Journal of Alzheimer's Disease - Volume 81, issue 1

Authors: Li, Xuanting | Yuan, Junliang | Qin, Wei | Yang, Lei | Yang, Shuna | Li, Yue | Hu, Wenli

Article Type: Research Article

Abstract: Background: Cerebral microbleed (CMB) is an increasingly important risk factor for cognitive impairment due to population aging. Controversies, however, remain regarding the exact association between CMB and cognitive dysfunction. Objective: We aimed to determine the relationship between CMB burden and cognitive impairment, and also explore the characteristics of cognitive decline in CMB patients for middle-aged and elderly people. Methods: The present cross-sectional study included 174 participants (87 CMB patients and 87 controls) who underwent brain magnetic resonance imaging and a battery of neuropsychological test. Global cognitive function was measured using Mini-Mental State Examination (MMSE) and Montreal …Cognitive Assessment (MoCA). Compound z-scores were calculated for three cognitive subdomains: memory, executive function and processing speed. Results: CMB patients had lower scores of MMSE (p  < 0.001) and MoCA (p  < 0.001). Patients at each category of CMB count had worse performance in global cognitive function and all three cognitive subdomains (p  < 0.001). In multiple linear regression models, CMB patients had significantly greater declines in executive function (p  < 0.001), processing speed (p  < 0.001), and MoCA (p  = 0.003) with increasing number of CMB. We found no relationship between CMB location and cognition (p  > 0.05). Conclusion: CMB is associated with impairment in global cognition as well as for all tested subdomains. Strongest effect sizes were seen for tests which rely on executive functioning, where performance deficits increased in proportion to degree of CMB burden. Prospective studies are needed to evaluate whether the association between CMB and executive dysfunction is causal. Show more

Keywords: Cerebral microbleed, cerebral small vessel disease, cognitive impairment, susceptibility weighted imaging

DOI: 10.3233/JAD-201202

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 255-262, 2021

Authors: Ma, Ya-Hui | Wang, Ya-Yu | Tan, Lan | Xu, Wei | Shen, Xue-Ning | Wang, Hui-Fu | Hou, Xiao-He | Cao, Xi-Peng | Bi, Yan-Lin | Dong, Qiang | Yang, Jiu-Long | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ1–42 and Aβ1–40 ) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using …self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ1–42 and T-tau/Aβ1–42 and high Aβ1–42 /Aβ1–40 ). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= –0.005, p  < 0.001), Aβ1–42 /Aβ1–40 (β= 0.481, p  = 0.001), and T-tau/Aβ1–42 (β= –0.047, p  < 0.001) were noted in preclinical AD stage than controls. Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, lifestyle, social network

DOI: 10.3233/JAD-201426

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 263-272, 2021

Authors: Pan, Danmin | Gu, Jin-Hua | Zhang, Jin | Hu, Yae | Liu, Fei | Iqbal, Khalid | Cekic, Nevena | Vocadlo, David J. | Dai, Chun-Ling | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle …of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD. Show more

Keywords: Alzheimer’s disease, O-GlcNAcylation, OGA, OGA inhibitor, tau hyperphosphorylation, Thiamme2-G

DOI: 10.3233/JAD-201450

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 273-286, 2021

Authors: Byeon, Gihwan | Byun, Min Soo | Yi, Dahyun | Lee, Jun Ho | Jeon, So Yeon | Ko, Kang | Jung, Gijung | Lee, Jun-Young | Kim, Yu Kyeong | Lee, Yun-Sang | Kang, Koung Mi | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE research group

Article Type: Research Article

Abstract: Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11 C] Pittsburgh Compound …B (PiB) PET, [18 F] AV-1451 PET, and brain MRI. Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer’s disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM. Show more

Keywords: Brain atrophy, diabetes mellitus, homocysteine, magnetic resonance imaging, positron emission tomography

DOI: 10.3233/JAD-210036

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 287-295, 2021

Authors: Morris, Robert | Luboff, Hunter | Jose, Rahul P. | Eckhoff, Kyle | Bu, Kun | Pham, Minh | Rohlsen-Neal, Dekai | Cheng, Feng

Article Type: Research Article

Abstract: Background: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer’s disease (AD) treatment. Objective: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. Methods: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took …over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. Results: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and the stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. Conclusion: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provided insight into the underlying molecular mechanisms that induce bradycardia by donepezil. Show more

Keywords: Acetylcholinesterase inhibitors, AChE, Alzheimer’s disease, bradycardia, donepezil, endothelial nitric oxide synthase

DOI: 10.3233/JAD-201551

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 297-307, 2021

Authors: Ikeda, Shunya | Mimura, Masaru | Ikeda, Manabu | Wada-Isoe, Kenji | Azuma, Mie | Inoue, Sachie | Tomita, Kiyoyuki

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) is the leading cause of long-term care in Japan. Objective: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families. Methods: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged …20–69 and informal care costs for all ADD family caregivers were estimated. Results: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20–69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion. Conclusion: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address. Show more

Keywords: Alzheimer’s disease dementia, burden of illness, clinical dementia rating, healthcare cost, long-term care cost, productivity cost

DOI: 10.3233/JAD-210075

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 309-319, 2021

Authors: Jitlal, Mark | Amirthalingam, Guru N.K. | Karania, Tasvee | Parry, Eve | Neligan, Aidan | Dobson, Ruth | Noyce, Alastair J. | Marshall, Charles R.

Article Type: Research Article

Abstract: Background: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. Objective: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. Methods: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with …likelihood of receiving a diagnosis of unspecified dementia. Results: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95% CI] in decile 1 : 0.528 [0.506 to 0.550], decile 10:0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95% CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95% CI] for decile 10:0.78 [0.76 to 0.80] relative to decile 1). Conclusion: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality. Show more

Keywords: Age at death, Alzheimer’s disease, dementia, deprivation, diagnosis, mortality, socioeconomic status

DOI: 10.3233/JAD-210089

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 321-328, 2021

Authors: Douros, Antonios | Santella, Christina | Dell’Aniello, Sophie | Azoulay, Laurent | Renoux, Christel | Suissa, Samy | Brassard, Paul

Article Type: Research Article

Abstract: Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up …to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed > 2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12–30 years (OR, 1.11; 95% CI, 1.05–1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, infection, neurodegenerative diseases

DOI: 10.3233/JAD-201534

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 329-338, 2021

Authors: Edlund, Anna K. | Chen, Kewei | Lee, Wendy | Protas, Hillary | Su, Yi | Reiman, Eric | Caselli, Richard | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose …(CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD. Show more

Keywords: APOE, apolipoprotein E, cerebral glucose metabolism, glucose, insulin

DOI: 10.3233/JAD-210065

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 339-354, 2021

Authors: Kleiman, Michael J. | Barenholtz, Elan | Galvin, James E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Detecting early-stage Alzheimer’s disease in clinical practice is difficult due to a lack of efficient and easily administered cognitive assessments that are sensitive to very mild impairment, a likely contributor to the high rate of undetected dementia. Objective: We aim to identify groups of cognitive assessment features optimized for detecting mild impairment that may be used to improve routine screening. We also compare the efficacy of classifying impairment using either a two-class (impaired versus non-impaired) or three-class using the Clinical Dementia Rating (CDR 0 versus CDR 0.5 versus CDR 1) approach. Methods: Supervised feature selection …methods generated groups of cognitive measurements targeting impairment defined at CDR 0.5 and above. Random forest classifiers then generated predictions of impairment for each group using highly stochastic cross-validation, with group outputs examined using general linear models. Results: The strategy of combining impairment levels for two-class classification resulted in significantly higher sensitivities and negative predictive values, two metrics useful in clinical screening, compared to the three-class approach. Four features (delayed WAIS Logical Memory, trail-making, patient and informant memory questions), totaling about 15 minutes of testing time (∼30 minutes with delay), enabled classification sensitivity of 94.53% (88.43% positive predictive value, PPV). The addition of four more features significantly increased sensitivity to 95.18% (88.77% PPV) when added to the model as a second classifier. Conclusion: The high detection rate paired with the minimal assessment time of the four identified features may act as an effective starting point for developing screening protocols targeting cognitive impairment defined at CDR 0.5 and above. Show more

Keywords: Alzheimer’s disease, data mining, mild cognitive impairment, neuropsychological tests, supervised machine learning

DOI: 10.3233/JAD-201377

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 355-366, 2021