Journal of Alzheimer's Disease - Volume 78, issue 4

Authors: Frings, Lars | Heimbach, Bernhard | Meyer, Philipp T. | Hellwig, Sabine

Article Type: Research Article

Abstract: Background: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD. Objective: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD. Methods: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123 I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared …between patients with and those without NSD as assessed by [123 I]FP-CIT SPECT. Results: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123 I]FP-CIT SPECT scan (p  < 0.05). Statistical analyses revealed no significant differences comparing reaction times to visual stimuli or dispersion of reaction times between groups. Exploratory analysis in a subgroup of patients with available [18 F]FDG PET revealed that longer reaction times were associated with decreased glucose metabolism in the prefrontal cortex (statistical parametric mapping, adjusted for age and sex; p  < 0.005, cluster extent > 50 voxels). Conclusion: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD. Show more

Keywords: Alertness, dementia with Lewy bodies, fluctuations, Lewy body diseases, [123I]FP-CIT SPECT, [18F]FDG PET

DOI: 10.3233/JAD-191277

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1721-1729, 2020

Authors: Esteban de Antonio, Ester | López-Álvarez, Jorge | Rábano, Alberto | Agüera-Ortiz, Luis | Sánchez-Soblechero, Antonio | Amaya, Laura | Portela, Sofía | Cátedra, Carlos | Olazarán, Javier

Article Type: Research Article

Abstract: Background: Comprehensive clinicopathological studies of neuropsychiatric symptoms (NPS) in dementia are lacking. Objective: To describe the pathological correlations of NPS in a sample of institutionalized people with dementia. Methods: We studied 59 people who were consecutively admitted to a nursing home and donated their brain. Correlations between pathological variables and NPS upon admission (n  = 59) and at one-year follow-up assessment (n  = 46) were explored and confirmed using bivariate and multivariate statistical methods. Results: Mean (SD) age at admission was 83.2 (6.4) years and mean (SD) age at demise was 85.4 (6.6); 73% of the …subjects were female and 98% presented advanced dementia. The most frequent etiological diagnosis was Alzheimer’s disease (AD; 74.6% clinical diagnosis, 67.8% pathological diagnosis). The pathological diagnosis of AD was associated with aggression (β est 0.31), depression (β est 0.31), anxiety (β est 0.38), and irritability (β est 0.28). Tau stage correlated with aggressive symptoms (β est 0.32) and anxiety (βest 0.33). Coexistence of AD and Lewy body pathology was associated with depression (β est 0.32), while argyrophilic grains were associated with eating symptoms (β est 0.29). Predictive models were achieved for apathy, including cognitive performance, basal ganglia ischemic lesions, and sex as predictors (R2 0.38) and for sleep disorders, including pathological diagnosis of AD and age at demise (R2 0.18) (all p -values <0.05, unadjusted). Conclusion: AD was the main pathological substrate of NPS in our sample of very elderly people with advanced dementia. However, correlations were mild, supporting a model of focal/asymmetric rather than diffuse brain damage, along with relevance of environmental and other personal factors, in the genesis of those symptoms. Show more

Keywords: Aged, Alzheimer’s disease, behavioral symptoms, dementia, neuropathology

DOI: 10.3233/JAD-200600

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1731-1741, 2020

Authors: Flax, Jarrod | Wilkins, Heather M. | Miller, Reegan | Griffith, Sarah | Cork, Gentry K. | Qiang, Amy | Thompson, Jeffrey | Swerdlow, Russell H. | Slawson, Chad

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) features reductions in key bioenergetic fluxes and perturbed mitochondrial function. Cytoplasmic hybrids (cybrids) generated through the transfer of AD subject mitochondria to mtDNA-depleted SH-SY5Y neuroblastoma cells recapitulate some of these features in an in vitro setting. Objective: For this study, we used the AD cybrid model to assess the impact of a nutrient-excess like-state via increasing O-GlcNAcylation on whole cell and mitochondrial homeostasis. Methods: We induced increased O-GlcNAc by treating AD and control cybrid cell lines with Thiamet G (TMG), an inhibitor of the O-GlcNAcase enzyme that mediates removal of the …nutrient-dependent O-GlcNAc modification. Results: Relative to control cybrid cell lines, AD cybrid lines showed a blunted response to TMG-induced O-GlcNAcylation. At baseline, AD cybrid cell line mitochondria showed partial activation of several proteins that help maintain bioenergetic homeostasis such as AMP-Regulated Kinase suggesting that AD mitochondria initiate a state of nutrient stress promoting energetic compensation; however, this compensation reduces the capacity of cells to respond to additional nutrient-related stresses such as TMG treatment. Also, TMG caused disruptions in acetylation and Sirtuin 3 expression, while lowing total energetic output of the cell. Conclusion: Together, these findings suggest that modulation of O-GlcNAc is essential for proper energetic function of the mitochondria, and AD mitochondrial capacity to handle nutrient-excess is limited. Show more

Keywords: Acetylation, cybrids, mitochondria, O-GlcNAc, O-GlcNAcase (OGA), O-GlcNAc transferase (OGT), oxidative phosphorylation, SIRT3

DOI: 10.3233/JAD-200996

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1743-1753, 2020

Authors: Oveisgharan, Shahram | Capuano, Ana W. | Kapasi, Alifiya | Buchman, Aron S. | Schneider, Julie A. | Bennett, David A. | Arvanitakis, Zoe

Article Type: Research Article

Abstract: Background: Vascular mechanisms may contribute to the accumulation of AD pathology. Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association. Methods: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau …levels and examined if the FRS modified the association of the amyloid-β with tau. Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = –0.00, p  = 0.918) or tau (r  = 0.01, p  = 0.701). However, the FRS as a whole (estimate = –0.022, SE = 0.008, p  = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = –0.033, SE = 0.012, p  = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP. Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another. Show more

Keywords: Alzheimer’s disease, amyloid, autopsy, blood pressure, diabetes mellitus, risk factors, smoking, tau proteins

DOI: 10.3233/JAD-200412

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1755-1764, 2020

Authors: Ii, Yuichiro | Ishikawa, Hidehiro | Matsuyama, Hirofumi | Shindo, Akihiro | Matsuura, Keita | Yoshimaru, Kimiko | Satoh, Masayuki | Taniguchi, Akira | Matsuda, Kana | Umino, Maki | Maeda, Masayuki | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Background: Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. Objective: We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. Methods: Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical …superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. Results: The two scores were positively correlated (ρ = 0.449, p  < 0.001). The prevalence of lobar dominant CMB distribution (p  < 0.001) and lacunes in the centrum semiovale (p  < 0.001) and the severity of WMH in the parieto-occipital lobes (p  = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. Conclusion: Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed. Show more

Keywords: Cerebral amyloid angiopathy, cerebral small vessel diseases, cognitive decline, hypertension, magnetic resonance imaging

DOI: 10.3233/JAD-200992

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1765-1774, 2020

Authors: Liu, Nanyang | Sun, Jiahui | Wang, Xiyuan | Zhao, Ming | Huang, Qianqian | Li, Hao

Article Type: Research Article

Abstract: Background: The emergence of the coronavirus disease 2019 (COVID-19) has brought large challenges to dementia patients. We reviewed the existing literature on COVID-19 to assess the incidence and mortality of dementia comorbidities in COVID-19 patients. Objective: To investigate the impact of pre-existing dementia comorbidities on COVID-19. Methods: We searched the PubMed, Embase, and Web of Science databases for patients with preexisting dementia who were diagnosed with COVID-19. The statistical data on the prevalence and mortality of dementia comorbidities were examined. A fixed-or random-effect model was used to calculate the overall pooled risk estimates. Forest plots were …generated to show the summarized results. Results: A total of 265 articles were retrieved from the three databases. After removing duplicates and performing two screenings, 10 articles were selected for meta-analysis, including 119,218 participants. Overall, the meta-analysis of the 10 studies showed that the incidence of dementia in COVID-19 patients was (R: 9%, [95% CI: 6% to 13%]). Moreover, the meta-analysis of 9 studies showed that the mortality rate of individuals with dementia after being infected with COVID-19 was higher than that of individuals with no dementia (OR: 5.17 [95% CI: 2.31 to 11.59]). Substantial heterogeneity was observed in this meta-analysis. Significant publication bias was also found. Conclusion: Emerging literature shows that dementia comorbidities are a high risk factor for the prevalence and mortality of COVID-19. Our results should have an impact on preventive interventions and encourage more targeted approaches to prioritize older people with specific risk factors, such as dementia. Show more

Keywords: Alzheimer’s disease, coronavirus disease 2019, dementia, meta-analysis

DOI: 10.3233/JAD-201016

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1775-1782, 2020

Authors: Rao, Shalini S. | Portbury, Stuart. D. | Lago, Larissa | Bush, Ashley I. | Adlard, Paul A.

Article Type: Correction

DOI: 10.3233/JAD-209009

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1783-1787, 2020

Article Type: Other

DOI: 10.3233/JAD-209010

Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1785-1798, 2020