs, namely switching, working memory, inhibition, and reasoning. We further investigated whether high educational attainment, a proxy measure for cognitive reserve, moderates the adverse effects of ɛ4 on …EFs. Methods: Cognitively unimpaired older participants were divided into groups based on APOE genotype and into subgroups based on educational attainment level. The demographic and clinical variables were matched between the groups. Four core components of the EFs were measured using a relatively comprehensive battery. Results: The results revealed that although no main effect of the APOE genotype was observed across the four EF components, the potentially adverse effects of ɛ4 on inhibition were alleviated by high educational attainment. A main effect of education on the reasoning component was also observed. The moderation analysis revealed that for older adults with 12 years of education or fewer, the relationship between the APOE ɛ4 genotype and inhibition performance became increasingly negative. Conclusion: This study highlights the distinctive role of response inhibition in the gene–environment interaction and underlines the importance of considering factors of both nature and nurture to understand the complex process of cognitive aging. Show more

Keywords: Apolipoproteins E, cognitive aging, cognitive reserve, education, executive function

DOI: 10.3233/JAD-210183

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1147-1157, 2021

Authors: Xia, Mingxu | Su, Ya | Fu, Jiayu | Xu, Jiajie | Wang, Qiong | Gao, Feng | Shen, Yong | Dong, Qiang | Cheng, Xin

Article Type: Research Article

Abstract: Background: Neuroimaging has played a primary role in predicting intracerebral hemorrhage (ICH) recurrence of cerebral amyloid angiopathy (CAA); however, the utilities of biomarkers in CAA-related ICH and cognitive impairment remain unexplored. Objective: To investigate the correlations of serum levels of matrix metalloproteinase-2 (MMP-2), MMP-3, and MMP-9 with CAA-related MRI markers, ICH recurrence, and cognitive status. Methods: 68 cases with first probable CAA-ICH and 69 controls were recruited. Clinical and imaging data were obtained at baseline and serum MMPs in the acute phase were measured by Luminex multiplex assays. Cognitive status was assessed with the Chinese version …of Mini-Mental State Examination within 10–14 days after ICH onset. Results: Serum MMP-2 level was significantly lower in CAA-ICH patients than controls while MMP-9 was significantly higher. In CAA-ICH patients, MMP-3 level was significantly associated with lobar cerebral microbleeds count after adjusting age, sex, and hypertension (adjusted coefficient 0.368, 95%CI 0.099–0.637, p  = 0.008). During a median follow-up of 2.4 years, higher level of MMP-2 predicted lower CAA-ICH recurrence after adjusting age (adjusted HR 0.326, 95%CI 0.122–0.871, p  = 0.025), ICH volume (adjusted HR 0.259, 95%CI 0.094–0.715, p  = 0.009), total MRI burden of SVD score (adjusted HR 0.350, 95%CI 0.131–0.936, p  = 0.037) respectively. Besides, higher level of MMP-2 was significantly associated with decreased risk of cognitive impairment independent of age and ICH volume (adjusted OR 0.054, 95%CI 0.005–0.570, p  = 0.015). Conclusion: Serum MMP-2 in acute phase might be a promising biomarker to predict CAA-ICH recurrence and to evaluate the risk of cognitive impairment. Show more

Keywords: Cerebral amyloid angiopathy, cognitive impairment, cerebral microbleeds, intracerebral hemorrhage, matrix metalloproteinases

DOI: 10.3233/JAD-210288

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1159-1170, 2021

Authors: Herd, Pamela | Sicinski, Kamil | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: There is a robust consensus, most recently articulated in the 2020 Lancet Commission, that the roots of dementia can be traced to early life, and that the path to prevention may start there as well. Indeed, a growing body of research demonstrates that early life disadvantage may influence the risk for later life dementia and cognitive decline. A still understudied risk, however, is early life rural residence, a plausible pathway given related economic and educational disadvantages, as well as associations between later life rural living and lower levels of cognitive functioning. Objective: We aim to examine whether …living in rural environments during early life has long term implications for cognitive health in later life. Methods: We employed the Wisconsin Longitudinal Study, which tracked 1 in every 3 high school graduates from the class of 1957, from infancy to ∼age 72. The data include a rich array of prospectively collected early life data, unique among existing studies, as well as later life measures of cognitive functioning. Results: We found a robust relationship between early life rural residence, especially living on a farm, and long-term risk for reduced cognitive performance on recall and fluency tasks. Controls for adolescent cognitive functioning, APOE ɛ 2 and APOE ɛ 4, as well as childhood and adult factors, ranging from early life socioeconomic conditions to later life health and rural and farm residency, did not alter the findings. Conclusion: Rural living in early life is an independent risk for lower levels of cognitive functioning in later life. Show more

Keywords: Aging, cognitive function, early life, rural, socioeconomic status

DOI: 10.3233/JAD-210224

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1171-1182, 2021

Authors: Paulo, Sara L. | Ribeiro-Rodrigues, Leonor | Rodrigues, Rui S. | Mateus, Joana M. | Fonseca-Gomes, João | Soares, Rita | Diógenes, Maria J. | Solá, Susana | Sebastião, Ana M. | Ribeiro, Filipa F. | Xapelli, Sara

Article Type: Research Article

Abstract: Background: The use of Alzheimer’s disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. Objective: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42 ). Methods: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, …tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration. Results: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. Conclusion: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, behavior, hippocampal plasticity, memory

DOI: 10.3233/JAD-201567

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1183-1202, 2021

Authors: Stickel, Ariana M. | Tarraf, Wassim | Gonzalez, Kevin A. | Isasi, Carmen R. | Kaplan, Robert | Gallo, Linda C. | Zeng, Donglin | Cai, Jianwen | Pirzada, Amber | Daviglus, Martha L. | Goodman, Zachary T. | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: The relationships between obesity and cognitive decline in aging are mixed and understudied among Hispanics/Latinos. Objective: To understand associations between central obesity, cognitive aging, and the role of concomitant cardiometabolic abnormalities among Hispanics/Latinos. Methods: Participants included 6,377 diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation for Neurocognitive Aging (SOL-INCA). Participants were 45 years and older at the first cognitive testing session (Visit 1). Cognitive outcomes (z-score units) included global composite and domain specific (learning, memory, executive functioning, processing speed) measures at a second visit (SOL-INCA, on average, 7 years …later), and 7-year change. We used survey linear regression to examine associations between central obesity (waist circumference≥88 cm and≥102 cm for women and men, respectively) and cognition. We also tested whether the relationships between obesity and cognition differed by cardiometabolic status (indication of/treatment for 2 + of the following: high triglycerides, hypertension, hyperglycemia, low high-density lipoprotein cholesterol). Results: Central obesity was largely unassociated with cognitive outcomes, adjusting for covariates. However, among individuals with central obesity, cardiometabolic abnormality was linked to poorer cognitive function at SOL-INCA (ΔGlobalCognition  =–0.165, p  < 0.001) and to more pronounced cognitive declines over the average 7 years (ΔGlobalCognition  = –0.109, p  < 0.05); this was consistent across cognitive domains. Conclusion: Central obesity alone was not associated with cognitive function. However, presence of both central obesity and cardiometabolic abnormalities was robustly predictive of cognition and 7-year cognitive declines, suggesting that in combination these factors may alter the cognitive trajectories of middle-aged and older Hispanics/Latinos. Show more

Keywords: Aging, cardiometabolic risk factors, cognition, diabetes mellitus, Hispanics, hyperlipidemias, hypertension, Latinos, obesity

DOI: 10.3233/JAD-210314

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1203-1218, 2021

Authors: Talbot, Louise A. | Thomas, Margaret | Bauman, Adrian | Manera, Karine E. | Smith, Ben J.

Article Type: Research Article

Abstract: Background: The number of people living with dementia is rising globally due to population aging. Mass media campaigns which aim to reduce the risk of people developing dementia have been conducted across many countries, but few have reported evaluation findings. Objective: The present study investigated the impact of the Your Brain Matters dementia risk reduction campaign in Australia. Methods: The campaign was evaluated by observational cross-sectional surveys of 1000 Australian adults aged 18–75 years before and 24 months after delivery. The national campaign utilized multiple media channels to promote messages about the importance of brain …health and reducing the risk of dementia. Dementia risk reduction knowledge, confidence, intentions and actions were measured at baseline and follow-up, and analyzed 2019–2020. Results: Earned television and radio were the most common exposure channels. The proportion of people who understood that it is beneficial to take action to reduce dementia risk before middle age increased (54.1% to 59.4%, OR 1.20 95% CI: 1.01–1.44). There was also an increase (28.5% to 32.8%, OR 1.30, 95% CI: 1.07–1.59) in the proportion who reported taking action to improve brain health. There was no improvement in knowledge about vascular risk factors, or confidence to reduce personal dementia risk. Conclusion: The findings showed some receptivity and positive responses to messages about the benefits of taking action to reduce the risk of dementia. The campaign demonstrated the potential for generating news coverage about this issue, which should highlight the preventive benefits of vascular health behaviors. Show more

Keywords: Alzheimer’s disease, dementia, dementia vascular, health behavior, healthy lifestyle

DOI: 10.3233/JAD-210317

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1219-1228, 2021

Authors: Pereiro, Arturo Xosé | Valladares-Rodríguez, Sonia | Felpete, Alba | Lojo-Seoane, Cristina | Campos-Magdaleno, María | Mallo, Sabela Carme | Facal, David | Anido-Rifón, Luis | Belleville, Sylvie | Juncos-Rabadán, Onésimo

Article Type: Research Article

Abstract: Background: The presence of subjective cognitive complaints (SCCs) is a core criterion for diagnosis of subjective cognitive decline (SCD); however, no standard procedure for distinguishing normative and non-normative SCCs has yet been established. Objective: To determine whether differentiation of participants with SCD according to SCC severity improves the validity of the prediction of progression in SCD and MCI and to explore validity metrics for two extreme thresholds of the distribution in scores in a questionnaire on SCCs. Methods: Two hundred and fifty-three older adults with SCCs participating in the Compostela Aging Study (CompAS) were classified as …MCI or SCD at baseline. The participants underwent two follow-up assessments and were classified as cognitively stable or worsened. Severity of SCCs (low and high) in SCD was established by using two different percentiles of the questionnaire score distribution as cut-off points. The validity of these cut-off points for predicting progression using socio-demographic, health, and neuropsychological variables was tested by machine learning (ML) analysis. Results: Severity of SCCs in SCD established considering the 5th percentile as a cut-off point proved to be the best metric for predicting progression. The variables with the main role in conforming the predictive algorithm were those related to memory, cognitive reserve, general health, and the stability of diagnosis over time. Conclusion: Moderate to high complainers showed an increased probability of progression in cognitive decline, suggesting the clinical relevance of standard procedures to determine SCC severity. Our findings highlight the important role of the multimodal ML approach in predicting progression. Show more

Keywords: Cognitive dysfunction, dementia, diagnosis, follow-up studies

DOI: 10.3233/JAD-210334

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1229-1242, 2021

Authors: Targum, Steven D. | Fosdick, Lisa | Drake, Kristen E. | Rosenberg, Paul B. | Burke, Anna D. | Wolk, David A. | Foote, Kelly D. | Asaad, Wael F. | Sabbagh, Marwan | Smith, Gwenn S. | Lozano, Andres M. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Background: Age may affect treatment outcome in trials of mild probable Alzheimer’s disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (“on”) or sham DBS-f (“off”) for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the “on” and “off” groups in the intent to treat (ITT) population. There was a …significant age by time interaction with the Alzheimer’s Disease Assessment Scale; ADAS-cog-13 (p  = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p  = 0.005). While not significant, post-hoc analyses favored DBS-f “off” versus “on” over 12 months in the < 65 age group but favored DBS-f “on” versus “off” in the≥65 age group on all clinical metrics. On the integrated Alzheimer’s Disease rating scale (iADRS), the effect size contrasting DBS-f “on” versus “off” changed from +0.2 (favoring “off”) in the < 65 group to –0.52 (favoring “on”) in the≥65 age group. Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials. Show more

Keywords: Age, Alzheimer’s disease, deep brain stimulation, clinical trials, subject selection

DOI: 10.3233/JAD-210530

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1243-1257, 2021