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

Authors: Agger, Mikkel Pejstrup | Carstensen, Marcus Schultz | Henney, Mark Alexander | Hansen, Luna Skytte | Baandrup, Anders Ohlhues | Nguyen, Mai | Petersen, Paul Michael | Madsen, Kristoffer Hougaard | Kjær, Troels Wesenberg

Article Type: Research Article

Abstract: Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous …light (CON) and 40 Hz stroboscopic light (STROBE). Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker. Show more

Keywords: 40 Hz, Alzheimer’s disease, electroencephalograph, functional MRI, gamma entrainment, GENUS, invisible spectral flicker, light-based neurostimulation, steady state visually evoked potentials

DOI: 10.3233/JAD-220081

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022

Authors: Liang, Yajun | Gao, Ya | Wang, Rui | Grande, Giulia | Monastero, Roberto | Dong, Yanhong | Jiang, Xin | Lv, Peiyuan | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: The potential impact of migraine on cognitive aging among older adults remains controversial. Objective: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. Methods: This population-based study included 3069 participants (age≥60) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001–2004, and participants were followed every 3 or 6 years until 2013–2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State Examination (MMSE). Dementia …was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. Results: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20–1.21) for migraine and 0.66 (0.26–1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68–0.89 (p  > 0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p  > 0.05). The nonsignificant associations did not vary substantially by age, APOE ɛ 4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions > 0.05). Conclusion: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults. Show more

Keywords: Cognitive aging, dementia, headache, migraine, population-based study

DOI: 10.3233/JAD-220013

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Drouin, Shannon M. | McFall, G. Peggy | Potvin, Olivier | Bellec, Pierre | Masellis, Mario | Duchesne, Simon | Dixon, Roger A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer’s disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses. Objective: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers. Methods: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n  = 351; Mean  = 75 years; 48.7% female). First, we applied latent class growth analyses to …left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class. Results: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aβ1–42 . Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aβ1–40 , higher depressive symptomology, and lower body mass index. Conclusion: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities. Show more

Keywords: Biomarker predictions, hippocampal atrophy, latent class growth analyses, random forest analyses, trajectory classes

DOI: 10.3233/JAD-215289

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2022

Authors: Zhang, Xingxing | Guan, Qing | Li, Yingjia | Zhang, Jianfeng | Zhu, Wanlin | Luo, Yuejia | Zhang, Haobo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: BOLD signals in the gray matter (GM) and white matter (WM) are tightly coupled. However, our understanding of the cross-tissue functional network in Alzheimer’s disease (AD) is limited. Objective: We investigated the changes of cross-tissue functional connectivity (FC) metrics for the GM regions susceptible to AD damage. Methods: For each GM region in the default mode (DMN) and limbic networks, we obtained its low-order static FC with any WM region, and the high-order static FC between any two WM regions based on their FC pattern similarity with multiple GM regions. The dynamic and directional properties …of cross-tissue FC were then acquired, specifically for the regional pairs whose low- or high-order static FCs showed significant differences between AD and normal control (NC). Moreover, these cross-tissue FC metrics were correlated with voxel-based GM volumes and MMSE in all participants. Results: Compared to NC, AD patients showed decreased low-order static FCs between the intra-hemispheric GM-WM pairs (right ITG-right fornix ; left MoFG-left posterior corona radiata ), and increased low-order static, dynamic, and directional FCs between the inter-hemispheric GM-WM pairs (right MTG-left superior/posterior corona radiata ). The high-order static and directional FCs between the left cingulate bundle -left tapetum were increased in AD, based on their FCs with the GMs of DMN. Those decreased and increased cross-tissue FC metrics in AD had opposite correlations with memory-related GM volumes and MMSE (positive for the decreased and negative for the increased). Conclusion: Cross-tissue FC metrics showed opposite changes in AD, possibly as useful neuroimaging biomarkers to reflect neurodegenerative and compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, directional, dynamic, functional connectivity, gray matter, high-order, static, white matter

DOI: 10.3233/JAD-215649

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2022

Authors: Contador, Israel | Alzola, Patricia | Bermejo-Pareja, Félix | del Ser, Teodoro | Llamas-Velasco, Sara | Fernández-Calvo, Bernardino | Benito-León, Julián

Article Type: Research Article

Abstract: Background: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. Objective: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). Methods: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N  = 5,278 persons). Participants were fully assessed at baseline (1994–1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of …3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. Results: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox’s regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p  = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p  = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox’s model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox’s regression. Conclusion: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations. Show more

Keywords: Cognitive reserve, illiteracy, low education, stroke, transient ischemic attack

DOI: 10.3233/JAD-220109

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Wu, Fen | Davey, Samuel | Clendenen, Tess V. | Koenig, Karen L. | Afanasyeva, Yelena | Zhou, Boyan | Bedi, Sukhleen | Li, Huilin | Zeleniuch-Jacquotte, Anne | Chen, Yu

Article Type: Research Article

Abstract: Background: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. Objective: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. Methods: In this cross-sectional study of 95 older women selected from the New York University Women’s Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus …< 2) and continuous SMCs. Results: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38–3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43–3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae . Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11–1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13–1.42), respectively (FDR-adjusted p  = 0.018 and 0.006, respectively). Conclusion: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction. Show more

Keywords: 16S RNA gene sequencing, cross-sectional, gut microbiota, NYUWHS, subjective memory complaints

DOI: 10.3233/JAD-220011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Ang, Su Fen | Low, Serena | Ng, Tze Pin | Tan, Clara S.H. | Ang, Keven | Lim, Ziliang | Tang, Wern Ee | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer’s disease and T2DM. Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. Methods: 590 Chinese patients aged 45–86 from the SMART2D study were genotyped for PAX4 R192H variation using …Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= –8.46, 95% CI [–13.71, –3.21], p  = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOE ɛ 4 allele. Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care. Show more

Keywords: Cognitive impairment, ethnic-specific, PAX4, type 2 diabetes

DOI: 10.3233/JAD-220036

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Manfredi, Natalia | Placidi, Fabio | Nuccetelli, Marzia | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep disorders may cause dysregulation of cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. Objective: This study aimed at measuring sleep, CSF Alzheimer’s disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. Methods: OSAS and PLMD patients underwent 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-β42 (Aβ42 ), total tau, and phosphorylated tau. All patients were compared to …controls, who were not affected by sleep or neurodegenerative disorders. Results: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aβ42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. Conclusion: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18 F-FDG PET AD biomarkers, namely reduction of CSF Aβ42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β , brain glucose consumption, cerebrospinal fluid, positron emission tomography, sleep

DOI: 10.3233/JAD-215734

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: Zhang, Yinghan | Hu, Yazhuo | Han, Zhitao | Geng, Yan | Xia, Zheng | Zhou, Yongsheng | Wang, Zhenfu | Wang, Yuanyuan | Kong, Eryan | Wang, Xiaoning | Jia, Jianjun | Zhang, Honghong

Article Type: Research Article

Abstract: Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer’s disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 …(PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results: CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment. Show more

Keywords: Alzheimer’s disease, APP/PS1 transgenic mice, palmitoylation, postsynaptic density protein 95

DOI: 10.3233/JAD-220009

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Welty, Starr | Thathiah, Amantha | Levine, Arthur Samuel

Article Type: Research Article

Abstract: Background: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s disease (AD). Objective: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation. Methods: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 …and Aβ42 . Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology. Results: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons. Conclusion: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , DNA repair, double strand breaks, etoposide, neurodegenerative disease, oxidative damage

DOI: 10.3233/JAD-220030

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022