Journal of Alzheimer's Disease - Volume 80, issue 3

Authors: Galle, Sara | Licher, Silvan | Milders, Maarten | Deijen, Jan Berend | Scherder, Erik | Drent, Madeleine | Ikram, Arfan | van Duijn, Cornelia M.

Article Type: Research Article

Abstract: Background: Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer’s disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. Objective: In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. Methods: Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia …was assessed from baseline (1997–1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. Results: During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer’s disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95%CI 0.84–1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p  = 0.002), smoking (B = 0.08, SE = 0.01, p  = < 0.001), and female sex (B = 0.03, SE = 0.01, p  = 0.03), but not with physical activity level (B = –0.01, SE = 0.01, p  = 0.06). Conclusion: The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia. Show more

Keywords: Aging, Alzheimer’s disease, brain-derived neurotropic factor, dementia, genetic epidemiology

DOI: 10.3233/JAD-200371

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1139-1149, 2021

Authors: Hinteregger, Barbara | Loeffler, Tina | Flunkert, Stefanie | Neddens, Joerg | Bayer, Thomas A. | Madl, Tobias | Hutter-Paier, Birgit

Article Type: Research Article

Abstract: Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: …We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development. Show more

Keywords: Alzheimer’s disease, behavior, biomarkers, neuronal degeneration, neuroinflammation, nuclear magnetic resonance

DOI: 10.3233/JAD-201204

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1151-1168, 2021

Authors: Lopis, Desirée | Le Pape, Thibault | Manetta, Céline | Conty, Laurence

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic, neurodegenerative disease resulting in a progressive decline of autobiographical memories (AMs) which favors the development of psycho-behavioral disorders. One of the most popular psychosocial interventions in dementia care, Reminiscence Therapy, commonly uses sensory cueing to stimulate AMs retrieval. However, few empirical studies have investigated the impact of sensory stimulation on AMs retrieval in AD. Objective: Our goal was to determine the most relevant cue for AMs retrieval in patients with early to mild AD when comparing odors, sounds and pictures. Methods: Sixty AD patients, 60 healthy older adults …(OA), and 60 healthy young adults (YA) participated in our study. Participants were presented with either 4 odors, 4 sounds, or 4 pictures. For each stimulus, they were asked to retrieve a personal memory, to rate it across 3 dimensions (emotionality, vividness, rarity) and then to date it. Results: Overall, results showed no clear dominance of one sensory modality over the others in evoking higher-quality AMs. However, they show that using pictures is the better way to stimulate AD patients’ AM, as it helps to retrieve a higher number of memories that are also less frequently retrieved, followed by odors. By contrast, auditory cueing with environmental sounds presented no true advantage. Conclusion: Our data should help dementia care professionals to increase the efficiency of Reminiscence Therapy using sensory elicitors. Other clinical implications and future directions are also discussed. Show more

Keywords: Alzheimer’s disease, autobiographical memory, Reminiscence Therapy, sensory cueing

DOI: 10.3233/JAD-200841

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1169-1183, 2021

Authors: Chapman, Silvia | Sunderaraman, Preeti | Joyce, Jillian L. | Azar, Martina | Colvin, Leigh E. | Barker, Megan S. | McKeague, Ian | Kreisl, William C. | Cosentino, Stephanie

Article Type: Research Article

Abstract: Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n  = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and …a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p  < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= –0.22, p  = 0.040, CI = –0.45, –0.01), associative memory (β= –0.26, p  = 0.018, CI = –0.45, –0.06), and list learning (β= –0.31, p  = 0.002, CI = –0.51, –0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= –0.25, p  = 0.012, CI = –0.44, –0.06; β= –0.29, p  = 0.003, CI = –0.47, –0.10) and list learning only (β= –0.25, p  = 0.014, CI = –0.45, –0.05; β= –0.28, p  = 0.004, CI = –0.48, –0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD. Show more

Keywords: Cognitive dysfunction, measurement, neuropsychological tests, preclinical Alzheimer’s disease, subjective cognitive decline, task-specific factors

DOI: 10.3233/JAD-201322

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1185-1196, 2021

Authors: Kim, Soyeon | Kim, Kiwon | Nho, Kwangsik | Myung, Woojae | Won, Hong-Hee

Article Type: Research Article

Abstract: Background: Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer’s disease (LOAD) is causal remains unclear. Objective: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. Methods: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ1–42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the …genetically predicted CSF biomarkers and LOAD risk. Results: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87×10–3 for AD; 95%confidence interval [CI], 1.54×10–4 –0.05; p  = 8.91×10–5 ). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50–2.52×102 ; p  = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57–7.29×102 ; p  = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). Conclusion: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, tau

DOI: 10.3233/JAD-200671

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1197-1207, 2021

Authors: Huang, Chuan | Kritikos, Minos | Clouston, Sean A.P. | Deri, Yael | Serrano-Sosa, Mario | Bangiyev, Lev | Santiago-Michels, Stephanie | Gandy, Sam | Sano, Mary | Bromet, Evelyn J. | Luft, Benjamin J.

Article Type: Research Article

Abstract: Background: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife. Objective: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders. Methods: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen’s Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry …examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas. Results: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning. Conclusions: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, diffusion spectrum imaging, incident mild cognitive impairment, midlife, white matter connectivity, World Trade Center responders

DOI: 10.3233/JAD-201237

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1209-1219, 2021

Authors: Shiner, Tamara | Mirelman, Anat | Rosenblum, Yevgenia | Kavé, Gitit | Weisz, Mali Gana | Bar-Shira, Anat | Goldstein, Orly | Thaler, Avner | Gurevich, Tanya | Orr-Urtreger, Avi | Giladi, Nir | Bregman, Noa

Article Type: Research Article

Abstract: Background: Glucocerebrosidase (GBA ) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. Objective: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. Methods: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. Results: Thirty-two (32%) patients with DLB were carriers of …GBA mutations and 33 (33%) carried an APOE ɛ4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p  = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p  < 0.005), and more severe parkinsonism as assessed with the Unified Parkinson’s Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p  = 0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE ɛ4 allele (n  = 9) had more severe cognitive (p  = 0.048) and motor dysfunction (p  = 0.037). Conclusion: We found a high frequency of both GBA mutations and the APOE ɛ4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination. Show more

Keywords: Apolipoprotein, dementia, glucocerebrosidase, Lewy body disease, parkinsonism

DOI: 10.3233/JAD-201295

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1221-1229, 2021

Authors: Jenkins, Amy | Tree, Jeremy | Tales, Andrea

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is increasingly recognized in both the clinical and research arenas as a risk factor for mild cognitive impairment (MCI) and dementia. Although SCD is etiologically heterogeneous and potentially treatable, in comparison to MCI and Alzheimer’s disease, SCD remains poorly characterized with its clinical relevance often questioned. Objective: This study’s aim was to improve the characterization of SCD within the general public. Methods: Individuals with SCD were compared to those without via a battery of measures. Results: Both the SCD and the non-SCD group correlational analysis identified significant relationships between …worse SCD, worse metacognitive dysfunction, negative affective symptoms, and greater levels of stress. The SCD group displayed additional correlational relationships between Cognitive Change Index (Self report) (CCI-S) scores, higher neuroticism scores, and poorer quality of life (QoL). Partial correlation analysis in the SCD group suggests CCI-S scores, anxiety, depression, and metacognition are intercorrelated. Ad hoc analyses using metacognition as the grouping variable found that those experiencing worse metacognitive dysfunction were significantly more likely to experience poorer SCD, psychological and social QoL, greater levels of anxiety, depression, stress, and neuroticism. Conclusion: The emerging pattern from the analysis indicates that SCD appears associated with sub-clinical negative affective difficulties, metacognitive, and other psycho-social issues, and poorer QoL. Dysfunctional cognitive control at a meta-level may impact someone’s ability to rationally identify cognitive changes, increase worry about cognitive changes, and allow such changes to impact their lives more than those with superior metacognitive control. Findings could impact SCD assessment, monitoring, early intervention, and ultimately reducing risk of further decline. Show more

Keywords: Alzheimer’s disease, anxiety, dementia, depression, metacognition, neuroticism, quality of life, stress, subjective cognitive decline

DOI: 10.3233/JAD-200882

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1231-1242, 2021

Authors: Ryman, Sephira G. | Yutsis, Maya | Tian, Lu | Henderson, Victor W. | Montine, Thomas J. | Salmon, David P. | Galasko, Douglas | Poston, Kathleen L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology. Objective: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD. Methods: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer’s Coordinating Center’s Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical). …Results: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage. Conclusion: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases. Show more

Keywords: Alzheimer’s disease, cognitive neuropsychology in dementia, dementia with Lewy bodies, Parkinson’s disease, Parkinson’s disease with dementia, parkinsonism

DOI: 10.3233/JAD-201187

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1243-1256, 2021

Authors: Liu, Xiaolei | Chen, Xinjie | Zhou, Xianbo | Shang, Yajun | Xu, Fan | Zhang, Junyan | He, Jingfang | Zhao, Feng | Du, Bo | Wang, Xuan | Zhang, Qi | Zhang, Weishan | Bergeron, Michael F. | Ding, Tao | Ashford, J. Wesson | Zhong, Lianmei

Article Type: Research Article

Abstract: Background: A valid, reliable, accessible, engaging, and affordable digital cognitive screen instrument for clinical use is in urgent demand. Objective: To assess the clinical utility of the MemTrax memory test for early detection of cognitive impairment in a Chinese cohort. Methods: The 2.5-minute MemTrax and the Montreal Cognitive Assessment (MoCA) were performed by 50 clinically diagnosed cognitively normal (CON), 50 mild cognitive impairment due to AD (MCI-AD), and 50 Alzheimer’s disease (AD) volunteer participants. The percentage of correct responses (MTx-% C), the mean response time (MTx-RT), and the composite scores (MTx-Cp) of MemTrax and the MoCA …scores were comparatively analyzed and receiver operating characteristic (ROC) curves generated. Results: Multivariate linear regression analyses indicated MTx-% C, MTx-Cp, and the MoCA score were significantly lower in MCI-AD versus CON and in AD versus MCI-AD groups (all with p ≤0.001). For the differentiation of MCI-AD from CON, an optimized MTx-% C cutoff of 81% had 72% sensitivity and 84% specificity with an area under the curve (AUC) of 0.839, whereas the MoCA score of 23 had 54% sensitivity and 86% specificity with an AUC of 0.740. For the differentiation of AD from MCI-AD, MTx-Cp of 43.0 had 70% sensitivity and 82% specificity with an AUC of 0.799, whereas the MoCA score of 20 had 84% sensitivity and 62% specificity with an AUC of 0.767. Conclusion: MemTrax can effectively detect both clinically diagnosed MCI and AD with better accuracy as compared to the MoCA based on AUCs in a Chinese cohort. Show more

Keywords: Alzheimer’s disease, cognitive assessment instrument, continuous recognition task paradigm, mild cognitive impairment

DOI: 10.3233/JAD-200936

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1257-1267, 2021