Journal of Alzheimer's Disease - Volume 81, issue 4

Authors: Camargo, Aldo | Wang, Ze | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cross-sectional studies have shown lower cerebral blood flow (CBF) in Alzheimer’s disease (AD), but longitudinal CBF changes in AD are still unknown. Objective: To reveal the longitudinal CBF changes in normal control (NC) and the AD continuum using arterial spin labeling perfusion magnetic resonance imaging (ASL MRI). Methods: CBF was calculated from two longitudinal ASL scans acquired 2.22±1.43 years apart from 140 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). At the baseline scan, the cohort contained 41 NC, 74 mild cognitive impairment patients (MCI), and 25 AD patients. 21 NC converted into MCI and …17 MCI converted into AD at the follow-up. Longitudinal CBF changes were assessed using paired-t test for non-converters and converters separately at each voxel and in the meta-ROI. Age and sex were used as covariates. Results: CBF reductions were observed in all subjects. Stable NC (n  = 20) showed CBF reduction in the hippocampus and precuneus. Stable MCI patients (n  = 57) showed spatially more extended CBF reduction patterns in hippocampus, middle temporal lobe, ventral striatum, prefrontal cortex, and cerebellum. NC-MCI converters showed CBF reduction in hippocampus and cerebellum and CBF increase in caudate. MCI-AD converters showed CBF reduction in hippocampus and prefrontal cortex. CBF changes were not related with longitudinal neurocognitive changes. Conclusion: Normal aging and AD continuum showed common longitudinal CBF reductions in hippocampus independent of disease and its conversion. Disease conversion independent longitudinal CBF reductions escalated in MCI subjects. Show more

Keywords: Aging, Alzheimer’s disease, arterial spin labeling, cerebral blood flow, longitudinal analysis

DOI: 10.3233/JAD-210116

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1727-1735, 2021

Authors: Koyanagi, Ai | Smith, Lee | Shin, Jae Il | Oh, Hans | Kostev, Karel | Jacob, Louis | Abduljabbar, Adel S. | Haro, Josep Maria

Article Type: Research Article

Abstract: Background: Data on the association between multimorbidity and subjective cognitive complaints (SCC) are lacking from low- and middle-income countries (LMICs). Objective: To assess the association between multimorbidity and SCC among adults from 48 LMICs. Methods: Cross-sectional, community-based data were analyzed from the World Health Survey 2002–2004. Ten chronic conditions (angina, arthritis, asthma, chronic back pain, depression, diabetes, edentulism, hearing problems, tuberculosis, visual impairment) were assessed. Two questions on subjective memory and learning complaints in the past 30 days were used to create a SCC scale ranging from 0 (No SCC) to 100 (worse SCC). Multivariable linear …regression and mediation analyses were conducted to explore the associations. Results: A total of 224,842 individuals aged≥18 years [mean (SD) age 38.3 (16.0) years; 49.3% males] constituted the final sample. Compared to no chronic conditions, the mean SCC score was higher by 7.13 (95% CI = 6.57–7.69), 14.84 (95% CI = 13.91–15.77), 21.10 (95% CI = 19.49–22.70), 27.48 (95% CI = 25.20–29.76), and 33.99 (95% CI = 31.45–36.53) points for 1, 2, 3, 4, and≥5 chronic conditions. Estimates by sex and age groups (18–44, 45–64,≥65 years) were similar. Nearly 30% of the association between multimorbidity (i.e.,≥2 chronic conditions) and SCC was explained by psychological factors (i.e., perceived stress, sleep problems, anxiety symptoms). Conclusion: Multimorbidity is associated with SCC among adults in LMICs. Future studies should investigate whether addressing psychological factors in people with multimorbidity can improve cognitive function, and whether screening for SCC in individuals with multimorbidity can be a useful tool to identify individuals at particularly high risk for future cognitive decline. Show more

Keywords: Chronic physical conditions, low- and middle-income countries, multimorbidity, subjective cognitive complaints

DOI: 10.3233/JAD-201592

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1737-1747, 2021

Authors: Du, Fang | Yu, Qing | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer’s disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice. Objective: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction. Methods: Using trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions. …Results: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuates mitochondrial defects and rescues neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for the clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation. Conclusion: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD. Show more

Keywords: Alzheimer’s disease, cybrid cells, mitochondrial dysfunction, mitophagy, PINK1

DOI: 10.3233/JAD-210095

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1749-1761, 2021

Authors: Hirsch, Joseph A. | Cuesta, George M. | Fonzetti, Pasquale | Comaty, Joseph | Jordan, Barry D. | Cirio, Rosanna | Levin, Leanne | Abrahams, Alex | Fry, Kathleen M.

Article Type: Research Article

Abstract: Background: Auditory naming tests are superior to visual confrontation naming tests in revealing word-finding difficulties in many neuropathological conditions. Objective: To delineate characteristics of auditory naming most likely to reveal anomia in patients with dementia, and possibly improve diagnostic utility, we evaluated a large sample of patients referred with memory impairment complaints. Methods: Patients with dementia (N  = 733) or other cognitive impairments and normal individuals (N  = 69) were evaluated for frequency of impairment on variables of the Auditory Naming Test (ANT) of Hamberger & Seidel versus the Boston Naming Test (BNT). Results: Naming impairment …occurred more frequently using the ANT total score (φ = 0.41) or ANT tip-of-the tongue score (TOT; φ = 0.19) but not ANT mean response time compared to the BNT in patients with dementia (p  < 0.001). Significantly more patients were impaired on ANT variables than on the BNT in Alzheimer’s disease (AD), vascular dementia (VaD), mixed AD/VaD, and multiple domain mild cognitive impairment (mMCI) but not in other dementias or amnestic MCI (aMCI). This differential performance of patients on auditory versus visual naming tasks was most pronounced in older, well-educated, male patients with the least cognitive impairment. Impaired verbal comprehension was not contributory. Inclusion of an ANT index score increased sensitivity in the dementia sample (92%). Poor specificity (41%) may be secondary to the inherent limitation of using the BNT as a control variable. Conclusion: The ANT index score adds diagnostic utility to the assessment of naming difficulties in patients with suspected dementia. Show more

Keywords: Alzheimer’s disease, anomia, auditory naming, boston naming test, dementia, mild cognitive impairment, neuropsychological assessment, word-finding

DOI: 10.3233/JAD-210322

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1763-1779, 2021

Authors: Hoffmann, Jessica | Busse, Stefan | von Hoff, Franz | Borucki, Katrin | Frodl, Thomas | Busse, Mandy

Article Type: Research Article

Abstract: Background: Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. Objective: An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer’s disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. …Results: Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. Conclusion: Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed. Show more

Keywords: B vitamins, dementia, homocysteine

DOI: 10.3233/JAD-201481

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1781-1792, 2021