Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

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. Pre-press, no. Pre-press, pp. 1-20, 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. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Pereiro, Arturo Xosé | Valladares-Rodriguez, 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. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Fernández, Gerardo | Parra, Mario A.

Article Type: Research Article

Abstract: Background: Biological information drawn from eye-tracking metrics is providing evidence regarding drivers of cognitive decline in Alzheimer’s disease. In particular, pupil size has proved useful to investigate cognitive performance during online activities. Objective: To investigate the oculomotor correlates of impaired performance of patients with mild Alzheimer’s Clinical Syndrome (ACS) on a recently developed memory paradigm, namely the Short-Term Memory Binding Test (STMBT). Methods: We assessed a sample of eighteen healthy controls (HC) and eighteen patients with a diagnosis of mild ACS with the STMBT while we recorded their oculomotor behaviors using pupillometry and eye-tracking. …Results: As expected, a group (healthy controls versus ACS) by condition (Unbound Colours versus Bound Colours) interaction was found whereby behavioral group differences were paramount in the Bound Colours condition. Healthy controls’ pupils dilated significantly more in the Bound Colours than in the Unbound Colours condition, a discrepancy not observed in ACS patients. Furthermore, ROC analysis revealed the abnormal pupil behaviors distinguished ACS patients from healthy controls with values of sensitivity and specify of 100%, thus outperforming both recognition scores and gaze duration. Conclusion: The biological correlates of Short-Term Memory Binding impairments appear to involve a network much wider than we have thought to date, which expands across cortical and subcortical structures. We discuss these findings focusing on their implications for our understanding of neurocognitive phenotypes in the preclinical stages of Alzheimer’s disease and potential development of cognitive biomarkers that can support ongoing initiatives to prevent dementia. Show more

Keywords: Alzheimer’s disease, eye-tracking, gaze duration, pupil behavior, short-term memory binding test

DOI: 10.3233/JAD-201189

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: François, Maxime | Karpe, Avinash | Liu, Jian-Wei | Beale, David | Hor, Maryam | Hecker, Jane | Faunt, Jeff | Maddison, John | Johns, Sally | Doecke, James | Rose, Stephen | Leifert, Wayne R.

Article Type: Research Article

Abstract: Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted …utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. Conclusion: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters. Show more

Keywords: Alzheimer’s disease, metabolomics, multi-omics integration, proteomics, saliva, systems biology

DOI: 10.3233/JAD-210283

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Umegaki, Hiroyuki | Suzuki, Yusuke | Komiya, Hitoshi | Watanabe, Kazuhisa | Yamada, Yosuke | Nagae, Masaaki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Few studies have investigated associations between types of clock drawing test (CDT) errors and cognitive impairment. Objective: To explore associations of qualitative errors in the CDT with comprehensive neurocognitive assessment scores and clinical diagnosis. Methods: Outpatients at a memory clinic were enrolled. Frequencies of errors determined by Cahn’s method were explored according to cognitive status (cognitively normal [CN] (n  = 279), mild cognitive impairment [MCI] (n  = 321), and Alzheimer’s disease [AD]) (n  = 575). Neuropsychological assessment scores were compared between participants with and without errors. Results: Stimulus-bound response (SB) was relatively rare (6.8%) in the …CN group but was markedly more common in the MCI (23.4%) and AD (33.2%) groups. Conceptual deficit (CD) was found in more than 20%of CN individuals, as well as about 50%of AD patients. Planning deficit (PD) frequencies were relatively similar among the groups. SB in both of CN and MCI individuals, and CD in both of CN and MCI individuals were associated with lower scores in several neuropsychological assessments. Meanwhile, PD was not associated with lower assessment scores in any of CN, MCI, or AD individuals. Conclusion: The frequencies of SB and CD increased from CN, MCI, to AD but showed somewhat different patterns. Both SB and CD were associated with lower cognition in all three cognitive stages. Show more

Keywords: Alzheimer’s disease, executive function, memory clinic, mild cognitive impairment, neuropsychological assessments

DOI: 10.3233/JAD-210456

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Pilotto, Andrea | Imarisio, Alberto | Carrarini, Claudia | Russo, Mirella | Masciocchi, Stefano | Gipponi, Stefano | Cottini, Elisabetta | Aarsland, Dag | Zetterberg, Henrik | Ashton, Nicholas J. | Hye, Abdul | Bonanni, Laura | Padovani, Alessandro

Article Type: Short Communication

Abstract: Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from …the early stages of DLB. Show more

Keywords: Biomarkers, cognitive progression, dementia with Lewy bodies, neurofilament light chain

DOI: 10.3233/JAD-210342

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Akushevich, Igor | Yashkin, Arseniy P. | Kravchenko, Julia | Yashin, Anatoliy I.

Article Type: Research Article

Abstract: Background: Understanding the dynamics of epidemiologic trends in Alzheimer’s disease (AD) and related dementias (ADRD) and their epidemiologic causes is vital to providing important insights into reducing the burden associated with these conditions. Objective: To model the time trends in age-adjusted AD/ADRD prevalence and incidence-based mortality (IBM), and identify the main causes of the changes in these measures over time in terms of interpretable epidemiologic quantities. Methods: Trend decomposition was applied to a 5%sample of Medicare beneficiaries between 1991 and 2017. Results: Prevalence of AD was increasing between 1992 and 2011 and declining thereafter, …while IBM increased over the study period with a significant slowdown in its rate of growth from 2011 onwards. For ADRD, prevalence and IBM increased through 2014 prior to taking a downwards turn. The primary determinant responsible for declines in prevalence and IBM was the deceleration in the increase and eventual decrease in incidence rates though changes in relative survival began to affect the overall trends in prevalence/IBM in a noticeable manner after 2008. Other components showed only minor effects. Conclusion: The prevalence and IBM of ADRD is expected to continue to decrease. The directions of these trends for AD are not clear because AD incidence, the main contributing component, is decreasing but at a decreasing rate suggesting a possible reversal. Furthermore, emerging treatments may contribute through their effects on survival. Improving ascertainment of AD played an important role in trends of AD/ADRD over the 1991-2009/10 period but this effect has exhausted itself by 2017. Show more

Keywords: Alzheimer’s disease, decomposition, dementia, incidence, Medicare, partitioning, relative survival, time trends

DOI: 10.3233/JAD-210273

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-12, 2021

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. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Qu, Mingyue | Shi, Hanxu | Wang, Kai | Wang, Xinggang | Yu, Nan | Guo, Baoshi

Article Type: Research Article

Abstract: Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with …95%confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95%CI: –1.67 to –0.05, p  = 0.04) and zeaxanthin (SMD = –0.59; 95%CI: –1.12 to –0.06, p  = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95%CI: –0.68 to 0.26, p  = 0.39), β-carotene (SMD = 0.04, 95%CI: –0.57 to 0.65, p  = 0.9), lycopene (SMD = –0.12, 95%CI: –0.96 to 0.72, p  = 0.78), and β-cryptoxanthin (SMD = –0.09, 95%CI: –0.83 to 0.65, p  = 0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings. Show more

Keywords: Alzheimer’s disease, carotenes, carotenoids, xanthophylls

DOI: 10.3233/JAD-210384

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Wang, Zuo-Teng | Li, Kun-Yan | Tan, Chen-Chen | Xu, Wei | Shen, Xue-Ning | Cao, Xi-Peng | Wang, Ping | Bi, Yan-Lin | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between alcohol consumption and Alzheimer’s disease (AD) pathology is unclear. Amyloid-β (Aβ) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. Objective: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. Methods: A total of 806 cognitively intact participants who had measurements of CSF Aβ, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol …consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE ) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers. Results: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (<  1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aβ 42 and tTau/Aβ42 . Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (>  65 years) participants. Conclusion: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage. Show more

Keywords: Alcohol consumption, Alzheimer’s disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, tau proteins

DOI: 10.3233/JAD-210140

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Babiloni, Claudio | Ferri, Raffaele | Noce, Giuseppe | Lizio, Roberta | Lopez, Susanna | Lorenzo, Ivan | Tucci, Federico | Soricelli, Andrea | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Cipollini, Virginia | Marizzoni, Moira | Güntekin, Bahar | Aktürk, Tuba | Hanoğlu, Lutfu | Yener, Görsev | Özbek, Yağmur | Stocchi, Fabrizio | Vacca, Laura | Frisoni, Giovanni B. | Del Percio, Claudio

Article Type: Research Article

Abstract: Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8–13 Hz). Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8–12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI). Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, …and alpha frequency bands, as well as fixed beta (14–30 Hz) and gamma (30–40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles). Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores. Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD. Show more

Keywords: Aging, exact Low-resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-201271

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 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 HAMD and AVLT-R 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. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Espay, Alberto J. | Sturchio, Andrea | Schneider, Lon S. | Ezzat, Kariem

Article Type: Research Article

Abstract: Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid …code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, clinico-pathologic, disease modification, precision medicine, neuroprotection

DOI: 10.3233/JAD-210415

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Lourenco, Mychael V. | Ribeiro, Felipe C. | Santos, Luis E. | Beckman, Danielle | Melo, Helen M. | Sudo, Felipe K. | Drummond, Cláudia | Assunção, Naima | Vanderborght, Bart | Tovar-Moll, Fernanda | De Felice, Fernanda G. | Mattos, Paulo | Ferreira, Sergio T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD …CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cytokines, homovanillic acid, inflammation, Lewy body disease, neurotransmitters, noradrenaline, vascular endothelial growth factor.

DOI: 10.3233/JAD-210147

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Castillo-Mendieta, Tzayaka | Arana-Lechuga, Yoaly | Campos-Peña, Victoria | Sosa, Ana Luisa | Orozco-Suarez, Sandra | Pinto-Almazán, Rodolfo | Segura-Uribe, Julia | Javier Rodríguez-Sánchez de Tagle, Aldo | Ruiz-Sánchez, Elizabeth | Guerra-Araiza, Christian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) causes memory deficit and alterations in other cognitive functions, mainly in adults over 60 years of age. As the diagnosis confirmation is performed by a postmortem neuropathological examination of the brain, this disease can be confused with other types of dementia at early stages. About 860,000 Mexicans are affected by dementia, most of them with insufficient access to adequate comprehensive health care services. Plasma biomarkers could be a rapid option for early diagnosis of the disease. Objective: This study aimed to analyze some plasma biomarkers (amyloid-β , tau, and lipids) in Mexican AD patients …and control subjects with no associated neurodegenerative diseases. Methods: Plasma amyloid-β peptides (Aβ 40 and Aβ 42 ), total and phosphorylated tau protein (T-tau and P-tau), and cholesterol and triglyceride levels were quantified enzyme-linked immunosorbent assay in AD patients and control subjects. Results: In Mexican AD patients, we found significantly lower levels of Aβ 42 (p  <  0.05) compared to the control group. In contrast, significantly higher levels of P-tau (p  <  0.05) and triglycerides (p  <  0.05) were observed in AD patients compared to controls. Furthermore, a significant correlation was found between the severity of dementia and plasma P-tau levels, Aβ 42 /Aβ 40 and P-tau/T-tau ratios, and triglycerides concentrations. This correlation increased gradually with cognitive decline. Conclusion: The detection of these plasma biomarkers is an initial step in searching for a timely, less invasive, and cost-efficient diagnosis in Mexicans. Show more

Keywords: Alzheimer’s disease, amyloid-β, early diagnosis, Mexican patients, tau protein

DOI: 10.3233/JAD-200912

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Won, Junyeon | Callow, Daniel D. | S. Pena, Gabriel | Jordan, Leslie S. | Arnold-Nedimala, Naomi A. | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Exercise training (ET) has neuroprotective effects in the hippocampus, a key brain region for memory that is vulnerable to age-related dysfunction. Objective: We investigated the effects of ET on functional connectivity (FC) of the hippocampus in older adults with mild cognitive impairment (MCI) and a cognitively normal (CN) control group. We also assessed whether the ET-induced changes in hippocampal FC (Δhippocampal-FC) are associated with changes in memory task performance (Δmemory performance). Methods: 32 older adults (77.0±7.6 years; 16 MCI and 16 CN) participated in the present study. Cardiorespiratory fitness tests, memory tasks (Rey Auditory Verbal …Learning Test (RAVLT) and Logical Memory Test (LM)), and resting-state fMRI were administered before and after a 12-week walking ET intervention. We utilized a seed-based correlation analysis using the bilateral anterior and posterior hippocampi as priori seed regions of interest. The associations of residualized ET-induced Δhippocampal-FC and Δmemory performance were assessed using linear regression. Results: There were significant improvements in RAVLT Trial 1 and LM test performance after ET across participants. At baseline, MCI, compared to CN, demonstrated significantly lower posterior hippocampal FC. ET was associated with increased hippocampal FC across groups. Greater ET-related anterior and posterior hippocampal FC with right posterior cingulate were associated with improved LM recognition performance in MCI participants. Conclusion: Our findings indicate that hippocampal FC is significantly increased following 12-weeks of ET in older adults and, moreover, suggest that increased hippocampal FC may reflect neural network plasticity associated with ET-related improvements in memory performance in individuals diagnosed with MCI. Show more

Keywords: Exercise training, functional connectivity, hippocampus, memory, mild cognitive impairment, older adults

DOI: 10.3233/JAD-210051

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Watanabe, Kazuhisa | Umegaki, Hiroyuki | Sugimoto, Taiki | Fujisawa, Chisato | Komiya, Hitoshi | Nagae, Masaaki | Yamada, Yosuke | Kuzuya, Masafumi | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Polypharmacy, usually defined as the use of 5 or more drugs, is associated with reduced quality of life, adverse events, and frailty. Slow gait speed is a component of physical frailty, and some studies have suggested an association between polypharmacy and slow gait speed. Objective: We aimed to determine the effects of polypharmacy on the gait difference according to stages of cognitive decline in a cross-sectional study of memory clinic patients. Methods: Participants were 431 outpatients aged 65 year or older who were cognitively normal (CN) or had mild cognitive impairment (MCI) or Alzheimer’s disease. …Participants were divided into a polypharmacy group and a non-polypharmacy group in each group. Multiple regression analysis and logistic analysis were used for data analysis. Results: There were 182 patients in the polypharmacy group and 249 patients in the non-polypharmacy group. Multiple regression analysis revealed that gait speed had significant negative associations with number of medications and polypharmacy status in the CN group (β: –0.026 [–0.041 to –0.0018] and –0.128 [–0.022 to –0.0033], respectively) and MCI group (–0.018 [–0.028 to –0.0009] and –0.100 [–0.166 to –0.0034]). Logistic regression analysis also showed that number of medications was associated with slow gait status (<  1 m/s) in the CN group (OR: 1.336 [1.115 to 1.601]) and MCI group (1.128 [1.022 to 1.244]). Conclusion: CN and MCI patients with polypharmacy have slower gait speed. Attention should be paid to decreased gait speed in older adults with polypharmacy even when their cognitive function is relatively preserved. Show more

Keywords: Alzheimer’s disease, cross-sectional study, gait speed, older adults, outpatient clinic, polypharmacy

DOI: 10.3233/JAD-201601

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Tsoy, Elena | Sideman, Alissa Bernstein | Piña Escudero, Stefanie D. | Pintado-Caipa, Maritza | Kanjanapong, Suchanan | Al-Rousan, Tala | Mbakile-Mahlanza, Lingani | de Oliveira, Maira Okada | De la Cruz Puebla, Myriam | Zygouris, Stelios | Mohamed, Aya Ashour | Ibrahim, Hany | Goode, Collette A. | Miller, Bruce L. | Valcour, Victor | Possin, Katherine L.

Article Type: Research Article

Abstract: Background: Timely diagnosis of dementia is a global healthcare priority, particularly in low to middle income countries where rapid increases in older adult populations are expected. Objective: To investigate global perspectives on the role of brief cognitive assessments (BCAs) in dementia diagnosis, strengths and limitations of existing measures, and future directions and needs. Methods: This is a qualitative study of 18 dementia experts from different areas of the world. Participants were selected using purposeful sampling based on the following criteria: 1) practicing in countries with projected growth of older adult population of over 100%by 2050; 2) …expertise in dementia diagnosis and treatment; 3) involvement in clinical practice and training; and 4) recognition as a national dementia expert based on leadership positions within healthcare system, research, and/or policy work. Participants were individually interviewed in their language of choice over secure videoconference sessions. Interviews were analyzed by a multidisciplinary team using theme identification approach. Results: Four domains with subthemes emerged illustrating participants’ perspectives: 1) strengths of BCAs; 2) limitations of BCAs; 3) needs related to the use of BCAs; and 4) characteristics of an ideal BCA. While most experts agreed that BCAs were important and useful for dementia diagnosis, the themes emphasized the need for development and validation of novel measures that are sensitive, psychometrically sound, and culturally appropriate. Conclusion: BCAs are important for guiding diagnosis and care for dementia patients. Findings provide a roadmap for novel BCA development to assist in diagnostic decision making for clinicians serving a rapidly growing and diverse dementia population. Show more

Keywords: Alzheimer’s disease, cultural diversity, dementia, mental status and dementia tests, mild cognitive impairment

DOI: 10.3233/JAD-201403

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Yamada, Yosuke | Umegaki, Hiroyuki | Kinoshita, Fumie | Huang, Chi Hsien | Sugimoto, Taiki | Fujisawa, Chisato | Komiya, Hitoshi | Watanabe, Kazuhisa | Nagae, Masaaki | Kuzuya, Masafumi | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Homocysteine is a common risk factor for cognitive impairment and sarcopenia. However, very few studies have shown an association between sarcopenia and serum homocysteine levels after adjustment for cognitive function. Objective: The purpose of this study was to investigate the relationship between homocysteine and sarcopenia in memory clinic patients. Methods: This cross-sectional study investigated outpatients in a memory clinic. We enrolled 1,774 participants (≥65 years old) with measured skeletal muscle mass index (SMI), hand grip strength (HGS), and homocysteine. All participants had undergone cognitive assessments and were diagnosed with dementia, mild cognitive impairment, or normal …cognition. Patient characteristics were compared according to sarcopenia presence, SMI level, or HGS. Multivariate logistic regression analysis was performed to determine the association of homocysteine with sarcopenia, low SMI, or low HGS. Next, linear regression analysis was performed using HGS as a continuous variable. Results: Logistic regression analysis showed that low HGS was significantly associated with homocysteine levels (p  = 0.002), but sarcopenia and low SMI were not. In linear regression analysis, HGS was negatively associated with homocysteine levels after adjustment for Mini-Mental State Examination score (β= –2.790, p  <  0.001) or clinical diagnosis of dementia (β= –3.145, p  <  0.001). These results were similar for men and women. Conclusion: Our results showed a negative association between homocysteine and HGS after adjustment for cognitive function. Our findings strengthen the assumed association between homocysteine and HGS. Further research is needed to determine whether lower homocysteine levels lead to prevent muscle weakness. Show more

Keywords: Cognitive impairment, hand grip strength, homocysteine, sarcopenia

DOI: 10.3233/JAD-210083

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Samara, Myrto | Levine, Stephen Z. | Yoshida, Kazufumi | Goldberg, Yair | Cipriani, Andrea | Efthimiou, Orestis | Iwatsubo, Takeshi | Leucht, Stefan | Furakawa, Toshiaki A.

Article Type: Research Article

Abstract: Background: In patients with Alzheimer’s disease, global assessment scales, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Clinician’s Interview-Based Impression Plus Caregiver Input (CIBI plus), and the Clinical Global Impression (CGI) are commonly used. Objective: To clinically understand and interpret the associations between these scales, we examined the linkages for the total and change scores of CDR-SB, CIBI plus, and CGI. Methods: Individual participant data (N = 2,198) from five pivotal randomized placebo-controlled trials of donepezil were included. Data were collected at baseline and scheduled visits for up to 6 months. Spearman’s correlation coefficients ρ were examined …between corresponding total and change scores of simultaneous CDR-SB, CIBI plus, and CGI ratings. To link between the simultaneous ratings, equipercentile linking was used. Results: We found strong evidence that the Spearman’s correlation coefficients between the CDR-SB and CGI, and CDR-SB and CIBI plus total scores were at least adequately correlated (ρ = 0.50 to 0.71, with p  <  0.01). The correlation coefficients between the change scores of CDR-SB and CGI were deemed adequate for weeks 6 to 24 (ρ = 0.44 to 0.65); the remaining correlations were smaller in magnitude (ρ = 0.09 to 0.35). Overall, the linkages were in-line with expectations, e.g., CDR-SB range score of 3-4 (= very mild dementia) was linked to a CGI score of 3 (= mildly ill), and an increase of CDR-SB of 1 was linked to a change of 5 (= minimal worsening) in both CGI and CIBI plus. Conclusion: The study findings can be useful for clinicians wishing to compare scores of different scales across patients. They can also help researchers understand results of studies using different scales and can facilitate meta-analyses, to increase statistical power. Show more

Keywords: Alzheimer’s disease, clinical dementia rating-sum of boxes, clinical global impression, clinician’s interview-based impression of change, clinician’s interview-based impression of severity, global ratings, minimal clinically important difference

DOI: 10.3233/JAD-201541

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Darmanthé, Nicolas | Tabatabaei-Jafari, Hossein | Cherbuin, Nicolas | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) are at high risk of progression to Alzheimer’s disease (AD) dementia, but some remain stable. There is a need to identify those at higher risk of progression to improve patient management and outcomes. Objective: To evaluate the trajectory of plasma neurofilament light chain (pNFL) prior to progression from MCI to AD dementia, the performance of pNFL, in combination with the Mini-Mental State Examination (MMSE), as a predictor of progression from MCI to AD dementia and to inform clinicians on the use of pNFL as a predictive biomarker. Methods: Participants …(n  = 440) with MCI and longitudinal follow-up (mean = 4.2 years) from the AD Neuroimaging Initiative dataset were included. pNFL as a marker for neurodegeneration and the MMSE as a cognitive measure were investigated as simple/practical predictors of progression. The risk of progressing from MCI to AD dementia associated with pNFL and MMSE scores was assessed using Cox and logistic regression models. Results: The current risk of progression to AD dementia was 37%higher in individuals with high pNFL (>  56 ng/L) compared to those with average pNFL (≤40 ng/L). A combination of baseline pNFL and MMSE could differentiate those who progressed within 5 years (AUC = 0.75) from stable individuals. Including change in MMSE over 6-12 months further improved the model (AUC = 0.84). Conclusion: Our findings reveal that combining pNFL with a simple dementia screener (MMSE) can reliably predict whether a person with MCI is likely to progress to AD dementia within 5 years. Show more

Keywords: Alzheimer’s disease, clinical progression, mild cognitive impairment, neurofilament, plasma biomarkers

DOI: 10.3233/JAD-210092

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Kvello-Alme, Marte | Bråthen, Geir | White, Linda R. | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer’s disease is associated with a substantial diagnostic delay in patients <  65 years. Objective: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer’s disease in central Norway. Methods: The main sources of patients were the databases at the Department of Neurology, University Hospital of …Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. Results: Time from first symptom to diagnosis in typical young onset Alzheimer’s disease was 5.5 years (n  = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). Conclusion: Typical Alzheimer’s disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer’s disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process. Show more

Keywords: Clinical characteristics, delayed diagnosis, diagnosis, early onset Alzheimer’s disease, early onset dementia, young onset dementia

DOI: 10.3233/JAD-210090

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Serra, Laura | D’Amelio, Marcello | Esposito, Sharon | Domenico, Carlotta Di | Koch, Giacomo | Marra, Camillo | Mercuri, Nicola Biagio | Caltagirone, Carlo | Artusi, Carlo Alberto | Lopiano, Leonardo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (RS-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and RS-fMRI to assess VTA connectivity at baseline and at follow-up. …Results: At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, dopaminergic system, functional connectivity, restingstate MRI, ventral tegmental area

DOI: 10.3233/JAD-210171

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Stoiljkovic, Milan | Gutierrez, Karel Otero | Kelley, Craig | Horvath, Tamas L. | Hajós, Mihály

Article Type: Research Article

Abstract: Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Objective: Our …aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Methods: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Results: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Conclusion: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations. Show more

Keywords: Alzheimer’s disease, hippocampus, microglia, theta oscillation, seizure, TREM2

DOI: 10.3233/JAD-210041

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: González-Alcaide, Gregorio | Fernández-Ríos, Mercedes | Redolat, Rosa | Serra, Emilia

Article Type: Research Article

Abstract: Background: The study of emotion recognition could be crucial for detecting alterations in certain cognitive areas or as an early sign of neurological disorders. Objective: The main objective of the study is to characterize research development on emotion recognition, identifying the intellectual structure that supports this area of knowledge, and the main lines of research attracting investigators’ interest. Methods: We identified publications on emotion recognition and dementia included in the Web of Science Core Collection, analyzing the scientific output and main disciplines involved in generating knowledge in the area. A co-citation analysis and an analysis of …the bibliographic coupling between the retrieved documents elucidated the thematic orientations of the research and the reference works that constitute the foundation for development in the field. Results: A total of 345 documents, with 24,282 bibliographic references between them, were included. This is an emerging research area, attracting the interest of investigators in Neurosciences, Psychology, Clinical Neurology, and Psychiatry, among other disciplines. Four prominent topic areas were identified, linked to frontotemporal dementia, autism spectrum disorders, Alzheimer’s disease, and Parkinson’s and Huntington disease. Many recent papers focus on the detection of mild cognitive impairment. Conclusion: Impaired emotion recognition may be a key sign facilitating the diagnosis and early treatment of different neurodegenerative diseases as well as for triggering the necessary provision of social and family support, explaining the growing research interest in this area. Show more

Keywords: Alzheimer’s disease, bibliometrics, dementia, emotions, facial recognition, knowledge discovery

DOI: 10.3233/JAD-210096

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Richard Chen, X. | Shao, Yongzhao | Sadowski, Martin J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: APOE ɛ 4 allele carriers present with increased risk for late-onset Alzheimer’s disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ 4 allele controls the rate of disease progression. Objective: To determine effects of the ɛ 4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. Methods: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of …73 ɛ 3/ɛ 3, 99 ɛ 3/ɛ 4, and 39 ɛ 4/ɛ 4 Alzheimer’s Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. Results: ɛ 4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ 4 allele-dose effects after dementia transition but not during MCI. The ɛ 4 effect was more prevalent in younger participants and in females. ɛ 4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Conclusion: Possession of the ɛ 4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design. Show more

Keywords: Alzheimer disease, APOE, cognitive decline, linear mixed model, MRI

DOI: 10.3233/JAD-210434

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Ancelin, Marie-Laure | Norton, Joanna | Scali, Jacqueline | Ritchie, Karen | Chaudieu, Isabelle | Ryan, Joanne

Article Type: Short Communication

Abstract: Diurnal salivary cortisol was measured in 334 older adults without dementia, at four times on two separate days, under quiet and stressful conditions. In multivariate Cox proportional hazard models, higher global diurnal cortisol secretion was associated with incident dementia (HR = 1.09 [1.02–1.15] per one-unit increase in cortisol measure, p  = 0.007) and Alzheimer’s disease (HR = 1.12 [1.04–1.21], p  = 0.003) over a mean(SD) of 8.1(4.0) years, independent of potential confounders and stressful conditions. Individuals with incident dementia had a slower rate of cortisol elimination under non-stressful conditions, reflected by higher cortisol levels in the evening, and an abnormal response to stress (blunted evening stress …response). Show more

Keywords: Cortisol, dementia, hypothalamic-pituitary-adrenal axis, prospective study, stress

DOI: 10.3233/JAD-210389

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Covatti Malcorra, Bárbara Luzia | Mota, Natália Bezerra | Weissheimer, Janaina | Schilling, Lucas Porcello | Wilson, Maximiliano Agustin | Hübner, Lilian Cristine

Article Type: Short Communication

Abstract: Connected speech is an everyday activity. We aimed to investigate whether connected speech can differentiate oral narrative production between adults with Alzheimer’s disease (AD; n  = 24) and cognitively healthy older adults (n  = 48). We used graph attributes analysis to represent connected speech. Participants produced oral narratives and performed semantic, episodic, and working memory tasks. AD patients produced less connected narratives than cognitively healthy older adults. Connectedness was associated with semantic memory in AD and with episodic memory in controls. Word-graphs connectedness represents a practical tool to assess cognitive impairment in AD patients.

Keywords: Alzheimer’s disease, cognitive decline, graph theory, natural language processing, semantic memory

DOI: 10.3233/JAD-210134

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Spera, Vincenza | Sitnikova, Tatiana | Ward, Meredith J. | Farzam, Parya | Hughes, Jeremy | Gazecki, Samuel | Bui, Eric | Maiello, Marco | De Taboada, Luis | Hamblin, Michael R. | Franceschini, Maria Angela | Cassano, Paolo

Article Type: Research Article

Abstract: Background: Transcranial photobiomodulation (tPBM) has recently emerged as a potential cognitive enhancement technique and clinical treatment for various neuropsychiatric and neurodegenerative disorders by delivering invisible near-infrared light to the scalp and increasing energy metabolism in the brain. Objective: We assessed whether transcranial photobiomodulation with near-infrared light modulates cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). Methods: We conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM), and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBF using diffuse correlation spectroscopy (DCS) in a sample of ten healthy …subjects [6F/4 M; mean age 28.6±12.9 years]. c-tPBM near-infrared radiation (NIR) (830 nm; 54.8 mW/cm2 ; 65.8 J/cm2 ; 2.3 kJ) and p-tPBM (830 nm; 10 Hz; 54.8 mW/cm2 ; 33%; 21.7 J/cm2 ; 0.8 kJ) were delivered concurrently to the frontal areas by four LED clusters. EEG and DCS recordings were performed weekly before, during, and after each tPBM session. Results: c-tPBM significantly boosted gamma (t  = 3.02, df = 7, p  <  0.02) and beta (t  = 2.91, df = 7, p  <  0.03) EEG spectral powers in eyes-open recordings and gamma power (t  = 3.61, df = 6, p  <  0.015) in eyes-closed recordings, with a widespread increase over frontal-central scalp regions. There was no significant effect of tPBM on CBF compared to sham. Conclusion: Our data suggest a dose-dependent effect of tPBM with NIR on cerebral gamma and beta neuronal activity. Altogether, our findings support the neuromodulatory effect of transcranial NIR. Show more

Keywords: Cerebral blood flow, EEG oscillations, light-emitting diode, photobiomodulation, transcranial light therapy, transcranial near-infrared light

DOI: 10.3233/JAD-210058

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Zhao, Xuan | Li, Cancan | Ding, Guoyong | Heng, Yuanyuan | Li, An | Wang, Wei | Hou, Haifeng | Wen, Jun | Zhang, Yanbo

Article Type: Research Article

Abstract: Background: The increasing prevalence of Alzheimer’s disease (AD), along with the associated burden on healthcare systems, presents a substantial public health challenge. Objective: This study aimed to investigate trends in AD mortality and the relevant burden across the United States (U.S.) from 1999 to 2018 and to predict mortality trends between 2019 and 2023. Methods: Data on AD-related deaths between 1999 and 2018 were collected from the WONDER database administered by the U.S. Centers for Disease Control and Prevention (CDC). The Joinpoint Regression Program was used to analyze mortality trends due to AD. Years of life …lost (YLL) were calculated to explore the burden of AD deaths. An autoregressive integrated moving average (ARIMA) model was employed to forecast mortality trends from 2019 to 2023. Results: Over a recent 20-year period, the number of AD deaths in the U.S. increased from 44,536 (31,145 females and 13,391 males) to 122,019 (84,062 females and 37,957 males). The overall age-adjusted mortality rate increased from 16.5/100,000 in 1999 to 30.5/100,000 in 2018. AD mortality is projected to reach 42.40/100000 within the year 2023. Overall, AD resulted in 322,773.00 YLL (2.33 per 1000 population) in 1999 and 658,501.87 YLL (3.68 per 1000 population) in 2018. Conclusion: Our findings demonstrate an increase in AD mortality in the U.S. from 1999 to 2018 as well as a rapid increase from 2019 to 2023. The high burden of AD deaths emphasizes the need for targeted prevention, early diagnosis, and hierarchical management. Show more

Keywords: Alzheimer’s disease, mortality, time series analysis, years of life lost

DOI: 10.3233/JAD-210225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Paradela, Regina Silva | Ferreira, Naomi Vidal | Nucci, Mariana Penteado | Cabella, Brenno | Martino, Luiza Menoni | Torres, Laura Aló | Costa, Danielle Irigoyen da | Consolim-Colombo, Fernanda Marciano | Suemoto, Claudia Kimie | Irigoyen, Maria Claudia

Article Type: Research Article

Abstract: Background: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals. Objective: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals. Methods: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2%female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using …education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted. Results: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance. Conclusion: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension. Show more

Keywords: Brain volume, cognitive dysfunction, executive function, hypertension, neuroimaging, social determinants of health, white matter hyperintensities

DOI: 10.3233/JAD-210143

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Schoemaker, Dorothee | Velilla, Lina | Zuluaga, Yesica | Baena, Ana | Ospina, Carolina | Bocanegra, Yamile | Alvarez, Sergio | Ochoa-Escudero, Martin | Guzmán-Vélez, Edmarie | Martinez, Jairo | Lopera, Francisco | Arboleda-Velasquez, Joseph F. | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer’s disease and vascular dementia. Objective: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer’s disease and vascular dementia. Methods: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer’s disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts …and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. Results: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = –0.06, p  <  0.05) and an increased severity of cerebral microbleeds (B = 0.13, p  <  0.001), lacunes (B = 0.30, p  <  0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p  <  0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p  <  0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. Conclusion: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks. Show more

Keywords: Autosomal dominant Alzheimer’s disease, CADASIL, cardiovascular risk factors, cerebral small vessel disease, cognition, magnetic resonance imaging

DOI: 10.3233/JAD-210313

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Bullock-Saxton, Joanne | Lehn, Alexander | Laakso, E-Liisa

Article Type: Research Article

Abstract: Background: Neuroprotection against Parkinson’s disease degeneration by photobiomodulation has been reported in animal models but no true placebo-controlled human studies have been published. Objective: To understand if photobiomodulation therapy can produce clinically significant differences in physical performance measures in people with Parkinson’s disease; and what frequency of treatment is necessary to initiate clinical change. Methods: In a participant and assessor-blinded, randomized, placebo-controlled pilot study, 22 participants received either sham and/or active laser photobiomodulation (904 nm, 60 mW/diode, 50 Hz) for 33 s to each of 21 points at the cranium and intra-orally, on one, two or three times/week for …4 weeks. Two treatment phases were separated by a 4-week wash-out (Phase 2). Upper and lower limb physical outcome measures were assessed before and after each treatment phase. The Montreal Cognitive Assessment was evaluated prior to treatment Phase 1, and at the end of treatment Phase 3. Results: Montreal Cognitive Assessment remained stable between start and end of study. No measures demonstrated statistically significant changes. With regular treatment, the spiral (writing) test and the dynamic step test were most sensitive to change in a positive direction; and the 9-hole peg test demonstrated a minimum clinically important difference worthy of further investigation in a larger, adequately powered clinical trial. A placebo effect was noted. Conclusion: The results support the notion that combined transcranial and intra-oral photobiomodulation therapy needs to be applied at least 2 to 3 times per week for at least four weeks before some improvement in outcome measures becomes evident. Longer courses of treatment may be required. Show more

Keywords: Cognition, Parkinson’s disease, photobiomodulation, physical functional performance

DOI: 10.3233/JAD-210170

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Rao, K.S. Jagannatha | Britton, Gabrielle | Rocha Arrieta, Luisa Lilia | Garcia-Cairasco, Norberto | Lazarowski, Alberto | Palacios, Adrián | Camins Espuny, Antoni | Maccioni, Ricardo B.

Article Type: Research Article

DOI: 10.3233/JAD-210245

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Sewell, Margaret C. | Neugroschl, Judith | Umpierre, Mari | Chin, Shehan | Zhu, Carolyn W. | Velasco, Nelly | Gonzalez, Sabrina | Acabá-Berrocal, Alexandra | Bianchetti, Luca | Silva, Gabriela | Collazo, Alma | Sano, Mary

Article Type: Research Article

Abstract: Background: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research. Objective: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters. Methods: The video was created by the ADRC and CAB. All senior center attendees were eligible …to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers. Results: 74 in the “Historical Cohort 1” and 104 in “Intervention Cohort 2” were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p  <  0.05) after controlling for age, education, and country of origin. In response to the question “Has the video influenced your willingness and interest to participate in research”, 88.7%of the participants in Cohort 2 reported being “more” or “much more” interested in research. Conclusion: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research. Show more

Keywords: Attitudes towards research, diversity, elder minorities, minorities in research, research participation

DOI: 10.3233/JAD-210027

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Niu, Jiahui | Iqbal, Khalid | Liu, Fei | Hu, Wen

Article Type: Research Article

Abstract: Background: Women have a two-fold higher risk than men to Alzheimer’s disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. Objective: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. Methods: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. Results: We …detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190 , Ser387 , and Ser395 (Ser199 , Ser396 , and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253 , Ser387 , PHF-1 (Ser387/395 ), and Ser413 sites, which correspond to Ser262 , Ser396 , Ser396/404 , and Ser422 of human tau, respectively. Conclusion: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes. Show more

Keywords: Alzheimer’s disease, entorhinal cortex, gender, hippocampus, protein phosphorylation, tau expression, tau isoforms

DOI: 10.3233/JAD-210341

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Alú, Francesca | Orticoni, Alessandro | Judica, Elda | Cotelli, Maria | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Background: Most common progressive brain diseases in the elderly are Alzheimer’s disease (AD) and vascular dementia (VaD). They present with relatively similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms are different. Objective: The aim is to explore the brain connectivity differences between AD and VaD patients compared to mild cognitive impairment (MCI) and normal elderly (Nold) subjects applying graph theory, in particular the Small World (SW) analysis. Methods: 274 resting state EEGs were analyzed in 100 AD, 80 MCI, 40 VaD, and 54 Nold subjects. Graph theory analyses were applied to undirected and …weighted networks obtained by lagged linear coherence evaluated by eLORETA tool. Results: VaD and AD patients presented more ordered low frequency structure (lower value of SW) than Nold and MCI subjects, and more random organization (higher value of SW) in low and high frequency alpha rhythms. Differences between patients have been found in high frequency alpha rhythms in VaD (higher value of SW) with respect to AD, and in theta band with a trend which is more similar to MCI and Nold than to AD. MCI subjects presented a network organization which is intermediate, in low frequency bands, between Nold and patients. Conclusion: Graph theory applied to EEG data has proved very useful in identifying differences in brain network patterns in subjects with dementia, proving to be a valid tool for differential diagnosis. Future studies will aim to validate this method to diagnose especially in the early stages of the disease and at single subject level. Show more

Keywords: Brain networks, EEG, functional coupling, LORETA, Small World

DOI: 10.3233/JAD-210394

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Ponvel, Pavapriya | Shahar, Suzana | Singh, Devinder Kaur Ajit | Ludin, Arimi Fitri Mat | Rajikan, Roslee | Rajab, Nor Fadilah Hj | Ai-Vyrn, Chin | Din, Normah Che | Ibrahim, Norhayati | Subramaniam, Ponnusamy | Haron, Hasnah | Ismail, Aniza | Sharif, Razinah | Ramasamy, Kalavathy | Majeed, Abu Bakar Abdul | Ali, Nazlena Mohamad | Mohamad, Mazlyfarina | Noah, Shahrul Azman Mohd | Ibrahim, Azianah Mohd | Safien, Aisyah Mohd | Khalid, Norhayati Mustafa | Fadzil, Nurul Hidayah Md | Mangialasche, Francesca | Kivipelto, Miia

Article Type: Research Article

Abstract: Background: Cognitive frailty (CF) is identified as one of the main precursors of dementia. Multidomain intervention has been found to delay or prevent the onset of CF. Objective: The aim of our present study is to determine the effectiveness of a comprehensive, multidomain intervention on CF; to evaluate its cost effectiveness and the factors influencing adherence toward this intensive intervention. Methods: A total of 1,000 community dwelling older adults, aged 60 years and above will be screened for CF. This randomized controlled trial involves recruitment of 327 older adults with CF from urban, semi-urban, and rural …areas in Malaysia. Multidomain intervention comprised of physical, nutritional, cognitive, and psychosocial aspects will be provided to participants in the experimental group (n  = 164). The control group (n  = 164) will continue their usual care with their physician. Primary outcomes include CF status, physical function, psychosocial and nutritional status as well as cognitive performance. Vascular health and gut microbiome will be assessed using blood and stool samples. A 24-month intensive intervention will be prescribed to the participants and its sustainability will be assessed for the following 12 months. The effective intervention strategies will be integrated as a personalized telerehabilitation package for the reversal of CF for future use. Results: The multidomain intervention developed from this trial is expected to be cost effective compared to usual care as well as able to reverse CF. Conclusion: This project will be part of the World-Wide FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) Network, of which common identifiable data will be shared and harmonized among the consortia. Show more

Keywords: Cognitive frailty, multidomain intervention, older adults, randomized control trial, reversal

DOI: 10.3233/JAD-201607

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Melo van Lent, Debora | O’Donnell, Adrienne | Beiser, Alexa S. | Vasan, Ramachandran S. | DeCarli, Charles S. | Scarmeas, Nikolaos | Wagner, Michael | Jacques, Paul F. | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Research Article

Abstract: Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy. Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study. Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and …7), cognitive testing at examination cycle 7 (present study baseline: 1998–2001) and after a mean±SD of 6.6±1.1 years from baseline (n  = 1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n  = 1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses. Results: Higher MIND diet scores were associated with better global cognitive function (β±SE,+0.03SD±0.01; p  = 0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, SBIs) or cognitive decline. Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline. Show more

Keywords: Apolipoprotein ɛ4, brain volume, cognition, dietary pattern, framingham heart study, MIND diet, silent brain infarcts

DOI: 10.3233/JAD-201238

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Svensson, Johan | Blomqvist, Maria | Kettunen, Petronella | Eckerström, Carl | Henricsson, Marcus | Jonsson, Michael | Bjerke, Maria | Månsson, Jan-Eric | Wallin, Anders

Article Type: Research Article

Abstract: Background: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. Objective: To study the diagnostic utility of CSF ST levels in SSVD. Methods: This was a mono-center, cross-sectional study of SSVD (n  = 16), Alzheimer’s disease (n  = 40), mixed dementia (n  = 27), and healthy controls (n  = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass …spectrometry (LC-MS/MS). Results: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r  = 0.64, p  <  0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r  = 0.30, p  <  0.05), but it did not correlate with CSF NFL level. Conclusion: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, mixed dementia, sulfatide species, sulfatides, subcortical small vessel type of dementia, white matter hyperintensities

DOI: 10.3233/JAD-201552

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Greco, Frank A. | McKee, Ann C. | Kowall, Neil W. | Hanlon, Eugene B.

Article Type: Research Article

Abstract: Background: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer’s disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need. Objective: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy. Methods: NIR spectra were acquired in …vivo . Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished “AD-alone” (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases. Results: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2). Conclusion: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo . A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, data analysis, mild cognitive impairment, near-infrared spectroscopy

DOI: 10.3233/JAD-201021

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Borg, Céline | Rouch, Isabelle | Pongan, Elodie | Getenet, Jean Claude | Bachelet, Romain | Herrmann, Mathieu | Bohec, Anne-Lise | Laurent, Bernard | COVCARE Group, | Rey, Romain | Dorey, Jean-Michel

Article Type: Research Article

Abstract: Background: People with dementia (PWD) and their caregivers are populations highly vulnerable to COVID-19 pandemic and its consequences. A better knowledge of the living conditions during the first lockdown is necessary to prevent the risk of poor mental health (PMH) in this population. Objective: The present study aimed to compare the mental health of caregivers of PWD living at home or in nursing-homes and to identify specific factors influencing their mental health. Methods: We conducted an anonymous cross-sectional online survey in France from March 17 to May 11, 2020. Three hundred and eighty-nine caregivers accompanying a …PWD living at home (HC) and 159 accompanying a PWD living in a nursing home (NHC) participated in the study. Caregivers’ mental health including anxiety, depression, stress, and burden was assessed with self-reported standardized scales. Results: Half of the caregivers exhibited PMH, including depression, anxiety, or self-reported stress. Similar PMH rates were provided whatever the PWD place of residence. Regarding HC, our results also highlighted a number of risk factors for PMH, including the fact that caregiver live with PWD, to give increased support to PWD, and to feel more isolated for managing PWD since lockdown. Conclusion: PMH was observed for caregivers of PWD during lockdown, whatever PWD living place, suggesting that concern for PWD may explain more of caregiver distress than increased material tasks. In the future, it will be necessary to pay attention to caregivers after the crisis by estimating the longer-term impact on their mental health. Show more

Keywords: Alzheimer’s disease, caregivers, COVID-19, dementia, lockdown, mental health

DOI: 10.3233/JAD-210079

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Ben Ayed, Ines | Castor-Guyonvarch, Naomie | Amimour, Souad | Naija, Salma | Aouichaoui, Chirine | Ben Omor, Sana | Tabka, Zouhair | El Massioui, Farid

Article Type: Research Article

Abstract: Background: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer’s disease (ADM) patients. Objective: Evaluating the effect of AAE on cognitive functions in ADM patients. Methods: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted …of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants’ cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks. Results: After the exercise, the participants’ attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session. Conclusion: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients. Show more

Keywords: Aerobic exercises, Alzheimer disease, attention, solving problem, working memory

DOI: 10.3233/JAD-201317

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Callahan, Brandy L. | McLaren-Gradinaru, Michael | Burles, Ford | Iaria, Giuseppe

Article Type: Research Article

Abstract: Background: Older adults with bipolar disorder (BD) have increased dementia risk, but signs of dementia are difficult to detect in the context of pre-existing deficits inherent to BD. Objective: To identify the emergence of indicators of early dementia in BD. Methods: One hundred and fifty-nine non-demented adults with BD from the National Alzheimer Coordinating Center (NACC) data repository underwent annual neuropsychological assessment up to 14 years (54.0 months average follow-up). Cognitive performance was examined longitudinally with linear mixed-effects models, and yearly differences between incident dementia and controls cases were examined in the six years prior to …diagnosis. Results: Forty participants (25.2%) developed dementia over the follow-up period (‘incident cases’). Alzheimer’s disease was the most common presumed etiology, though this was likely a result of sampling biases within NACC. Incident cases showed declining trajectories in memory, language, and speeded attention two years prior to dementia onset. Conclusion: In a sample of BD patients enriched for Alzheimer’s type dementia, prodromal dementia in BD can be detected up to two years before onset using the same cognitive tests used in psychiatrically-healthy older adults (i.e., measures of verbal recall and fluency). Cognition in the natural course of BD is generally stable, and impairment or marked decline on measures of verbal episodic memory or semantic retrieval may indicate an early neurodegenerative process. Show more

Keywords: Aging, cognitive dysfunction, neuropsychology, psychiatry

DOI: 10.3233/JAD-201240

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Korpioja, Anita | Krüger, Johanna | Koivuluoma, Susanna | Pylkäs, Katri | Moilanen, Virpi | Helisalmi, Seppo | Hiltunen, Mikko | Remes, Anne M.

Article Type: Research Article

Abstract: Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1 variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290 * ) and eight missense variants …in SORL1 . This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD. Show more

Keywords: Dementia, early onset Alzheimer’s disease, gene, human, mutation, neurodegenerative disease, single nucleotide polymorphism, SORL1

DOI: 10.3233/JAD-210207

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Makino, Taeko | Umegaki, Hiroyuki | Ando, Masahiko | Cheng, Xian Wu | Ishida, Koji | Akima, Hiroshi | Oshida, Yoshiharu | Yoshida, Yasuko | Uemura, Kazuki | Shimada, Hiroyuki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Physical exercise is suggested to be effective for preventing cognitive decline in older adults, but the relative efficacy of different types of exercise have yet to be clarified. Objective: This single-blinded randomized controlled trial was designed to investigate the differential effects of aerobic exercise training (AT), resistance exercise training (RT), and combined exercise training (CT) on cognition in older adults with subjective memory complaints (SMC). Methods: Community-dwelling older adults with SMC (n  = 415; mean age = 72.3 years old) were randomly assigned to one of the four groups: AT, RT, CT, or control group. The study consisted …of two phases: a 26-week intervention and a 26-week follow-up. The participants were evaluated at baseline, 26 weeks (postintervention), and 52 weeks (follow-up). The primary outcome of this study was memory function, which was assessed using the Logical Memory II subtest of the Wechsler Memory Scale-Revised (WMS-R) score. The secondary outcomes included global cognitive function, verbal fluency, working memory, processing speed, and executive functions. Results: Intention-to-treat analysis by a mixed-effect model repeated measure showed that the AT group had significantly improved performance on the WMS-R Logical Memory II test (2.74 [1.82–3.66] points) than the control group (1.36 [0.44–2.28] points) at the postintervention assessment (p  = 0.037). The effect was more pronounced in those without amnesia than those with amnesia. No significant improvement was observed in the RT and CT groups. Conclusion: This study suggests that AT intervention can improve delayed memory in community-dwelling older adults, particularly in individuals without objective memory decline. Show more

Keywords: Amnesia, cognition, cognitive dysfunction, executive function, exercise, memory, physical activity, randomized controlled trial, resistance training, wechsler memory scale

DOI: 10.3233/JAD-210047

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021