Journal of Alzheimer's Disease - Volume 88, issue 3

Authors: Kobayashi, Masatomo | Yamada, Yasunori | Shinkawa, Kaoru | Nemoto, Miyuki | Nemoto, Kiyotaka | Arai, Tetsuaki

Article Type: Research Article

Abstract: Background: Automatic analysis of the drawing process using a digital tablet and pen has been applied to successfully detect Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, most studies focused on analyzing individual drawing tasks separately, and the question of how a combination of drawing tasks could improve the detection performance thus remains unexplored. Objective: We aimed to investigate whether analysis of the drawing process in multiple drawing tasks could capture different, complementary aspects of cognitive impairments, with a view toward combining multiple tasks to effectively improve the detection capability. Methods: We collected drawing data …from 144 community-dwelling older adults (27 AD, 65 MCI, and 52 cognitively normal, or CN) who performed five drawing tasks. We then extracted motion- and pause-related drawing features for each task and investigated the associations of the features with the participants’ diagnostic statuses and cognitive measures. Results: The drawing features showed gradual changes from CN to MCI and then to AD, and the changes in the features for each task were statistically associated with cognitive impairments in different domains. For classification into the three diagnostic categories, a machine learning model using the features from all five tasks achieved a classification accuracy of 75.2%, an improvement by 7.8% over that of the best single-task model. Conclusion: Our results demonstrate that a common set of drawing features from multiple drawing tasks can capture different, complementary aspects of cognitive impairments, which may lead to a scalable way to improve the automated, reliable detection of AD and MCI. Show more

Keywords: Alzheimer’s disease, digital technology, drawing, handwriting, machine learning, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-215714

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1075-1089, 2022

Authors: Brown, Belinda M. | de Frutos Lucas, Jaisalmer | Porter, Tenielle | Frost, Natalie | Vacher, Michael | Peiffer, Jeremiah J. | Laws, Simon M.

Article Type: Research Article

Abstract: Background: Previous research suggests physical activity attenuates grey and white matter loss; however, there appears to be individual variability in this effect. Understanding factors that can influence the relationship between physical activity and brain volume may enable prediction of individual response. Objective: The current study examined the relationship between objectively-measured physical activity and brain volume; and whether this relationship is moderated by age, sex, or a priori candidate genetic factors, brain-derived neurotrophic factor (BDNF ) Val66Met, or apolipoprotein (APOE ) ɛ4 allele carriage. Methods: Data from 10,083 men and women (50 years and over) of …the UK Biobank were used to examine the study objectives. All participants underwent a magnetic resonance imaging scan to quantify grey and white matter volumes, physical activity monitoring via actigraphy, and genotyping. Results: Physical activity was associated with total grey matter volume, total white matter volume, and right hippocampal volume. Only males had an association between higher physical activity levels and greater cortical grey matter volume, total grey matter volume, and right hippocampal volume. Age moderated the relationship between physical activity and white matter volume. Conclusion: Our results indicate that in males, but not females, an association exists between objectively-measured physical activity and grey matter volume. Age may also play a role in impacting the relationship between physical activity and brain volume. Future research should evaluate longitudinal brain volumetrics to better understand the nature of age and sex-effects on the physical activity and brain volume relationship. Show more

Keywords: Dementia, genotype, hippocampus, sex differences

DOI: 10.3233/JAD-220114

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1091-1101, 2022

Authors: Khedr, Eman M. | Omeran, Nehad | Karam-Allah Ramadan, Haidi | Ahmed, Gellan K. | Abdelwarith, Ahmed M.

Article Type: Research Article

Abstract: Background: Dysbiosis of gut microbiota has been reported to be enrolled in the pathogenesis of Alzheimer’s disease (AD). However, there is a lack of relevant studies on this topic in Egyptian patients with AD. Objective: To investigate different species of gut microbiota in Egyptian patients with AD and correlate microbiota bacterial abundance with clinical data. Methods: The study included 25 patients with AD and 25 healthy volunteers as age and sex-matched controls. Clinical data was taken for each patient, including medical history and examination; Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed for …each participant. Bacterial DNA was extracted from stool, and abundance quantified via qPCR using 16S rRNA group-specific primers. Results: Akkermansia , Enterobacteria , Bacteroidetes , Bacillus cereus , Prevotella , and Clostridium cluster IV were more abundant in the AD group than in the control group, although there was significantly less abundance of Bifidobacterium spp., Firmicutes , and Actinobacteria in patients with AD than in controls, whereas no such significance was found for lactic acid bacteria between both groups. Lactic acid bacteria and Prevotella abundance was negatively correlated with cognitive impairment (p  = 0.03 with MMSE, and p  = 0.03 with MoCA). Prevotella abundance was positively correlated with age of onset and duration of illness and negatively correlated with smoking and coronary heart disease (p  = 0.007, p  = 0.03, p  = 0.035, and p  = 0.047, respectively). Conclusion: The current work highlighted a significant relationship between AD and gut microbiota dysbiosis. A higher abundance of Prevotella species and lactic acid bacteria was correlated with cognition. Show more

Keywords: Alzheimer’s disease, cognition, gut microbiota, mini-mental state examination, montreal cognitive assessment

DOI: 10.3233/JAD-220176

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1103-1114, 2022

Authors: Pan, Rui | Luo, Shuyi | Huang, Qing | Li, Weiwei | Cai, Tianshu | Lai, Kelin | Shi, Xiaolei

Article Type: Research Article

Abstract: Background: Increasing evidence has suggested that iron accumulation plays an important role in the onset and development of Alzheimer’s disease (AD). However, the potential mechanism remains unclear. Objective: The present study investigated the associations of cerebrospinal fluid (CSF) ferritin, an indicator for brain iron load, with neurodegenerative and inflammatory changes in AD. Methods: The study involved 302 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). They were classified as normal controls (A–T–N–, n  = 48), AD continuum (A+TN–, n  = 46; A+TN+, n  = 166), and suspected non-AD pathology (A–TN+, n  = 42), according to the amyloid/tau/neurodegeneration (ATN) system. Group …comparisons of CSF ferritin among groups were performed using one-way ANOVA. Linear regression models were used to test the relationships between CSF ferritin and cognitive assessments, and the associations between CSF ferritin and other biomarkers, respectively. Results: We found that CSF ferritin showed significant differences among the ATN groups, with higher concentration in more advanced categories (A+TN+). Furthermore, CSF ferritin level was independently related to cognitive performance (MMSE, ADAS-Cog13, and ADNI-mem). Linear regression analysis indicated positive relationships between CSF ferritin and phosphorylated tau and total tau, rather than Aβ42 . Significant associations were revealed between CSF ferritin and inflammatory proteins, including TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, TGF-β1, IL-9, and IP-10, respectively. Conclusion: Our results provide new insight into iron dysfunction in AD pathology and highlight elevated brain iron as a possible mechanism of neurodegeneration and neuroinflammation along AD continuum. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, ferritin, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-220002

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1115-1125, 2022

Authors: Ali, Doaa G. | Bahrani, Ahmed A. | Barber, Justin M. | El Khouli, Riham H. | Gold, Brian T. | Harp, Jordan P. | Jiang, Yang | Wilcock, Donna M. | Jicha, Gregory A.

Article Type: Research Article

Abstract: Background: Global amyloid-β (Aβ) deposition in the brain can be quantified by Aβ-PET scans to support or refute a diagnosis of preclinical Alzheimer’s disease (pAD). Yet, Aβ-PET scans enable quantitative evaluation of regional Aβ elevations in pAD, potentially allowing even earlier detection of pAD, long before global positivity is achieved. It remains unclear as to whether such regional changes are clinically meaningful. Objective: Test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in pAD. Methods: Global and regional standardized uptake value ratios (SUVr) …from 18 F-florbetapir PET/CT scanning were determined using the Siemens Syngo.via® Neurology software package across a sample of 99 clinically normal participants with Montreal Cognitive Assessment (MoCA) scores≥23. Relationships between regional SUVr and cognitive test scores were analyzed using linear regression models adjusted for age, sex, and education. Participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in cognitive test scores were analyzed using ANCOVA models. Results: Executive function performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p  < 0.05). There were no significant associations between memory and Aβ-PET SUVr in any regions of the brain. Conclusion: These data demonstrate that increased Aβ deposition in the precuneus and posterior cingulate (the earliest brain regions affected with Aβ pathology) is associated with changes in executive function that may precede memory decline in pAD. Show more

Keywords: Amyloid-β positron emission tomography, cognition, preclinical Alzheimer’s disease, regional standardized uptake value ratio

DOI: 10.3233/JAD-220294

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1127-1135, 2022

Authors: Aguilar-Calvo, Patricia | Sevillano, Alejandro M. | Rasool, Suhail | Cao, Kevin J. | Randolph, Lyndsay M. | Rissman, Robert A. | Sarraf, Stella T. | Yang, Jerry | Sigurdson, Christina J.

Article Type: Research Article

Abstract: Background: Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease. Objective: Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy. Methods: We performed retinal imaging on an experimental mouse model of prion-associated cerebral amyloid angiopathy in a longitudinal study. An amyloid-binding fluorophore was intravenously administered, and retinal imaging was performed …at timepoints corresponding to early, mid-, and terminal prion disease. Retinal amyloid deposits were quantified and compared to the amyloid load in the brain. Results: We report that by early prion disease (50% timepoint), discrete fluorescent foci appeared adjacent to the optic disc. By later timepoints, the fluorescent foci surrounded the optic disc and tracked along retinal vasculature. Conclusion: The progression of perivascular amyloid can be directly monitored in the eye by live imaging, illustrating the utility of this technology for diagnosing and monitoring the progression of cerebral amyloid angiopathy. Show more

Keywords: Alzheimer’s disease, amyloid, cerebral amyloid angiopathy, diagnostic, early diagnosis, eye, fluorophore, neurodegeneration, prion, protein misfolding, retina, retinal amyloid

DOI: 10.3233/JAD-220314

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1137-1145, 2022

Authors: Novotný, Jan S. | Gonzalez-Rivas, Juan P. | Vassilaki, Maria | Krell-Roesch, Janina | Geda, Yonas E. | Stokin, Gorazd B.

Article Type: Research Article

Abstract: Background: Considering the world’s rapidly increasing life expectancy, with people working and maintaining active lifestyles longer than ever before, addressing the effects of aging on cognition is of utmost importance. A greater understanding of cognitive aging may also be critical in distinguishing natural cognitive aging from pre-clinical stages of Alzheimer’s disease and related cognitive disorders. Objective: To systematically examine the association between aging and cognitive performance in a cognitively and otherwise healthy probability population-based sample using a computer-based method. Methods: This cross-sectional study enrolled 673 cognitively and otherwise healthy participants aged 25–89 years (mean age 52.3±14.2 …years, 52.5% of whom were female) from the Kardiovize study cohort. Mild cognitive impairment and dementia cases were excluded, followed by measurement of cognitive performance with the computer-administered Cogstate Brief Battery. We used ANCOVA and Modified Signed-Likelihood Ratio tests to examine patterns of cognition across age groups. Results: We found a gradual decrease in cognitive performance across the lifespan, which required two decades to demonstrate significant changes. In contrast to attention and learning, psychomotor speed and working memory showed the most significant age-related decrease and variability in performance. The established pattern of cognitive aging was not altered by sex or education. Conclusion: These findings corroborate, validate, and extend the current understanding of natural cognitive aging and pinpoint specific cognitive domains with the most extensive age-related interindividual differences. This will contribute to the development of strategies to preserve cognition with aging and may also serve to improve early diagnostics of cognitive disorders using computer-based methods. Show more

Keywords: Aging, Alzheimer’s disease, cognition, physiology, pre-clinical diagnostics

DOI: 10.3233/JAD-220312

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1147-1155, 2022

Authors: Dumuid, Dorothea | Mellow, Maddison L. | Olds, Tim | Tregoweth, Emma | Greaves, Danielle | Keage, Hannah | Smith, Ashleigh E.

Article Type: Research Article

Abstract: Background: The 24 h time-use composition of physical activity, sedentary behavior, and sleep is linked to cognitive function in adults and may contribute to future dementia risk. However, the impact of reallocating time between behaviors may differ depending on an individual’s genetic dementia risk. Objective: To explore if there is an interaction between 24 h time-use composition and genetic dementia risk in relation to cognitive function, and to simulate how time-reallocations are associated with cognitive function across different levels of genetic dementia risk. Methods: Cross-sectional global cognition, executive function, genetic dementia risk (at least one apolipoprotein (APOE ) …ɛ4 allele versus none) and 7 days of 24 h accelerometry (average daily time-use composition of moderate-to-vigorous physical activity (MVPA), light physical activity, sedentary behavior, sleep) were collected from 82 adults (65.6±7.5 years, 49 females). Linear regression was used to explore the relationship between time-use composition and cognitive measures, testing for interaction between APOE ɛ4 status and time-use composition. The models were used to simulate time reallocations in both APOE ɛ4 status groups. Results: The 24 h time-use composition was associated with global cognition (F = 2.4, p  = 0.02) and executive function (F = 2.6, p  = 0.01). For both measures, the association differed according to genetic risk (interactions p  < 0.001). In both APOE groups, reallocating time to MVPA was beneficially associated with measures of cognitive function, but associations were larger among those with at least one APOE ɛ4 allele. Conclusion: Genetic dementia risk may impact the effectiveness of activity interventions. Increasing MVPA may provide greater benefits among those with higher genetic dementia risk. Show more

Keywords: Aging, cognition, compositional data analysis, physical activity, sedentary behavior, sleep

DOI: 10.3233/JAD-220181

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1157-1165, 2022

Authors: Khalil, Rania M. | Alaa, Shereen | Eissa, Hanan | Youssef, Ibrahim

Article Type: Research Article

Abstract: Background: The relationship between diabetes mellitus and neurodegenerative disorders has been of great interest. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine in which a variety of signaling cascades are activated through it. MIF has been involved in the pathogenesis of several diseases and can predict early pre-symptomatic stages of neurodegeneration in diabetic patients. Objective: To investigate whether serum MIF could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients. Methods: We examined adults with type 2 diabetes mellitus and compared with normal control adults using a short form of the IQCODE and …biochemical examination, including assessment of HA1C , fasting blood glucose, lipid profile, and MIF which was measured by ELISA technique. Correlations between parameters were studied. Computational PathLinker bioinformatic tool was used to search for potential pathway reconstructions for the insulin/amyloid-β/MIF signaling. Results: We demonstrated that MIF level was increased in the serum at the early pre-symptomatic stages of neurodegenerative disorder in diabetic patients. In addition, network analysis demonstrates that insulin receptor substrate 1 can ameliorate amyloid-β protein precursor through COP9 signalosome complex subunit 5 that enhances MIF elevation. Conclusion: Diagnosis processes could not be used as routine examinations for still pre-symptomatic neurodegenerative disorders. This may be due to the time constraints and the heavy dependence on the physician’s experience. Therefore, serum MIF level could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients which may support its potential utility as a clinically useful biomarker. Show more

Keywords: Biological network, IQCODE, macrophage migration inhibitory factor, neurodegenerative disorder, PathLinker, pre-symptomatic stages

DOI: 10.3233/JAD-215561

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1167-1177, 2022

Authors: Loreto, Flavia | Fitzgerald, Anna | Golemme, Mara | Gunning, Stephen | Win, Zarni | Patel, Neva | Carswell, Christopher | Perry, Richard | Kennedy, Angus | Edison, Paul | Malhotra, Paresh

Article Type: Research Article

Abstract: Background: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer’s disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. Objective: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. Methods: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with …amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. Results: One hundred forty-two (47%) patients had a history of significant depressive symptoms (‘D+’). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. Conclusion: Approximately half of patients who meet appropriate use criteria for amyloid PET have a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-PET, clinical cohort, dementia, depression, diagnostic uncertainty

DOI: 10.3233/JAD-220170

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1179-1187, 2022

Authors: Cairns, Dana M. | Itzhaki, Ruth F. | Kaplan, David L.

Article Type: Research Article

Abstract: Background: Varicella zoster virus (VZV) has been implicated in Alzheimer’s disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain. Objective: To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected …with HSV-1. Methods: We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and sought the presence of AD-related phenotypes such as amyloid-β (Aβ) and P-tau accumulation, gliosis, and neuroinflammation. Results: Cells infected with VZV did not show the main AD characteristics, Aβ and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZV’s action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aβ and P-tau accumulation. Conclusion: Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in AD/dementia via reactivation of HSV-1 in brain. Show more

Keywords: Alzheimer’s disease, 3D brain model, herpes simplex virus type 1, latent, quiescent, reactivation, varicella zoster virus

DOI: 10.3233/JAD-220287

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1189-1200, 2022

Authors: Sarpalius, Jenny

Article Type: Book Review

DOI: 10.3233/JAD-220553

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1201-1202, 2022