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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210530

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-201567

Citation: Journal of Alzheimer's Disease, vol. 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