Journal of Alzheimer's Disease - Volume 86, issue 4

Authors: Takechi, Hajime | Yoshino, Hiroshi | Kawakita, Hitomi

Article Type: Research Article

Abstract: Background: Dementia cafés have been attracting attention as a new approach to dementia care, but the effects of the participation of medical professionals remain unclear. Objective: To clarify the significance of collaboration between medical professionals and dementia cafés. Methods: Questionnaires regarding the numbers of staff and guests, whether medical professionals introduced guests, whether cafés announced their activities to medical institutions, and whether people with dementia played a role were sent to dementia cafés throughout Japan. The responding dementia cafés were then divided into two groups according to the presence or involvement of medical professionals and institutions …and compared. Results: Responses were received from 148 dementia cafés, among which, medical professionals participated in 96 (64.9%). Significantly more people with dementia living at home attended cafés run or staffed with medical professionals (p  = 0.021 and p  = 0.017, respectively), as well as when medical professionals introduced guests to the café or when the café announced their activities to medical institutions (p  = 0.001 and p  = 0.002, respectively). Significantly more people with dementia played a role in cafés where medical professionals were administrators or staff (p  = 0.008 and p  = 0.018, respectively). Similar effects were observed for family caregivers. Conclusion: The participation and involvement of medical professionals and institutions in dementia cafés increased the attendance of people with dementia, especially those living at home. These results suggest that dementia cafés are an effective hub for connecting care for dementia with medical care, and thus help avoid fragmentation in dementia care. Show more

Keywords: Caregiver, community network, dementia, psychosocial intervention, social support

DOI: 10.3233/JAD-215472

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1775-1782, 2022

Authors: Ji, Xintong | Li, Chenxia | Zhu, Xiaozheng | Yu, Wenlei | Cai, Yanyu | Zhu, Xinyi | Lu, Linjie | Qian, Qiwei | Hu, Yu | Zhu, Xuan | Wang, Huanhuan

Article Type: Research Article

Abstract: Background: Fine particulate matter (particulate matter 2.5, PM2.5 ) is considered one of the harmful factors to neuronal functions. Apoptosis is one of the mechanisms of neuronal injury induced by PM2.5 . Methylcobalamine (MeCbl) has been shown to have anti-apoptotic and neuroprotective effects. Objective: The current work tried to explore the neuroprotective effects and mechanisms that MeCbl protects mice against cognitive impairment and neuronal apoptosis induced by chronic real-time PM2.5 exposure. Methods: Twenty-four 6-week-old male C57BL/6 mice were exposed to ambient PM2.5 and fed with MeCbl for 6 months. Morris water maze was used …to evaluate the changes of spatial learning and memory ability in mice. PC12 cells and primary hippocampal neurons were applied as the in vitro model. Cell viability, cellular reactive oxygen species (ROS) and the expressions of apoptosis-related proteins were examined. And cells were stained with JC-1 and mitochondrial membrane potential was evaluated. Results: In C57BL/6 mice, MeCbl supplementation alleviated cognitive impairment and apoptosis-related protein expression induced by PM2.5 exposure. In in vitro cell model, MeCbl supplementation could effectively rescue the downregulation of cell viability induced by PM2.5 , and inhibited the increased levels of ROS, cellular apoptosis, and the expressions of apoptosis related proteins related to PM2.5 treatment, which may be associated with modulation of mitochondrial function. Conclusion: MeCbl treatment alleviated cognitive impairment and neuronal apoptosis induced by PM2.5 both in vivo and in vitro . The mechanism for the neuroprotective effects of MeCbl may at least be partially dependent on the regulation of mitochondrial apoptosis. Show more

Keywords: Methylcobalamine, mitochondria, neuronal apoptosis, PM2.5

DOI: 10.3233/JAD-215384

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1783-1796, 2022

Authors: Abdullah, Shahbaz | Critchfield, Matthew | Maltby, John | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Cognitive decline is classically attributed to organic causes such as dementia; however, depression can play a role in cognitive decline. Objective: To evaluate cognitive screening tools and the 4-item Geriatric Depression Scale (GDS-4) for use in primary care to distinguish cognitive decline secondary to depression. Method: Clinical data collected over 2.5 years for assessed patients in a secondary clinical service for younger adults. Cognitive screening tools (General Practitioner Assessment of Cognition, Addenbrooke’s Cognitive Examination-III, Rowland Universal Dementia Assessment Scale, Salzburg Dementia Test Prediction) and GDS-4 were analyzed for their accuracy to differentiate …patients with cognitive decline due to depression from those with subjective cognitive complaints. Results: 180 young adults seen in a memory clinic setting (< 65 years) were included. These individuals either had a diagnosis of depression (n  = 46) or no cognitive impairment on assessment (n  = 134) despite having subjective cognitive complaints. All used cognitive tools had poor accuracy in differentiating cognitive decline secondary to depression from subjective cognitive complaints. The GDS-4 alone, however, was able to differentiate with high accuracy (AUC = 0.818) individuals who had cognitive problems secondary to depression. Conclusion: Cognitive screening tools used alone are ineffective in discriminating cognitive decline secondary to depression. Incorporating the GDS-4 into the screening process by primary practitioners could facilitate early identification and treatment of depression in younger people, avoiding unnecessary referrals memory services. Show more

Keywords: Cognitive decline, cognitive tools, depression, 4-item geriatric depression score

DOI: 10.3233/JAD-215552

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1797-1804, 2022

Authors: Li, Wenchao | Yang, Defu | Yan, Chenggang | Chen, Minghan | Li, Quefeng | Zhu, Wentao | Wu, Guorong | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mounting evidence shows that the neuropathological burdens manifest preference in affecting brain regions during the dynamic progression of Alzheimer’s disease (AD). Since the distinct brain regions are physically wired by white matter fibers, it is reasonable to hypothesize the differential spreading pattern of neuropathological burdens may underlie the wiring topology, which can be characterized using neuroimaging and network science technologies. Objective: To study the dynamic spreading patterns of neuropathological events in AD. Methods: We first examine whether hub nodes with high connectivity in the brain network (assemble of white matter wirings) are susceptible to a …higher level of pathological burdens than other regions that are less involved in the process of information exchange in the network. Moreover, we propose a novel linear mixed-effect model to characterize the multi-factorial spreading process of neuropathological burdens from hub nodes to non-hub nodes, where age, sex, and APOE4 indicators are considered as confounders. We apply our statistical model to the longitudinal neuroimaging data of amyloid-PET and tau-PET, respectively. Results: Our meta-data analysis results show that 1) AD differentially affects hub nodes with a significantly higher level of pathology, and 2) the longitudinal increase of neuropathological burdens on non-hub nodes is strongly correlated with the connectome distance to hub nodes rather than the spatial proximity. Conclusion: The spreading pathway of AD neuropathological burdens might start from hub regions and propagate through the white matter fibers in a prion-like manner. Show more

Keywords: Alzheimer’s disease, brain networks, hub node, linear mixed-effect model, longitudinal neuroimages

DOI: 10.3233/JAD-215596

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1805-1816, 2022

Authors: Vacher, Michael | Porter, Tenielle | Milicic, Lidija | Bourgeat, Pierrick | Dore, Vincent | Villemagne, Victor L | Laws, Simon M. | Doecke, James D.

Article Type: Research Article

Abstract: Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain …regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOE ɛ 4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, brain atrophy, linear mixed model, MRI, single nucleotide polymorphisms

DOI: 10.3233/JAD-210644

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1817-1829, 2022

Authors: Rahmani, Farzaneh | Wang, Qing | McKay, Nicole S. | Keefe, Sarah | Hantler, Nancy | Hornbeck, Russ | Wang, Yong | Hassenstab, Jason | Schindler, Suzanne | Xiong, Chengjie | Morris, John C. | Benzinger, Tammie L.S. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We …identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD. Show more

Keywords: Aging, Alzheimer’s disease, body mass index, connectome, diffusion magnetic resonance imaging, white matter

DOI: 10.3233/JAD-215329

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1831-1848, 2022

Authors: Hu, Hao | Fu, Jun-Ting | Bi, Yan-Lin | Ma, Ya-Hui | Huang, Yu-Yuan | Wang, Xin | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer’s disease (AD) core pathologies in modulating this process have not been fully delineated. Objective: This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers. Methods: A total of 1,079 non-demented participants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation …effects. Results: Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p  < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aβ pathology (p  < 0.01). In addition, smokers with older age or APOE ɛ 4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOE ɛ 4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p  < 0.05). Conclusion: Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments. Show more

Keywords: Alzheimer’s diseases, cerebrospinal fluid biomarkers, cigarette smoking, cognitive impairment

DOI: 10.3233/JAD-215618

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1849-1859, 2022

Authors: Cao, Han | Zhou, Xiaopu | Chen, Yu | Ip, Fanny C.F. | Chen, Yuewen | Lai, Nicole C.H. | Lo, Ronnie M.N. | Tong, Estella P.S. | Mok, Vincent C.T. | Kwok, Timothy C.Y. | Alzheimer’s Disease Neuroimaging Initiative | Fu, Amy K.Y. | Ip, Nancy Y.

Article Type: Research Article

Abstract: Background: Genetic studies reveal that single-nucleotide polymorphisms (SNPs) of SPI1 are associated with Alzheimer’s disease (AD), while their effects in the Chinese population remain unclear. Objective: We aimed to examine the AD-association of SPI1 SNPs in the Chinese population and investigate the underlying mechanisms of these SNPs in modulating AD risk. Methods: We conducted a genetic analysis of three SPI1 SNPs (i.e., rs1057233, rs3740688, and rs78245530) in a Chinese cohort (n  = 333 patients with AD, n  = 721 normal controls). We also probed public European-descent AD cohorts and gene expression datasets to investigate the …putative functions of those SNPs. Results: We showed that SPI1 SNP rs3740688 is significantly associated with AD in the Chinese population (odds ratio [OR] = 0.72 [0.58–0.89]) and identified AD-protective SPI1 haplotypes β (tagged by rs1057233 and rs3740688) and γ (tagged by rs3740688 and rs78245530). Specifically, haplotypes β and γ are associated with decreased SPI1 gene expression level in the blood and brain tissues, respectively. The regulatory roles of these haplotypes are potentially mediated by changes in miRNA binding and the epigenetic landscape. Our results suggest that the AD-protective SPI1 haplotypes regulate pathways involved in immune and neuronal functions. Conclusion: This study is the first to report a significant association of SPI1 with AD in the Chinese population. It also identifies SPI1 haplotypes that are associated with SPI1 gene expression and decreased AD risk. Show more

Keywords: Alzheimer’s disease, genetics, haplotype analysis, SPI1, transcriptome

DOI: 10.3233/JAD-215311

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1861-1873, 2022

Authors: Kalecký, Karel | German, Dwight C. | Montillo, Albert A. | Bottiglieri, Teodoro

Article Type: Research Article

Abstract: Background: Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer’s disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis. Objective: In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers. Methods: This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer’s Research and Care Consortium – TARCC) and 71 postmortem …cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500). Results: We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95  = 75–88%); for females specifically, AUC = 88% (CI95  = 80–95%). A reduced model using 20 features achieves AUC = 79% (CI95  = 71–85%); for females AUC = 84% (CI95  = 74–92%). Conclusion: Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis. Show more

Keywords: Alzheimer’s disease, antioxidants, bacterial toxins, biomarkers, human microbiome, hyperlipidemia, lipidomics, metabolic pathways, metabolomics, polyamines

DOI: 10.3233/JAD-215448

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1875-1895, 2022

Authors: Sha, Feng | Zhao, Ziyi | Wei, Chang | Li, Bingyu

Article Type: Research Article

Abstract: Background: Previous studies found that about 24% of the mild cognitive impairment (MCI) patients reverse to cognitive normal (CN) status. However, it is unclear which modifiable factors are associated with this reversion. Objective: To identify potential modifiable factors associated with the reversion of MCI to CN status. Methods: We conducted a prospective community-based cohort study based on 2002–2018 Chinese Longitudinal Health Longevity Survey (CLHLS). Multivariable Cox regression with least absolute shrinkage and selection operator (LASSO) penalty for variable selection was adopted to investigate the associations between reversion to CN and potential modifiable dietary/lifestyle, …cardiometabolic, and psychological factors. Results: Our analysis included 7,422 MCI participants [average age: 90.0 (SD 9.5) years]. Among these participants, 1,604 (21.6%) reversed from MCI to CN with a mean (SD) follow-up of 2.9 (1.8) years. Several dietary/lifestyle factors, including daily consumption of fresh fruits (Hazard Ratio [HR]: 1.28, 95% CI: 1.15 to 1.42), engagement in reading (HR: 1.24, 95% CI: 1.00 to 1.54), housework (HR: 1.21, 95% CI: 1.08 to 1.35), and mah-jongg or other card games (HR: 1.23, 95% CI: 1.08 to 1.39), were positively associated with possibility of reversion. Cigarette smoking (HR: 0.92, 95% CI: 0.84 to 1.00) and duration of alcohol drinking (HR: 0.97, 95% CI: 0.94 to 0.99) were negatively associated with possibility of reversion. None of the modifiable cardiometabolic and psychological factors was found to be significantly associated with reversion to CN. Conclusion: This study identified several dietary/lifestyle factors associated with MCI reversion that may transfer into large-scale dementia prevention practices. Show more

Keywords: Cognitive health, dementia prevention, dietary/lifestyle factors, mild cognitive impairment, modifiable factors

DOI: 10.3233/JAD-215677

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1897-1906, 2022