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

Authors: Liu, Ruijie | Gao, Chenhao | Shang, Junkui | Sun, Ruihua | Wang, Wenjing | Li, Wei | Gao, Dandan | Huo, Xuejing | Shi, Yingying | Wang, Yanliang | Wang, Fengyu | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear. Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL. Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro . The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD …) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis. Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G >  A, p. A564T) in two pedigrees. In vitro , the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis. Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations. Show more

Keywords: Apoptosis, CADASIL, cysteine-sparing NOTCH3 mutation, flow cytometry, mitochondrial dysfunction

DOI: 10.3233/JAD-215256

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

Authors: Henderson, Catherine | Knapp, Martin | Martyr, Anthony | Gamble, Laura D. | Nelis, Sharon M. | Quinn, Catherine | Pentecost, Claire | Collins, Rachel | Wu, Yu-Tzu | Jones, Ian R. | Victor, Christina R. | Pickett, James A. | Jones, Roy W. | Matthews, Fiona E. | Morris, Robin G. | Rusted, Jennifer | Thom, Jeanette M. | Clare, Linda | on behalf of the IDEAL programme team

Article Type: Research Article

Abstract: Background: The drivers of costs of care for people with dementia are not well understood and little is known on the costs of care for those with rarer dementias. Objective: To characterize use and costs of paid and unpaid care over time in a cohort of people with dementia living in Britain. To explore the relationship between cohort members’ demographic and clinical characteristics and service costs. Methods: We calculated costs of health and social services, unpaid care, and out-of-pocket expenditure for people with mild-to-moderate dementia participating in three waves of the IDEAL cohort (2014– 2018). Latent …growth curve modelling investigated associations between participants’ baseline sociodemographic and diagnostic characteristics and mean weekly service costs. Results: Data were available on use of paid and unpaid care by 1,537 community-dwelling participants with dementia at Wave 1, 1,199 at Wave 2, and 910 at Wave 3. In models of paid service costs, being female was associated with lower baseline costs and living alone was associated with higher baseline costs. Dementia subtype and caregiver status were associated with variations in baseline costs and the rate of change in costs, which was additionally influenced by age. Conclusion: Lewy body and Parkinson’s disease dementias were associated with higher service costs at the outset, and Lewy body and frontotemporal dementias with more steeply increasing costs overall, than Alzheimer’s disease. Planners of dementia services should consider the needs of people with these relatively rare dementia subtypes as they may require more resources than people with more prevalent subtypes. Show more

Keywords: Dementia, dementia with Lewy bodies, frontotemporal dementia, health services, Parkinson’s disease dementia, social services, unpaid caregivers

DOI: 10.3233/JAD-215117

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

Authors: Alatorre-Cruz, Graciela C. | Fernández, Thalía | Castro-Chavira, Susana A. | González-López, Mauricio | Sánchez-Moguel, Sergio M. | Silva-Pereyra, Juan

Article Type: Research Article

Abstract: Background: In healthy older adults, excess theta activity is an electroencephalographic (EEG) predictor of cognitive impairment. In a previous study, neurofeedback (NFB) treatment reinforcing reductions theta activity resulted in EEG reorganization and cognitive improvement. Objective: To explore the clinical applicability of this NFB treatment, the present study performed a 1-year follow-up to determine its lasting effects. Methods: Twenty seniors with excessive theta activity in their EEG were randomly assigned to the experimental or control group. The experimental group received an auditory reward when the theta absolute power (AP) was reduced. The control group received the reward …randomly. Results: Both groups showed a significant decrease in theta activity at the training electrode. However, the EEG results showed that only the experimental group underwent global changes after treatment. These changes consisted of delta and theta decreases and beta increases. Although no changes were found in any group during the period between the posttreatment evaluation and follow-up, more pronounced theta decreases and beta increases were observed in the experimental group when the follow-up and pretreatment measures were compared. Executive functions showed a tendency to improve two months after treatment which became significant one year later. Conclusion: These results suggest that the EEG and behavioral benefits of this NFB treatment persist for at least one year, which adds up to the available evidence contributing to identifying factors that increase its efficacy level. The relevance of this study lies in its prophylactic features of addressing a clinically healthy population with EEG risk of cognitive decline. Show more

Keywords: Biofeedback, cognitive aging, EEG, follow-up, healthy aging, neurofeedback, older adults

DOI: 10.3233/JAD-215538

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

Authors: Morin, Alexandre | Pressat-Laffouilhere, Thibaut | Sarazin, Marie | Lagarde, Julien | Roue-Jagot, Carole | Olivieri, Pauline | Paquet, Claire | Cognat, Emmanuel | Dumurgier, Julien | Pasquier, Florence | Lebouvier, Thibaut | Ceccaldi, Matthieu | Godefroy, Olivier | Martinaud, Olivier | Grosjean, Julien | Zarea, Aline | Maltête, David | Wallon, David

Article Type: Research Article

Abstract: This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March–May 2020). The objective was to evaluate the effect of a telemedicine consultation on treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer’s disease. A control group of patients referred March–May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of –4% (p  = 0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.

Keywords: Alzheimer’s disease, COVID-19, psychoactive drugs, telemedicine, treatments in dementia

DOI: 10.3233/JAD-215459

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

Authors: Jung, Keun-Hwa | Park, Kyung-Il | Lee, Woo-Jin | Son, Hyo-Shin | Chu, Kon | Lee, Sang Kun

Article Type: Research Article

Abstract: Background: Cerebral white matter lesions (WML) are related to a higher risk of vascular and Alzheimer’s dementia. Moreover, oligomerized amyloid-β (OAβ) can be measured from blood for dementia screening. Objective: We aimed to investigate the relationship of plasma OAβ levels with clinical and radiological variables in a health screening population. Methods: WML, other volumetric parameters of magnetic resonance images, cognitive assessment, and plasma OAβ level were evaluated. Results: Ninety-two participants were analyzed. The majority of participants’ clinical dementia rating was 0 or 0.5 (96.7%). White matter hyperintensities (WMH) increased with age, but OAβ levels …did not (r2  = 0.19, p  <  0.001, r2  = 0.03, p  = 0.10, respectively). No volumetric data, including cortical thickness/hippocampal volume, showed any significant correlation with OAβ. Log-WMH volume was positively correlated with OAβ (r  = 0.24, p  = 0.02), and this association was significant in the periventricular area. White matter signal abnormalities from 3D-T1 images were also correlated with the OAβ in the periventricular area (p  = 0.039). Multivariate linear regression showed that log-WMH values were independently associated with OAβ (B  = 0.879 (95% confidence interval 0.098 –1.660, p  = 0.028)). Higher tertiles of WMH showed higher OAβ levels than lower tertiles showed (p  = 0.044). Using a cutoff of 0.78 ng/mL, the high OAβ group had a larger WMH volume, especially in the periventricular area, than the low OAβ group (p  = 0.036). Conclusion: Both WML and plasma OAβ levels can be early markers for neurodegeneration in the healthcare population. The lesions, especially in the periventricular area, might be related to amyloid pathogenesis, which strengthens the importance of WML in the predementia stage. Show more

Keywords: Cortical thickness, healthcare population, plasma oligomerized amyloid-β, white matter hyperintensity

DOI: 10.3233/JAD-215399

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

Authors: Kurano, Makoto | Tsukamoto, Kazuhisa | Sakai, Eri | Hara, Masumi | Yatomi, Yutaka

Article Type: Research Article

Abstract: Background: Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer’s disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer’s disease. Objective: We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system. Methods: We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4. Results: In the brains of Apoeshl …mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4. Conclusion: The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer’s disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ApoE isoforms, apolipoprotein M, ceramide, sphingosine 1-phosphate

DOI: 10.3233/JAD-215205

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

Authors: Luo, Xiao | Hong, Hui | Wang, Shuyue | Li, Kaicheng | Zeng, Qingze | Hong, Luwei | Liu, Xiaocao | Li, Zheyu | Fu, Yanv | Jiaerken, Yeerfan | Xu, XiaoPei | Yu, Xinfeng | Huang, Peiyu | Zhang, Minming

Article Type: Research Article

Abstract: Background: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. Objective: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. Methods: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers …as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). Results: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p  < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = –0.25) and EC (r = –0.25) of middle temporal gyrus was related with SPPB in all participants (p  < 0.05, corrected). Conclusion: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions. Show more

Keywords: Cerebral microinfarcts, cerebral small vascular disease, degree centrality, eigenvector centrality, motor function, resting-state functional MRI

DOI: 10.3233/JAD-215227

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

Authors: Ren, Yifei | Dong, Yi | Hou, Tingting | Han, Xiaolei | Liu, Rui | Wang, Yongxiang | Xu, Shan | Wang, Xiang | Monastero, Roberto | Cong, Lin | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Few studies have examined occurrence and progression of cognitive impairment, no dementia (CIND) in rural China. Objective: To determine the prevalence and incidence of CIND in rural-dwelling Chinese older adults, and to examine risk and protective factors associated with progression to CIND and dementia. Methods: This population-based study included 2,781 dementia-free participants (age≥65 years) who were examined at baseline (2014) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected following a structured questionnaire. We defined CIND according to subjective cognitive complaints and the age- and education-specific Mini-Mental State Examination (MMSE) score. Data …were analyzed with the multinomial logistic regression models. Results: The overall prevalence of CIND was 10.54% and the incidence was 28.26 per 1,000 person-years. CIND at baseline was associated with the multi-adjusted odds ratio (OR) of 2.06 (95% confidence interval = 1.23–3.47) for incident dementia. Multinomial logistic regression analysis suggested that compared with no CIND, the multi-adjusted OR of incident CIND was 2.21 (1.51–3.23) for women and 0.62 (0.38–0.99) for high social support, whereas the multi-adjusted OR of incident dementia was 1.14 (1.09–1.18) for older age, 0.29 (0.16–0.53) for high education, and 2.91 (1.47–5.74) for having a stroke history. Conclusion: CIND affects over one-tenth of older adults living in rural communities of western Shandong province. People with CIND are twice as likely to progress to dementia as people without CIND. Female sex, low education, stroke history, and low social support are associated with an increased risk of progression from normal cognition to CIND or dementia. Show more

Keywords: Cognitive impairments, incidence, population-based study, prevalence, risk factors, rural

DOI: 10.3233/JAD-215236

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

Authors: Wang, Xiaoqi | Bi, Qiuhui | Lu, Jie | Chan, Piu | Hu, Xiaochen | Su, Li | Jessen, Frank | Lin, Hua | Han, Chunlei | Shu, Ni | Liu, Hesheng | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer’s disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. Objective: We aims to explore the differences in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. Methods: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18 F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was …quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n  = 34) and sd-SCD (n  = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. Results: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F  = 5.033, p  = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F  = 12.309, p  = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. Conclusion: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals. Show more

Keywords: Alzheimer’s disease, amyloid, multidomain, single memory domain, subjective cognitive decline

DOI: 10.3233/JAD-215373

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

Authors: Wang, Jianlin | Wang, Pan | Jiang, Yuan | Wang, Zedong | Zhang, Hong | Li, Hongyi | Biswal, Bharat B.

Article Type: Research Article

Abstract: Background: The hippocampus with varying degrees of atrophy was a crucial neuroimaging feature resulting in the declining memory and cognitive function in Alzheimer’s disease (AD). However, the abnormal dynamic functional connectivity (DFC) in both white matter (WM) and gray matter (GM) from the left and right hippocampus remains unclear. Objective: To explore the abnormal DFC within WM and GM from the left and right hippocampus across the different stages of AD. Methods: Current study employed the OASIS-3 dataset including 43 mild cognitive impairment (MCI), 71 pre-mild cognitive impairment (pre-MCI), and matched 87 normal …cognitive (NC). Adopting the FMRIB’s Integrated Registration and Segmentation Tool, we obtained the left and right hippocampus mask. Based on above hippocampus mask as seed point, we calculated the DFC between left/right hippocampus and all voxel time series within whole brain. One-way ANOVA analysis was performed to estimate the abnormal DFC among MCI, pre-MCI, and NC groups. Results: We found that MCI and pre-MCI groups showed the common abnormalities of DFC in the Temporal_Mid_L, Cingulum_Mid_L, and Thalamus_L. Specific abnormalities were found in the Cerebelum_9_L and Precuneus of MCI group and Vermis_8 and Caudate_L of pre-MCI group. In addition, we found that DFC within WM regions also showed the common low DFC for the Cerebellum anterior lobe-WM, Corpus callosum, and Frontal lobe-WM in MCI and pre-MCI group. Conclusion: Our findings provided a novel information for discover the pathophysiological mechanisms of AD and indicate WM lesions were also an important cause of cognitive decline in AD. Show more

Keywords: Alzheimer’s disease, dynamic functional connectivity, hippocampus, mild cognitive impairment, white matter BOLD signal

DOI: 10.3233/JAD-215239

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