Journal of Alzheimer's Disease - Volume 96, issue 3

Authors: Köhler, Sebastian | Soons, Lion M. | Tange, Huibert | Deckers, Kay | van Boxtel, Martin P.J.

Article Type: Research Article

Abstract: Background: Sleep disturbances have been linked with cognitive decline and a higher risk of dementia. However, there is a lack of studies with sufficient follow-up duration, a detailed neuropsychological assessment and adequate control of main confounders. Objective: To investigate the relation between self-reported sleep quality and cognitive decline over 12 years in cognitively healthy individuals from the general population. Methods: We used data from the Maastricht Aging Study (MAAS), a Dutch population-based prospective cohort study of 1,823 community-dwelling adults aged 24 to 82 years at baseline. Cognitive performance was measured at baseline, 6 and 12 years …on verbal memory, executive functions, and information processing speed. Sleep quality was assessed at baseline using the sleep subscale score of the 90-item Symptom Checklist (SCL-90). Additional modifiable dementia risk factors were summarized in the LIfestyle for BRAin health (LIBRA) risk score. Weighted linear mixed models tested the association between continuous scores and tertiles of subjective sleep quality and change in cognitive performances over time. Models were adjusted for age, gender, educational level, LIBRA, and use of hypnotic (sleep) medication. Results: Worse sleep quality was associated with faster decline in processing speed. At older age (≥65 years), it was also associated with faster decline in verbal memory. Association were independent of other modifiable dementia risk factors and use of hypnotic medication. Directionally similar but non-significant associations were found between worse sleep quality and executive functions. Conclusions: In this population-based study across the adult age range, poor self-reported sleep was associated with accelerated cognitive decline. Show more

Keywords: Adult, aging, Alzheimer’s disease, cognitive function, lifestyle, risk factors, sleep quality

DOI: 10.3233/JAD-230213

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1041-1049, 2023

Authors: Chwa, Won Jong | Raji, Cyrus A. | Toups, Kat | Hathaway, Ann | Gordon, Deborah | Chung, Henrianna | Boyd, Alan | Hill, Benjamin D. | Hausman-Cohen, Sharon | Attarha, Mouna | Jarrett, Michael | Bredesen, Dale E.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. Objective: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). Methods: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with …AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. Results: Montreal Cognitive Assessment scores (p  < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons. Show more

DOI: 10.3233/JAD-230481

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1051-1058, 2023

Authors: Lu, Jiajie | Huang, Rihong | Peng, Yuecheng | Zhang, Jinming | Liang, Kairong | Wang, Yezhong | Feng, Yi | Wang, Zhaotao

Article Type: Research Article

Abstract: Background: The coronavirus disease 2019 (COVID-19) has been a major challenge to global health and a financial burden. Little is known regarding the possible causal effects of COVID-19 on the macro- and micro-structures of the human brain. Objective: To determine the causal links between susceptibility, hospitalization, and the severity of COVID-19 and brain imaging-derived phenotypes (IDPs). Methods: Mendelian randomization (MR) analyses were performed to investigate the causal effect of three COVID-19 exposures (SARS-CoV-2 infection, hospitalized COVID-19, and critical COVID-19) on brain structure employing summary datasets of genome-wide association studies. Results: In terms of cortical …phenotypes, hospitalization due to COVID-19 was associated with a global decrease in the surface area (SA) of the cortex structure (β= –624.77, 95% CI: –1227.88 to –21.66, p  = 0.042). At the regional level, SARS-CoV-2 infection was found to have a nominally causal effect on the thickness (TH) of the postcentral region (β= –0.004, 95% CI: –0.007 to –0.001, p  = 0.01), as well as eight other IDPs. Hospitalized COVID-19 has a nominally causal relationship with TH of postcentral (β= –0.004, 95% CI: –0.007 to –0.001, p  = 0.01) and other 6 IDPs. The nominally causal effects of critical COVID-19 on TH of medial orbitofrontal (β=0.004, 95% CI: 0.001to 0.007, p  = 0.004) and other 7 IDPs were revealed. Conclusions: Our study provides compelling genetic evidence supporting causal relationships between three COVID-19 traits and brain IDPs. This discovery holds promise for enhancing predictions and interventions in brain imaging. Show more

Keywords: Alzheimer’s disease, brain structure, COVID-19, Mendelian randomization

DOI: 10.3233/JAD-230626

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1059-1070, 2023

Authors: Zhou, Jie | Wang, Zhi-Bo | Sun, Yan | Fu, Yan | Li, Da | Tan, Lan

Article Type: Research Article

Abstract: Background: Numerous studies have shown that the complement system plays an important role in Alzheimer’s disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with AD pathology, especially in the early stage of AD, is still unclear. Objective: We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD. Methods: The study included a total of 287 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 …in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely Aβ42 , P-tau, and T-tau. Results: The level of CSF C4 decreased in the A + T- group compared with the A-T- group (p  = 0.04) and it increased in the A-T+ group compared to the A + T- group (p  = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p  < 0.05), but only in the A + group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes. Conclusions: Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain Aβ pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, complement 4, tau

DOI: 10.3233/JAD-230513

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1071-1081, 2023

Authors: Mendes, Aline | Bergh, Sverre | Cesana, Bruno Mario | Handels, Ron | Ciccone, Alfonso | Cognat, Emmanuel | Fabbo, Andrea | Fascendini, Sara | Frisoni, Giovanni B. | Froelich, Lutz | Jori, Maria Cristina | Mecocci, Patrizia | Merlo, Paola | Peters, Oliver | Tsolaki, Magdalini | Defanti, Carlo Alberto

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) bring complexity in the clinical management of people with dementia; therefore, it is important to evaluate different models of care, such as Special Care Units (SCU-B).∥ Objective: To evaluate the SCU-B effectiveness toward alleviating BPSD and improving the quality of life (QoL) of patients and their caregivers.∥ Methods: ReCAGE was a multicenter, controlled, longitudinal study where 508 patients with BPSD were enrolled in two cohorts: 262 patients from centers endowed with a SCU-B, and 246 from centers without SCU-B. Statistical analyses included factorial ANCOVA for comparison among centers. …The primary endpoint was effectiveness of the SCU-B, measured through the Neuropsychiatric Inventory (NPI) changes. Secondary endpoints were change in QoL of patients and caregivers, and the tertiary endpoint was time to nursing home admission.∥ Results: The NPI scores decreased in both arms, with a statistically significant difference from baseline to 36 months (p  < 0.0001) in both cohorts. Over time, NPI decreased more steeply during the first year in the SCU-B arm, but in the following two years the slope was clearly in favor of the control arm. This different pattern of the two cohorts reached statistical significance at the interaction “cohort by time” (p  < 0.0001). Conflicting results were found regarding the outcomes of quality of life, while there were no differences in time to institutionalization in both cohorts.∥ Conclusion: The RECage study did not confirm the long-term superiority of the pathway comprising a SCU-B. A post-hoc analysis revealed data supporting their acute effectiveness during behavioral crises. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, caregiver burden, dementia, Neuropsychiatric Inventory, special care unit

DOI: 10.3233/JAD-230708

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1083-1096, 2023

Authors: Brosens, Niek | Samouil, Dimitris | Stolker, Sabine | Katsika, Efthymia Vasilina | Weggen, Sascha | Lucassen, Paul J. | Krugers, Harm J.

Article Type: Research Article

Abstract: Background: Exposure to stress early in life increases the susceptibility to Alzheimer’s disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have remained elusive. Objective: To investigate 1) effects of early life stress (ELS) on early functional signs that precede the advanced neuropathological changes, and 2) correlate synaptosomal protein content with cognition to identify neural correlates of AD. Methods: APPswe/PS1dE9 mice and littermates were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days 2-9. At 3 months of age, an age where no cognitive …loss or amyloid-β (Aβ) pathology is typically reported in this model, we assessed hippocampal Aβ pathology, synaptic strength and synapse composition and interneuron populations. Moreover, cognitive flexibility was assessed and correlated with synaptosomal protein content. Results: While ELS did not affect Aβ pathology, it increased synaptic strength and decreased the number of calretinin+ interneurons in the hippocampal dentate gyrus. Both genotype and condition further affected the level of postsynaptic glutamatergic protein content. Finally, APP/PS1 mice were significantly impaired in cognitive flexibility at 3 months of age, and ELS exacerbated this impairment, but only at relatively high learning criteria. Conclusions: ELS reduced cognitive flexibility in young APP/PS1 mice and altered markers for synapse and network function. These findings at an early disease stage provide novel insights in AD etiology and in how ELS could increase AD susceptibility. Show more

Keywords: Alzheimer’s disease, calretinin, cognitive flexibility, early life stress, glutamatergic proteins, synapses

DOI: 10.3233/JAD-230727

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1097-1113, 2023

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

Article Type: Research Article

Abstract: Background: Few studies have examined the relationship between non-cognitive factors and activities of daily living (ADL) according to Alzheimer’s disease (AD) stage. Objective: We aimed to identify the differences in non-cognitive factors according to AD stages and their involvement in basic and instrumental ADL performance by using intrinsic capacity (IC) in groups with cognition ranging from normal to moderate or severe AD. Methods: We enrolled 6397 patients aged≥65 years who visited our memory clinic. Non-cognitive IC was assessed using the locomotion, sensory, vitality, and psychological domains. Multiple logistic regression was performed to identify how non-cognitive IC …declines over the AD course and examine the correlation between non-cognitive IC and basic and instrumental ADL performance. Results: Non-cognitive IC declined from the initial AD stage and was significantly correlated with both basic and instrumental ADL performance from the aMCI stage through all AD stages. In particular, the relationship between IC and basic ADL was stronger in mild and moderate to severe AD than in the aMCI stage. On the other hand, the relationship between IC and instrumental ADL was stronger in aMCI than in later AD stages. Conclusions: The results show non-cognitive factors, which decline from the aMCI stage, are correlated with ADL performance from the aMCI stage to almost all AD stages. Considering that the relationship strength varied by ADL type and AD stage, an approach tailored to ADL type and AD stage targeting multiple risk factors is likely needed for effectively preventing ADL performance declines. Show more

Keywords: Alzheimer’s disease, basic activities of daily living, instrumental activities of daily living, intrinsic capacity

DOI: 10.3233/JAD-230786

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1115-1127, 2023

Authors: Liu, Xiaoran | Finno, Carrie J. | Beck, Todd | Dhana, Klodian | Tangney, Christy | Desai, Pankaja | Krueger, Kristin | Evans, Denis A. | Rajan, Kumar B.

Article Type: Research Article

Abstract: Background: The association of different types of tocopherols (vitamin E) with cognition might vary by the APOE ɛ 4 allele status. Objective: We examined the association of dietary tocopherols with cognitive decline among participants with and without the APOE ɛ 4 allele over a median of 12 years. Methods: 2,193 participants from the Chicago Health and Aging Project were included in the analyses. Global cognition was assessed in three-year cycles. We used a 144-item FFQ to assess dietary intakes of tocopherols and hME Sequenom mass-array platform to assess APOE genotype. We used linear …mixed effects models to examine the relationship between tocopherol from food sources and global cognitive decline. Results: The mean baseline age was 74.1 (SD = 5.9) years. Among APOE ɛ 4 carriers, participants in the highest quintile of intakes of dietary vitamin E had a slower cognitive decline of 0.022 SDU (95% CI: 0.000, 0.043) compared to those in the lowest quintile. A higher intake of dietary α -tocopherol from food sources only was associated with slower cognitive decline in APOE ɛ 4 carriers (p for trend 0.002) but not among the non-carriers (p for trend 0.937). Among APOE ɛ 4 carriers, those in the highest quintile of intake of α -tocopherol had a 16.4% slower rate of decline of global cognition compared to those in the lowest quintile (β= 0.034, 95% CI: 0.013, 0.054). Conclusions: Individuals consuming high α -tocopherol from food sources had slower cognitive decline among APOE ɛ 4 carriers. In older adults, different forms of vitamin E might moderate the relationship of APOE ɛ 4 with global cognition. Show more

Keywords: Alpha-tocopherol, Alzheimer’s disease, antioxidant, APOE, bi-racial, cognitive decline, dietary, longitudinal cohort, nutrients, vitamin E

DOI: 10.3233/JAD-230797

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1129-1138, 2023

Authors: Puthusseryppady, Vaisakh | Bregola, Allan | Camino, Julieta | Backhouse, Tamara | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: Various intrinsic (related to dementia) and extrinsic (not related to dementia) factors have been suggested to contribute separately to disability in people living with dementia (PLwD). Objective: To investigate if the combination of specific intrinsic and extrinsic factors at baseline is associated with longitudinal declines in activities of daily living (ADL) performance of PLwD at 12-month follow-up. Methods: 141 community-dwelling PLwD-carer dyads were assessed on their global cognition (ACE-III), apathy (CBI-R), carer management styles (DMSS), medical comorbidities (CCI), and ADL performance (DAD) at baseline, and for a subset of participants (n  = 53), at 12-month follow-up. …Multiple linear regression models were run to assess: 1) the relationships between PLwD’s DAD scores and the remaining variables at baseline and 2) whether these variables’ scores at baseline were associated with longitudinal change in the PLwD’s DAD scores. Results: At baseline, having lower ACE-III (β= 0.354, p  < 0.001), higher CBI-R (β= –0.284, p  < 0.001), higher DMSS criticism (β= –0.367, p  = 0.013), lower DMSS encouragement (β= 0.370, p  = 0.014), and higher CCI scores (β= –2.475, p  = 0.023) were significantly associated with having lower DAD scores. The PLwD’s DAD scores significantly declined from baseline to follow-up (p  < 0.001, d  = 1.15), however this decline was not associated with the baseline scores of any of the independent variables. Instead, it was associated with declines in the PLwD’s ACE-III scores from baseline to follow-up (β= 1.021, p  = 0.001). Conclusions: In our limited sample, cognitive changes seem to be the main factor underlying longitudinal decline in ADL performance for PLwD. Carer management styles appear associated with current ADL performance but not with longitudinal ADL decline. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, disability studies, functional independence, longitudinal studies, risk factors

DOI: 10.3233/JAD-230075

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1139-1149, 2023

Authors: Azami, Hamed | Daftarifard, Elham | Humeau-Heurtier, Anne | Fernandez, Alberto | Abasolo, Daniel | Rajji, Tarek K.

Article Type: Research Article

Abstract: Background: Nonlinear dynamical measures, such as fractal dimension (FD), entropy, and Lempel-Ziv complexity (LZC), have been extensively investigated individually for detecting information content in magnetoencephalograms (MEGs) from patients with Alzheimer’s disease (AD). Objective: To compare systematically the performance of twenty conventional and recently introduced nonlinear dynamical measures in studying AD versus mild cognitive impairment (MCI) and healthy control (HC) subjects using MEG. Methods: We compared twenty nonlinear measures to distinguish MEG recordings from 36 AD (mean age = 74.06±6.95 years), 18 MCI (mean age = 74.89±5.57 years), and 26 HC subjects (mean age = 71.77±6.38 years) in different brain regions and also …evaluated the effect of the length of MEG epochs on their performance. We also studied the correlation between these measures and cognitive performance based on the Mini-Mental State Examination (MMSE). Results: The results obtained by LZC, zero-crossing rate (ZCR), FD, and dispersion entropy (DispEn) measures showed significant differences among the three groups. There was no significant difference between HC and MCI. The highest Hedge’s g effect sizes for HC versus AD and MCI versus AD were respectively obtained by Higuchi’s FD (HFD) and fuzzy DispEn (FuzDispEn) in the whole brain and was most prominent in left lateral. The results obtained by HFD and FuzDispEn had a significant correlation with the MMSE scores. DispEn-based techniques, LZC, and ZCR, compared with HFD, were less sensitive to epoch length in distinguishing HC form AD. Conclusions: FuzDispEn was the most consistent technique to distinguish MEG dynamical patterns in AD compared with HC and MCI. Show more

Keywords: Alzheimer’s disease, entropy, fractal dimension, magnetoencephalogram, mild cognitive impairment, nonlinear dynamics

DOI: 10.3233/JAD-230544

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1151-1162, 2023