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

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. Pre-press, no. Pre-press, pp. 1-11, 2021

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

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. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Chapman, Silvia | Sunderaraman, Preeti | Joyce, Jillian L. | Azar, Martina | Colvin, Leigh E. | Barker, Megan S. | McKeague, Ian | Kreisl, William C. | Cosentino, Stephanie

Article Type: Research Article

Abstract: Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n  = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and …a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) was endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p  <  0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= –0.22, p  = 0.040, CI = –0.45, –0.01), associative memory (β= –0.26, p  = 0.018, CI = –0.45, –0.06), and list learning (β= –0.31, p  = 0.002, CI = –0.51, –0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= –0.25, p  = 0.012, CI = –0.44, –0.06; β= –0.29, p  = 0.003, CI = –0.47, –0.10) and list learning only (β= –0.25, p  = 0.014, CI = –0.45, –0.05; β= –0.28, p  = 0.004, CI = –0.48, –0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD. Show more

Keywords: Cognitive dysfunction, measurement, neuropsychological tests, preclinical Alzheimer’s disease, subjective cognitive decline, task-specific factors

DOI: 10.3233/JAD-201322

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 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 (β perT - 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. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: VanDusen, Keith W. | Li, Yi-Ju | Cai, Victor | Hall, Ashley | Hiles, Sarah | Will Thompson, J. | Arthur Moseley, M. | 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. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Rhodes, Emma | Insel, Philip S. | Butters, Meryl A. | Morin, Ruth | Bickford, David | Tosun, Duygu | Gessert, Devon | Rosen, Howie J. | Aisen, Paul | Raman, Rema | Landau, Susan | Saykin, Andrew | Toga, Arthur | Jack, Clifford R. | Weiner, Michael W. | Nelson, Craig | Mackinon, Scott | on behalf of the Alzheimer’s Disease Neuroimaging Initiative | the ADNI Depression Project

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6%of the LLD sample demonstrating impairment in at least …one cognitive domain compared to 42.9%of controls (H  = 7.13, p  = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p  = 0.044), Logical Memory II (p  = 0.011), and Trail Making Test –B (p  = 0.032), and APOE ɛ 4 genotype was associated with worse performance on Logical Memory I (p  = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD. Show more

Keywords: Amyloid, apolipoprotein E, cognitive impairment, late life depression

DOI: 10.3233/JAD-201089

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 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 interaction 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. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Ryman, Sephira G. | Yutsis, Maya | Tian, Lu | Henderson, Victor W. | Montine, Thomas J. | Salmon, David P. | Galasko, Douglas | Poston, Kathleen L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology. Objective: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD. Methods: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer’s Coordinating Center’s Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical). …Results: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage. Conclusion: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases. Show more

Keywords: Alzheimer’s disease, cognitive neuropsychology in dementia, dementia with Lewy bodies, Parkinson’s disease, Parkinson’s disease with dementia, parkinsonism

DOI: 10.3233/JAD-201187

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Wright, Clinton B. | DeRosa, Janet T. | Moon, Michelle P. | Strobino, Kevin | DeCarli, Charles | Cheung, Ying Kuen | Assuras, Stephanie | Levin, Bonnie | Stern, Yaakov | Sun, Xiaoyan | Rundek, Tatjana | Elkind, Mitchell S.V. | Sacco, Ralph L.

Article Type: Research Article

Abstract: Background: Variability in dementia rates across racial and ethnic groups has been estimated at 60% . Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited. Objective: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates. Methods: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the …prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3). Results: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity. Conclusion: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships. Show more

Keywords: African American, cohort studies, dementia, Hispanic American, mild cognitive impairment

DOI: 10.3233/JAD-201370

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

Authors: Kontos, Pia | Radnofsky, Mary L. | Fehr, Phyllis | Belleville, Mike R. | Bottenberg, Frances | Fridley, Mary | Massad, Susan | Grigorovich, Alisa | Carson, Jennifer | Rogenski, Kari | Carpenter, Kyrié S. | Dupuis, Sherry | Battalen, Jill | McDonagh, David | Fassbender, Kathryne | Whitehouse, Peter

Article Type: Research Article

Abstract: The rapid emergence of COVID-19 has had far-reaching effects across all sectors of health and social care, but none more so than for residential long-term care homes. Mortality rates of older people with dementia in residential long-term care homes have been exponentially higher than the general public. Morbidity rates are also higher in these homes with the effects of government-imposed COVID-19 public health directives (e.g., strict social distancing), which have led most residential long-term care homes to adopt strict “no visitor” and lockdown policies out of concern for their residents’ physical safety. This tragic toll of the COVID-19 pandemic highlights …profound stigma-related inequities. Societal assumptions that people living with dementia have no purpose or meaning and perpetuate a deep and pernicious fear of, and disregard for, persons with dementia. This has enabled discriminatory practices such as segregation and confinement to residential long-term care settings that are sorely understaffed and lack a supportive, relational, and enriching environment. With a sense of moral urgency to address this crisis, we forged alliances across the globe to form “Reimagining Dementia: A Creative Coalition for Justice. ” We are committed to shifting the culture of dementia care from centralized control, safety, isolation, and punitive interventions to a culture of inclusion, creativity, justice, and respect. Drawing on the emancipatory power of the imagination with the arts (e.g., theatre, improvisation, music), and grounded in authentic partnerships with persons living with dementia, we aim to advance this culture shift through education, advocacy, and innovation at every level of society. Show more

Keywords: Arts, coalition, COVID-19, culture change, relational caring, residential long-term care, social justice

DOI: 10.3233/JAD-210057

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021