Journal of Alzheimer's Disease - Volume 85, issue 4

Authors: Liu, Qingqing | Ling, Zaisheng | Zhang, Jinpeng | Yu, Hongli | Wang, Ye | Xue, Yang | Wang, Chunyan | Zhao, Jiwei | Cao, Jingwei | Duan, Shurong | Zhao, Jingkun

Article Type: Research Article

Abstract: Background: Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer’s disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Objective: Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. Methods: The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the …colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. Results: MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. Conclusion: MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research. Show more

Keywords: Alzheimer’s disease, autophagy, lncRNAs MIR600HG, mitochondrial dysfunction, PINK1

DOI: 10.3233/JAD-215194

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1783-1794, 2022

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. 85, no. 4, pp. 1795-1806, 2022

Authors: Giannakopoulos, Panteleimon | Rodriguez, Cristelle | Montandon, Marie-Louise | Garibotto, Valentina | Haller, Sven | Herrmann, François R.

Article Type: Research Article

Abstract: Background: Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. Objective: This study explores the impact of personality on widely used Alzheimer’s disease (AD) and vascular imaging markers. Methods: We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify …predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Results: Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Conclusion: Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age. Show more

Keywords: Amyloid load, cortical volume, gray matter density, normal aging, personality

DOI: 10.3233/JAD-215062

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1807-1817, 2022

Authors: Day, Sally | Roberts, Stefanie | Launder, Nathalie H. | Goh, Anita M.Y. | Draper, Brian | Bahar-Fuchs, Alex | Loi, Samantha M. | Laver, Kate | Withall, Adrienne | Cations, Monica

Article Type: Research Article

Abstract: Background: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning. Objective: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Methods: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. …Quantitative meta-analysis was conducted where studies reported sufficient data for pooling. Results: Thirty studies met all inclusion criteria (people with AD (n  = 26), FTD (n  = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = –0.07; 95% CI –0.14 to 0.00; p  = 0.045). Most studies that stratified their sample reported that younger AD onset (usually < 65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive. Conclusion: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias. Show more

Keywords: Alzheimer’s disease, disease progression, frontotemporal dementia, prognosis, vascular dementia

DOI: 10.3233/JAD-215360

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1819-1833, 2022

Authors: Jung, Keun-Hwa | Park, Kyung-Il | Lee, Woo-Jin | Son, Hyoshin | 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. 85, no. 4, pp. 1835-1844, 2022