Journal of Alzheimer's Disease - Volume 89, issue 2

Authors: Kong, Yu | Chen, Zhongyun | Wang, Xue | Wang, Wenjiao | Zhang, Jing

Article Type: Research Article

Abstract: Background: Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of α -synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker. Objective: The aim of this study was to assess the diagnostic power of CSF α -synuclein in discriminating CJD from non-prion disorders. Methods: The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR α -synuclein). The …difference in CSF α -synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I2  > 50%) or fixed-effects models (I2  < 50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger’s test. Results: Ten studies were included in this study. The concentrations of CSF α -synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95% CI 1.60 to 2.36, p  < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68, p  < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44, p  < 0.00001), or Alzheimer’s (SMD = 1.14, 95% CI 0.95 to 1.33, p  < 0.00001). CSF α -synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80–95%), specificity of 92% (95% CI 86–95%), and AUC of 0.96 (95% CI: 0.94–0.97). Conclusion: CSF α -synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility. Show more

Keywords: α-synuclein, Creutzfeldt-Jakob disease, CSF biomarkers, meta-analysis, systematic review

DOI: 10.3233/JAD-220425

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 493-503, 2022

Authors: Yao, Weina | Zhang, Xiao | Zhao, Hui | Xu, Yun | Bai, Feng

Article Type: Research Article

Abstract: Objective: Background: Plasma neurofilament light chain (NFL) is a recognized biomarker for Alzheimer’s disease (AD) and inflammation. Intrinsically organized default mode network core subsystem and frontoparietal network (FPN) and their interactions support complex cognitive function. The present study investigated the inflammatory effect on cognitive integrity via plasma NFL coupling internetwork interactions in AD. Objective: Objective: This study investigates the hypothesis that inflammation-related plasma NFL could affect the interactions of the core subsystem and FPN, which leads to the aggravation of the clinical symptoms of AD-spectrum patients. Objective: Methods: A total of 112 AD-spectrum …participants underwent complete resting-state fMRI, neuropsychological tests, and plasma NFL at baseline (n  = 112) and after approximately 17 months of follow-up (n  = 112). The specific intersystem changes in the core subsystem and FPN were calculated and compared across groups. Then, the classifications of different AD-spectrum groups were analyzed using the association of plasma NFL and the changed intersystem interacting regions. Finally, mediation analysis was applied to investigate the significance of plasma NFL coupling networks on cognitive impairments in these subjects. Objective: Results: Discrimination of disease-related interactions of the core subsystem and FPN was found in AD-spectrum patients, which was the neural circuit fundamental to plasma NFL disrupting cognitive integrity. Furthermore, the clinical significance of plasma NFL coupling networks on AD identification and monitoring cognitive impairments were revealed in these subjects. Conclusion: The characteristic change in inflammation-related plasma NFL coupled with brain internetwork interactions could be used as a potential observation indicator in the progression of AD patients. Show more

Keywords: Alzheimer’s disease, cognitive integrity, core subsystem, frontoparietal network, plasma neurofilament light chain

DOI: 10.3233/JAD-220475

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 505-518, 2022

Authors: Li, Chenxi | Li, Youjun | Wu, Jianqian | Wu, Min | Peng, Fang | Chao, Qiuling

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is considered to be a transitional stage between Alzheimer’s disease (AD) and normal cognitive state because it has the same clinical symptoms as AD but with lower severity. Studies have confirmed that patients with aMCI are more likely to develop to AD. Although studies on resting state functional connectivity have revealed the abnormal organization of brain networks, the dynamic changes of the functional connectivity across the scans have been ignored. Objective: Dynamic functional connectivity is a novel method to reveal the temporal variation of brain networks. This paper aimed to investigate the …dynamic characteristics of brain functional connectivity in the early and late phases of aMCI. Methods: Based on the “triple network” model, we used the sliding time window approach to construct dynamical functional networks and then analyzed the dynamic characteristics of the functional connectivity across the entire scan. Results: The results showed that patients with aMCI had longer dwell times in weaker network connection than in the strong network. The transitions between different states become more frequent, and the stability of the patient’s brain core network deteriorates. This study also found the correlation between the altered dynamic properties of the core functional networks and the patient’s clinical Mini-Mental State Examination assessment scale sores. Conclusion: This study revealed that the characteristics of dynamic functional networks constructed by the core cognitive networks varied in distinct ways at different stages of aMCI, which could provide a new idea for exploring the neuro-mechanisms of neurological disorders. Show more

Keywords: Amnestic mild cognitive impairment, dynamic functional connectivity network, temporal variability, triple network

DOI: 10.3233/JAD-220282

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 519-533, 2022

Authors: Caprioglio, Camilla | Garibotto, Valentina | Jessen, Frank | Frölich, Lutz | Allali, Gilles | Assal, Frédéric | Frisoni, Giovanni B. | Altomare, Daniele

Article Type: Research Article

Abstract: Background: Recent advances occurred in the field of Alzheimer’s disease (AD) biomarkers and the introduction of a research framework grounded on a biomarker-based definition of AD might have fostered an increased clinical use of AD biomarkers. For this reason, an up-to-date depiction of the clinical use of AD biomarkers is needed. Objective: To investigate the clinical use of the main AD biomarkers in patients with mild cognitive impairment (MCI) by examining the beliefs and preferences of professionals (clinicians and biomarker experts) of the European Alzheimer’s Disease Consortium (EADC). Methods: 150 professionals filled in an online survey …from May to September 2020. The investigated biomarkers were medial temporal lobe atrophy score (MTA) on structural MRI, typical AD (i.e., temporoparietal and posterior cingulate) hypometabolism on FDG-PET, CSF (Aβ42 , p-tau, t-tau), amyloid-PET and tau-PET. Results: The frequency of responders reporting a frequent-to-constant use of MTA (77%) is higher than that of those reporting a frequent-to-constant use of the other AD biomarkers (i.e., CSF: 45%, p  = 0.014; FDG-PET: 32%, p  < 0.001; amyloid-PET: 8%, p  < 0.001; and tau-PET: 2%, p  < 0.001). CSF is considered the most valuable biomarker in terms of additional diagnostic value, followed by amyloid-PET, tau-PET, and typical AD hypometabolism on FDG-PET. Conclusion: AD biomarkers are widely used across European memory clinics with a clinical research background for the diagnosis of MCI. Overall, we observed that CSF is currently considered as the most useful biomarker, followed by amyloid-PET. Show more

Keywords: Alzheimer’s disease, amyloid-PET, APOE , biomarkers, cerebrospinal fluid, clinical use, FDG-PET, magnetic resonance imaging, mild cognitive impairment, tau-PET

DOI: 10.3233/JAD-220333

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 535-551, 2022

Authors: Lai, Po-Yu | Wang, Wen-Fu | Chang, Ming-Che | Jhang, Kai-Ming

Article Type: Research Article

Abstract: Background: The global population with dementia is growing rapidly. Dementia patients have been included in the services of the long-term care Act 2.0, supported by Taiwan’s government since 2017. Community aging care centers are extensively established, which are places providing social connections and group physical and cognitive training programs for elderly people. Objective: To elucidate the efficacy of community aging care centers on cognitive function in people with dementia. Methods: A total of 1,277 patients with dementia diagnosed at the Changhua Christian Hospital outpatient departments were enrolled. A total of 113 patients who used community aging …care centers and 452 subjects matched for age, education, and initial score of clinical dementia rating scale sum of boxes (CDR-SOB) control group were analyzed. The primary outcome was the change in CDR-SOB scores before and after utilization of community aging care centers. Results: The mean annual change of CDR-SOB scores were 1.72±2.97, 1.08±2.36, and 1.04±3.64 in control, Community Service Centers for Dementia, and community elderly stations, respectively, after about 1.5 years follow-up. Patients with dementia using community aging care centers had significantly less progression in CDR-SOB scores than those in the control group (–0.65; 95% CI: –1.27, –0.03; p  = 0.041). Using one more day of community aging care centers per week significantly promotes 0.16 points of CDR-SOB decline (–0.16, 95% CI: –0.31; –0.00; p  = 0.045). Conclusion: Community aging care centers, based on the long-term care Act 2.0 in Taiwan, were effective in delaying the decline in global function in people living with dementia. Show more

Keywords: Cognitive dysfunction, community care, dementia, long-term care

DOI: 10.3233/JAD-220372

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 553-562, 2022

Authors: Hoffmann, Coles M. | Nianogo, Roch A. | Yaffe, Kristine | Rosenwohl-Mack, Amy | Carrasco, Anna | Barnes, Deborah E.

Article Type: Research Article

Abstract: Background: We recently estimated that 36.9% of Alzheimer’s disease and related dementias (ADRD) cases in the US may be attributable to modifiable risk factors, but it is not known whether national estimates generalize to specific states or regions. Objective: To compare national estimates of modifiable risk factors of ADRD to California, overall and by sex and race/ethnicity, and to estimate number of cases potentially preventable by reducing the prevalence of key risk factors by 25%. Methods: Adults ≥18 years who participated in the Behavioral Risk Factor Surveillance Survey in California (n  = 9,836) and the US (n … = 378,615). We calculated population attributable risks (PARs) for eight risk factors (physical inactivity, current smoking, depression, low education, diabetes mellitus, midlife obesity, midlife hypertension, and hearing loss) and compared estimates in California and the U.S. Results: In California, overall, 28.9% of ADRD cases were potentially attributable to the combination of risk factors, compared to 36.9% in the U.S. The top three risk factors were the same in California and the U.S., although their relative importance differed (low education [CA:14.9%; U.S.:11.7% ], midlife obesity [CA:14.9%; U.S.:17.7% ], and physical inactivity [CA:10.3%; U.S.:11.8% ]). The number of ADRD cases attributable to the combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent more than 40,000 cases in California and 445,000 cases in the U.S. Conclusion: Our findings highlight the importance of examining risk factors of ADRD regionally, and within sex and race/ethnic groups to tailor dementia risk reduction strategies. Show more

Keywords: Alzheimer’s disease, dementia, public health, prevention, risk factors

DOI: 10.3233/JAD-220278

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 563-570, 2022

Authors: Canario, Edgar | Chen, Donna | Han, Ying | Niu, Haijing | Biswal, Bharat

Article Type: Research Article

Abstract: Background: A minimum spanning tree (MST) is a unique efficient network comprising the necessary connections needed to connect all regions in a network while retaining the lowest possible cost of connection weight. Objective: This study aimed to utilize functional near-infrared spectroscopy (fNIRS) to analyze brain activity in different regions and then construct MST-based regions to characterize the brain topologies of participants with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and normal controls (NC). Methods: A 46 channel fNIRS setup was used on all participants, with correlation being calculated for each channel pair. An MST was constructed …from the resulting correlation matrix, from which graph theory measures were calculated. The average number of connections within a lobe in the left versus right hemisphere was calculated to identify which lobes displayed and abnormal amount of connectivity. Results: Compared to those in the MCI group, the AD group showed a less integrated network structure, with a higher characteristic path length, but lower leaf fraction, maximum degree, and degree divergence. The AD group also showed a higher number of connections in the frontal lobe within the left hemisphere and a lower number between hemispheric frontal lobes as compared to MCI. Conclusion: These results indicate a deviation in network structure and connectivity within patient groups that is consistent with the theory of dysconnectivity for AD. Additionally, the AD group showed strong correlations between the Hamilton depression rating scale and different graph metrics, suggesting a link between network organization and the recurrence of depression in AD. Show more

Keywords: Amyloid, cognitive decline, depression, functional neuroimaging

DOI: 10.3233/JAD-215573

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 571-581, 2022

Authors: Cao, Qiao-Ling | Sun, Yan | Hu, Hao | Wang, Zuo-teng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The links between cerebral small vessel disease (CSVD) burden and neuropsychiatric symptoms (NPS) have not been fully studied. Objective: We aimed to explore the associations of the CSVD burden with Neuropsychiatric Inventory (NPI) total scores and its subsyndromes in the elderly without dementia. Methods: We investigated 630 non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. All of them had NPI assessments and 3 Tesla MRI scans at baseline and 616 had longitudinal NPI assessments during the follow-up. Linear mixed-effects models were used to investigate the cross-sectional and longitudinal associations of CSVD burden with NPI total …scores and its subsyndromes. Results: Higher CSVD burden longitudinally predicted more serious neuropsychiatric symptoms, including NPS (p  < 0.0001), hyperactivity (p  = 0.0006), affective symptoms (p  = 0.0091), and apathy (p  < 0.0001) in the total participants. Lacunar infarcts (LIs), white matter hyperactivities (WMHs), and cerebral microbleeds (CMBs) might play important roles in the occurrence of NPS, since they were longitudinally associated with specific neuropsychiatric subsyndromes. LIs contributed to hyperactivity (p  = 0.0092), psychosis (p  = 0.0402), affective symptoms (p  = 0.0156), and apathy (p  < 0.0001). WMHs were associated with hyperactivity (p  = 0.0377) and apathy (p  = 0.0343). However, CMBs were only related to apathy (p  = 0.0141). Conclusion: CSVD burden was associated with multiple neuropsychiatric symptoms, suggesting the importance of monitoring and controlling vascular risk factors. Different markers of CSVD were associated with specific subsyndromes of NPS, suggesting that different markers tended to occur in different encephalic regions. Show more

Keywords: Alzheimer’s Disease Neuroimaging Initiative, cerebral small vessel disease burden, neuropsychiatric subsyndrome, non-demented elders

DOI: 10.3233/JAD-220128

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 583-592, 2022

Authors: Liu, Zi-Yue | Zhai, Fei-Fei | Han, Fei | Li, Ming-Li | Zhou, Lixin | Ni, Jun | Yao, Ming | Zhang, Shu-Yang | Cui, Li-Ying | Jin, Zheng-Yu | Zhu, Yi-Cheng

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in the elderly population. Exploring patterns of white matter damage at the microstructural level would give important indications for the underlying mechanisms. Objective: To investigate the spatial patterns of white matter microstructure and structural network alternations in relation to different cognition domains Methods: Participants from the community-based Shunyi Study were included to investigate the association between white matter measurements and cognition cross-sectionally, via both global and local analysis. Cognitive functions were assessed using digit span, trail making test (TMT)-A/B, Fuld object Memory, and 12-Word Philadelphia Verbal Learning Test (PVLT). White matter …measurements including fractional anisotropy (FA), mean diffusivity (MD), and structural network parameters were calculated based on diffusion tensor imaging. Results: Of the 943 participants included, the mean (SD) age was 55.8 (9.1) years, and the mean (SD) education level was 6.7 (3.2) years. We found the whole set of cognitive measurements was related to diffused white matter microstructural integrity damage and lower global efficiency. Poor executive functions (TMTA/B complete time) were related to lower FA and higher MD predominantly on the anterior white matter skeleton, while verbal memory loss (PVLT test scores) was related to sub-network dysconnectivity in the midline and the right temporal lobe. Conclusion: The anterior brain is dominantly involved in executive dysfunction, while midline and right temporal brain disconnection are more prominent in verbal memory loss. Global and regional disruption of white matter integrity and network connectivity is the anatomical basis of the cognitive impairment in the aging population. Show more

Keywords: Aging, cognitive function, diffuse tensor imaging, white matter network

DOI: 10.3233/JAD-220191

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 593-603, 2022

Authors: Contini, Cristina | Serrao, Simone | Manconi, Barbara | Olianas, Alessandra | Iavarone, Federica | Bizzarro, Alessandra | Masullo, Carlo | Castagnola, Massimo | Messana, Irene | Diaz, Giacomo | Cabras, Tiziana

Article Type: Research Article

Abstract: Background: Aging is a risk factor for several pathologies as Alzheimer’s disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential. Objective: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects. Methods: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) …years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis. Results: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin β4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups. Conclusion: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status. Show more

Keywords: Aging, α-defensins, Alzheimer’s disease, RF analysis, salivary proteome, S100A8, S100A9, thymosin β4

DOI: 10.3233/JAD-220246

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 605-622, 2022

Authors: Janssen, Niels | Handels, Ron L. | Wimo, Anders | Antikainen, Riitta | Laatikainen, Tiina | Soininen, Hilkka | Strandberg, Timo | Tuomilehto, Jaakko | Kivipelto, Miia | Evers, Silvia M.A.A. | Verhey, Frans R.J. | Ngandu, Tiia

Article Type: Research Article

Abstract: Background: The association between health-related quality of life (HRQoL) and care costs in people at risk for cognitive decline is not well understood. Studying this association could reveal the potential benefits of increasing HRQoL and reducing care costs by improving cognition. Objective: In this exploratory data analysis we investigated the association between cognition, HRQoL utilities and costs in a well-functioning population at risk for cognitive decline. Methods: An exploratory data analysis was conducted using longitudinal 2-year data from the FINGER study (n = 1,120). A change score analysis was applied using HRQoL utilities and total …medical care costs as outcome. HRQoL utilities were derived from the Short Form Health Survey-36 (SF-36). Total care costs comprised visits to a general practitioner, medical specialist, nurse, and days at hospital. Analyses were adjusted for activities of daily living (ADL) and depressive symptoms. Results: Although univariable analysis showed an association between cognition and HRQoL utilities, multivariable analysis showed no association between cognition, HRQoL utilities and total care costs. A one-unit increase in ADL limitations was associated with a -0.006 (p < 0.001) decrease in HRQoL utilities and a one-unit increase in depressive symptoms was associated with a -0.004 (p < 0.001) decrease in HRQoL utilities. Conclusion: The level of cognition in people at-risk for cognitive decline does not seem to be associated with HRQoL utilities. Future research should examine the level at which cognitive decline starts to affect HRQoL and care costs. Ideally, this would be done by means of cross-validation in populations with various stages of cognitive functioning and decline. Show more

Keywords: At-risk, care costs, cognition,, cognitive decline, dementia,, HRQoL utilities, sf-6d

DOI: 10.3233/JAD-215304

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 623-632, 2022

Authors: Weigand, Alexandra J. | Macomber, Alyssa J. | Walker, Kayla S. | Edwards, Lauren | Thomas, Kelsey R. | Bangen, Katherine J. | Nation, Daniel A. | Bondi, Mark W.

Article Type: Research Article

Abstract: Background: Studies have demonstrated that both tau and cardiovascular risk are associated with cognitive decline, but the possible synergistic effects of these pathologic markers remain unclear. Objective: To explore the interaction of AD biomarkers with a specific vascular risk marker (pulse pressure) on longitudinal cognition. Methods: Participants included 139 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Biomarkers of tau, amyloid-β (Aβ), and vascular risk (pulse pressure) were assessed. Neuropsychological assessment provided memory, language, and executive function domain composite scores at baseline and 1-year follow-up. Multiple linear regression examined interactive effects of pulse pressure with …tau PET independent of Aβ PET and Aβ PET independent of tau PET on baseline and 1-year cognitive outcomes. Results: The interaction between pulse pressure and tau PET significantly predicted 1-year memory performance such that the combined effect of high pulse pressure and high tau PET levels was associated with lower memory at follow-up but not at baseline. In contrast, Aβ PET did not significantly interact with pulse pressure to predict baseline or 1-year outcomes in any cognitive domain. Main effects revealed a significant effect of tau PET on memory, and no significant effects of Aβ PET or pulse pressure on any cognitive domain. Conclusion: Results indicate that tau and an indirect marker of arterial stiffening (pulse pressure) may synergistically contribute to memory decline, whereas Aβ may have a lesser role in predicting cognitive progression. Tau and vascular pathology (particularly in combination) may represent valuable targets for interventions intended to slow cognitive decline. Show more

Keywords: Amyloid PET, cardiovascular risk, cognition, executive function, memory, pulse pressure, tau PET

DOI: 10.3233/JAD-220026

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 633-640, 2022

Authors: Dominguez Perez, Sophia | Phillips, Jeffrey S. | Norise, Catherine | Kinney, Nikolas G. | Vaddi, Prerana | Halpin, Amy | Rascovsky, Katya | Irwin, David J. | McMillan, Corey T. | Xie, Long | Wisse, Laura E.M. | Yushkevich, Paul A. | Kallogjeri, Dorina | Grossman, Murray | Cousins, Katheryn A.Q.

Article Type: Research Article

Abstract: Background: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Methods: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. Results: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), …more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Conclusion: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD. Show more

Keywords: Alzheimer’s disease, behavioral, behavioral variant frontotemporal dementia, cognitive domains, cortical thinning, frontal variant, hippocampal volumes, neuropsychiatric symptoms

DOI: 10.3233/JAD-215728

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 641-658, 2022

Authors: Richards, Marcus | James, Sarah N. | Lu, Kirsty | Livingston, Gill | Schott, Jonathan M. | Lane, Christopher A. | Barnes, Josephine | Parker, Thomas D. | Sudre, Carole H. | Cash, David M. | Coath, William | Fox, Nicholas | Davis, Daniel H.J.

Article Type: Research Article

Abstract: Background: Using the British 1946 birth cohort we previously estimated life course paths to the Addenbrooke’s Cognitive Examination (ACE-III). Objective: We now compared those whose ACE-III scores were expected, worse and better than predicted from the path model on a range of independent variables including clinical ratings of cognitive impairment and neuroimaging measures. Methods: Predicted ACE-III scores were categorized into three groups: those with Expected (between –1.5 and 1.5 standard deviation; SD); Worse (< –1.5 SD); and Better (>1.5 SD) scores. Differences in the independent variables were then tested between these three groups. Results: …Compared with the Expected group, those in the Worse group showed independent evidence of progressive cognitive impairment: faster memory decline, more self-reported memory difficulties, more functional difficulties, greater likelihood of being independently rated by experienced specialist clinicians as having a progressive cognitive impairment, and a cortical thinning pattern suggestive of preclinical Alzheimer’s disease. Those in the Better group showed slower verbal memory decline and absence of independently rated progressive cognitive impairment compared to the Expected group, but no differences in any of the other independent variables including the neuroimaging variables. Conclusion: The residual approach shows that life course features can map directly to clinical diagnoses. One future challenge is to translate this into a readily usable algorithm to identify high-risk individuals in preclinical state, when preventive strategies and therapeutic interventions may be most effective. Show more

Keywords: Addenbrooke’s Cognitive Examination-III, birth cohort, cognitive state, life course, residuals

DOI: 10.3233/JAD-220296

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 659-667, 2022

Authors: Xu, Qing | Zou, Kai | Deng, Zhao’an | Zhou, Jianbang | Dang, Xinghong | Zhu, Shenglong | Liu, Liang | Fang, Chunxia

Article Type: Research Article

Abstract: Background: For community-dwelling elderly individuals without enough clinical data, it is important to develop a method to predict their dementia risk and identify risk factors for the formulation of reasonable public health policies to prevent dementia. Objective: A community elderly survey data was used to establish machine learning prediction models for dementia and analyze the risk factors. Methods: In a cluster-sample community survey of 9,387 elderly people in 5 subdistricts of Wuxi City, data on sociodemographics and neuropsychological self-rating scales for depression, anxiety, and cognition evaluation were collected. Machine learning models were developed to predict their …dementia risk and identify risk factors. Results: The random forest model (AUC = 0.686) had slightly better dementia prediction performance than logistic regression model (AUC = 0.677) and neural network model (AUC = 0.664). The sociodemographic data and psychological evaluation revealed that depression (OR = 3.933, 95% CI = 2.995–5.166); anxiety (OR = 2.352, 95% CI = 1.577–3.509); multiple physical diseases (OR = 2.486, 95% CI = 1.882–3.284 for three or above); “disability, poverty or no family member” (OR = 1.859, 95% CI = 1.337–2.585) and “empty nester” (OR = 1.339, 95% CI = 1.125–1.595) in special family status; “no spouse now” (OR = 1.567, 95% CI = 1.118–2.197); age older than 80 years (OR = 1.645, 95% CI = 1.335–2.026); and female (OR = 1.214, 95% CI = 1.048–1.405) were risk factors for suspected dementia, while a higher education level (OR = 0.365, 95% CI = 0.245–0.546 for college or above) was a protective factor. Conclusion: The machine learning models using sociodemographic and psychological evaluation data from community surveys can be used as references for the prevention and control of dementia in large-scale community populations and the formulation of public health policies. Show more

Keywords: Community survey, dementia, machine learning, prediction model, risk factors

DOI: 10.3233/JAD-220316

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 669-679, 2022

Authors: Cascini, Silvia | Agabiti, Nera | Marino, Claudia | Acampora, Anna | Balducci, Maria | Calandrini, Enrico | Davoli, Marina | Bargagli, Anna Maria

Article Type: Research Article

Abstract: Background: The identification of risk factors for SARS-CoV-2 infection and mortality in patients with dementia is a key aspect to support clinical decisions and public health interventions. Objective: To assess the incidence of SARS-CoV-2 infection and COVID-19 related death in a cohort of patients with dementia residing in the Lazio region and to investigate predicting factors for both infection and mortality. Methods: This population-based study used information from administrative databases and the SARS-CoV-2 infection surveillance system. Patients with dementia (age ≥65) were enrolled as of December 31, 2019 and followed-up until February 28, 2021. Cumulative risk …of infection and death within 60 days of infection onset, and age-standardized incidence (SIR) and mortality (SMR) ratios were calculated. Logistic regression models were applied to identify factors associated with infection and mortality. Results: Among 37,729 dementia patients, 2,548 had a diagnosis of SARS-CoV-2 infection. The crude risk of infection was 6.7%. An increase in risk of infection was observed both in women (SIR 1.72; 95% CI 1.64–1.80) and men (SIR 1.43; 95% CI 1.33–1.54). Pneumonia, cerebrovascular and blood diseases, femur fracture, anxiety, antipsychotic and antithrombotic use were associated with an increased risk of infection. The crude risk of death was 31.0%, the SMRs 2.32 (95% CI 2.05–2.65) for men, and 2.82 (95% CI 2.55–3.11) for women. Factors associated with mortality included: male gender, age ≥85, symptoms at the diagnosis, antipsychotic and systemic antibiotics treatment. Conclusion: These findings emphasize the need of close and tailored monitoring of dementia patients to reduce the impact of COVID-19 on this fragile population. Show more

Keywords: Administrative databases, Alzheimer’s disease, cohort study, COVID-19, dementia, prognostic factors, SARS-CoV-2 infection

DOI: 10.3233/JAD-220369

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 681-693, 2022

Authors: Tahami Monfared, Amir Abbas | Stern, Yaakov | Doogan, Stephen | Irizarry, Michael | Zhang, Quanwu

Article Type: Research Article

Abstract: Background: Social media data may be especially effective for studying diseases associated with high stigma, such as Alzheimer’s disease (AD). Objective: We primarily aimed to identify issues/challenges experienced by patients with AD using natural language processing (NLP) of social media posts. Methods: We searched 130 public social media sources between January 1998 and December 2021 for AD stakeholder social media posts using NLP to identify issues/challenges experienced by patients with AD. Issues/challenges identified by ≥10% of any AD stakeholder type were described. Illustrative posts were selected for qualitative review. Secondarily, issues/challenges were organized into a conceptual …AD identification framework (ADIF) and representation of ADIF categories within clinical instruments was assessed. Results: We analyzed 1,859,077 social media posts from 30,341 AD stakeholders (21,011 caregivers; 7,440 clinicians; 1,890 patients). The most common issues/challenges were Worry/anxiety (34.2%), Pain (33%), Malaise (28.7%), Confusional state (27.1%), and Falls (23.9%). Patients reported a markedly higher volume of issues/challenges than other stakeholders. Patient posts reflected the broader scope of patient burden, caregiver posts captured both patient and caregiver burden, and clinician posts tended to be targeted. Less than 5% of the high frequency issues/challenges were in the “function and independence” and “social and relational well-being” categories of the ADIF, suggesting these issues/challenges may be difficult to capture. No single clinical instrument covered all ADIF categories; “social and relational well-being” was least represented. Conclusion: NLP of AD stakeholder social media data revealed a broad spectrum of real-world insights regarding patient burden. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, natural language processing, online social networking, patient reported outcome measures, social media

DOI: 10.3233/JAD-220422

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 695-708, 2022

Authors: Liampas, Ioannis | Hatzimanolis, Alex | Siokas, Vasileios | Yannakoulia, Mary | Kosmidis, Mary H. | Sakka, Paraskevi | Hadjigeorgiou, Georgios M. | Scarmeas, Nikolaos | Dardiotis, Efthimios

Article Type: Research Article

Abstract: Background: It is unclear whether the main antihypertensive medication classes (diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers (ARBs)) are associated with different risks of cognitive decline. Published evidence is conflicting and stems mainly from observational studies. Objective: To investigate the differential effects of antihypertensives on the risks of developing dementia and cognitive decline, with a specific focus on the vascular component of the mechanisms underlying these interactions. Methods: Older adults with a history of hypertension and without dementia were drawn from the population-based HELIAD cohort. Age-, gender-, education-, and antihypertensive …medication- (five dichotomous exposures) adjusted Cox proportional-hazards models and generalized estimating equations were performed to appraise the associations of baseline antihypertensive therapy with dementia incidence and cognitive decline (quantified using a comprehensive neuropsychological battery). Analyses were subsequently adjusted for clinical vascular risk (dyslipidemia, diabetes mellitus, smoking, cardiovascular, and cerebrovascular history) and genetic susceptibility to stroke (using polygenic risk scores generated according to the MEGASTROKE consortium GWAS findings). Results: A total of 776 predominantly female participants (73.61±4.94 years) with hypertension and a mean follow-up of 3.02±0.82 years were analyzed. Baseline treatment was not associated with the risk of incident dementia. ARB users experienced a slower yearly global cognitive [2.5% of a SD, 95% CI = (0.1, 4.9)] and language [4.4% of a SD, 95% CI = (1.4, 7.4)] decline compared to non-users. The fully adjusted model reproduced similar associations for both global cognitive [β= 0.027, 95% CI =  (–0.003, 0.057)], and language decline [β= 0.063, 95% CI = (0.023, 0.104)]. Conclusion: ARBs may be superior to other antihypertensive agents in the preservation of cognition, an association probably mediated by vascular-independent mechanisms. Show more

Keywords: Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, diuretics, genetic predisposition to disease, longitudinal

DOI: 10.3233/JAD-220439

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 709-719, 2022

Authors: Bu, Kun | Patel, Devashru | Morris, Robert | Han, Weiru | Umeukeje, Gibret | Zhu, Tianrui | Cheng, Feng

Article Type: Research Article

Abstract: Background: Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer’s disease (AD) treatment. Objective: The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). Methods: The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration. Results: When compared …to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50–70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events. Conclusion: Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase. Show more

Keywords: Exelon, FAERS, FDA, patch, pharmacovigilance, pneumonia, swallow, transdermal

DOI: 10.3233/JAD-220583

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 721-731, 2022

Authors: Bawa, Kritleen K. | Ba, Joycelyn | Kiss, Alex | Wang, RuoDing | Feng, Vivian | Swardfager, Walter | Andreazza, Ana | Gallagher, Damien | Marotta, Giovanni | Herrmann, Nathan | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown. Objective: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI. Methods: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and …late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated. Results: Participants (n  = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p  < 0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤–1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t  = 4.852, p  < 0.001) and executive function (B(SE) = –0.19 (0.079), t  = –2.377, p  = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t  = 3.149, p  = 0.002). Conclusion: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI. Show more

Keywords: Apathy, cardiac rehabilitation, cognition, cognitive dysfunction, coronary artery disease, executive function, lipid peroxidation, oxidative stress

DOI: 10.3233/JAD-220274

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 733-743, 2022

Authors: Dhana, Klodian | Aggarwal, Neelum T. | Beck, Todd | Holland, Thomas M. | Dhana, Anisa | Cherian, Laurel J. | Desai, Pankaja | Evans, Denis A. | Rajan, Kumar B.

Article Type: Research Article

Abstract: Background: Patients with stroke are at a higher risk of cognitive impairment and Alzheimer’s disease dementia. Objective: To quantify the role of lifestyle pre-stroke, post-stroke, and changes in lifestyle before and after stroke with cognitive decline in community-dwelling stroke survivors. Methods: Utilizing data from the Chicago Health and Aging Project, a population-based cohort study, we studied 1,078 individuals with stroke (662 incident and 416 prevalent) who underwent cognitive testing during the study period. A healthy lifestyle score was defined by scoring four behaviors: non-smoking, exercising, being cognitively active, and having a high-quality diet. The global cognitive …score was derived from a comprehensive battery of 4 standardized tests. Results: The mean age at incident stroke was 78.2 years, and 60.1% were women. A healthy lifestyle pre-incident stroke was associated with a slower rate of cognitive decline after stroke. Participants with 3–4 healthy lifestyle factors pre-incident stroke had a slower cognitive decline after stroke by 0.046 units/year (95% CI 0.010, 0.083), or 47.7% slower, than participants with 0–1 healthy lifestyle factor. Lifestyle score post-prevalent stroke was not associated with cognitive decline. Changes in lifestyle behaviors from pre- to post-incident stroke were related to cognitive decline after stroke. Individuals who deteriorated their lifestyle quality after stroke had a faster cognitive decline by 0.051 units/year (β –0.051, 95% CI –0.090, –0.012) than participants with no change in lifestyle score. Conclusion: A healthy lifestyle pre-stroke was associated with a slower rate of cognitive decline in stroke survivors, highlighting the importance of primary prevention. After the stroke, changes in lifestyle behaviors may influence the cognitive abilities of older adults as they age. Show more

Keywords: Cognition, cognitive decline, cohort study, healthy lifestyle, stroke patients

DOI: 10.3233/JAD-220305

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 745-754, 2022

Authors: Friedland, Robert P.

Article Type: Book Review

DOI: 10.3233/JAD-220697

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 755-755, 2022