Journal of Alzheimer's Disease - Volume 80, issue 3

Authors: Piers, Ryan J. | Liu, Yulin | Ang, Ting F.A. | Tao, Qiushan | Au, Rhoda | Qiu, Wei Qiao

Article Type: Research Article

Abstract: Background: Depression and Apolipoprotein E4 (APOE4 ) are associated with decreased cognitive function and differences in brain structure. Objective: This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure. Methods: Stroke- and dementia-free participants (n  = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status. Results: Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, …elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4  + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample. Conclusion: Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4  + . Show more

Keywords: APOE4 , cognition, depression, framingham offspring study, magnetic resonance imaging

DOI: 10.3233/JAD-200998

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1269-1279, 2021

Authors: VanDusen, Keith W. | Li, Yi-Ju | Cai, Victor | Hall, Ashley | Hiles, Sarah | Thompson, J. Will | Moseley, M. Arthur | Cooter, Mary | Acker, Leah | Levy, Jerrold H. | Ghadimi, Kamrouz | Quiñones, Quintin J. | Devinney, Michael J. | Chung, Stacey | Terrando, Niccolò | Moretti, Eugene W. | Browndyke, Jeffrey N. | Mathew, Joseph P. | Berger, Miles | for the MADCO-PC Investigators

Article Type: Research Article

Abstract: Background: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1–12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. Objective: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. Methods: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks …after major non-cardiac surgery in older adults who did (n  = 8) or did not develop POCD (n  = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. Results: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus without POCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44* 10–13 ). Conclusion: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD. Show more

Keywords: Inflammation, mass spectrometry, neurocognitive disorders, postoperative cognitive dysfunction, proteomics

DOI: 10.3233/JAD-201544

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1281-1297, 2021

Authors: Zhao, Zhiyong | Cai, Huaying | Zheng, Weihao | Liu, Tingting | Sun, Di | Han, Guocan | Zhang, Yi | Wu, Dan

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated that hippocampal atrophy is a hallmark of dementia and can be used to predict the outcome of post-stroke demented (PSD) patients. The hippocampus consists of several subfields but their involvement in the pathophysiology of the PSD remains unclear. Objective: The present study aimed to investigate volumetric alterations of hippocampal subfields in patients with PSD. Methods: High-resolution T1-weighted images were collected from 27 PSD and 28 post-stroke nondemented (PSND) patients who recovered from ischemic stroke, and 17 age-matched normal control (NC). We estimated the volumes of the hippocampal subfields using FreeSurfer 6.0 …which segmented the hippocampus into 12 subfields in each hemisphere. The volumetric differences between the groups were evaluated by the two-sample tests after regressing out the age, sex, education, and total intracranial volume. Results: Compared with NC group, PSD group showed smaller volumes in the entire hippocampus and its subfields, and such differences were not found in PSND group. Moreover, we found the dementia-specific atrophy in the left granule cell layer of dentate gyrus (GC-DG) and CA4 in the PSD patients compared with NC and PSND. Regression analysis showed positive correlations between the changes of cognitive performance and the asymmetry index in the CA3/4 and GC-DG of the PSD group. Furthermore, we found that the volumes of hippocampal subfields provided a better classification performance than the entire hippocampus. Conclusion: Our findings suggest that the hippocampus is reduced in the PSD patients and it presents a selective subfield involvement. Show more

Keywords: Dementia, hippocampal subfields, magnetic resonance imaging, stroke, volume

DOI: 10.3233/JAD-200804

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1299-1309, 2021

Authors: An, Na | Fu, Yu | Shi, Jie | Guo, Han-Ning | Yang, Zheng-Wu | Li, Yong-Chao | Li, Shan | Wang, Yin | Yao, Zhi-Jun | Hu, Bin | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The volume loss of the hippocampus and amygdala in non-demented individuals has been reported to increase the risk of developing Alzheimer’s disease (AD). Many neuroimaging genetics studies mainly focused on the individual effects of APOE and CLU on neuroimaging to understand their neural mechanisms, whereas their synergistic effects have been rarely studied. Objective: To assess whether APOE and CLU have synergetic effects, we investigated the epistatic interaction and combined effects of the two genetic variants on morphological degeneration of hippocampus and amygdala in the non-demented elderly at baseline and 2-year follow-up. …Methods: Besides the widely-used volume indicator, the surface-based morphometry method was also adopted in this study to evaluate shape alterations. Results: Our results showed a synergistic effect of homozygosity for the CLU risk allele C in rs11136000 and APOE ɛ 4 on the hippocampal and amygdalar volumes during a 2-year follow-up. Moreover, the combined effects of APOE ɛ 4 and CLU C were stronger than either of the individual effects in the atrophy progress of the amygdala. Conclusion: These findings indicate that brain morphological changes are caused by more than one gene variant, which may help us to better understand the complex endogenous mechanism of AD. Show more

Keywords: APOE , CLU , morphometry, subcortical structures, synergistic

DOI: 10.3233/JAD-201162

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1311-1327, 2021

Authors: Mur, Jure | McCartney, Daniel L. | Chasman, Daniel I. | Visscher, Peter M. | Muniz-Terrera, Graciela | Cox, Simon R. | Russ, Tom C. | Marioni, Riccardo E.

Article Type: Research Article

Abstract: Background: The genetic variant rs9923231 (VKORC1 ) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p  = 1.8×10–7 ), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic …regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1 , risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p  < 4.6×10–6 ). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele  = –0.29, p  < 2×10–16 ) and risk of vascular dementia (OR = 1.17, p  = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia. Show more

Keywords: Alzheimer disease, genetics, vascular dementia, warfarin

DOI: 10.3233/JAD-201256

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1329-1337, 2021