Journal of Alzheimer's Disease - Volume 89, issue 3

Authors: Diaz, Ariel | Martin-Jimenez, Cynthia | Woo, Yena | Merino, Paola | Torre, Enrique | Yepes, Manuel

Article Type: Research Article

Abstract: Background: Urokinase-type plasminogen activator (uPA) is a serine proteinase found in excitatory synapses located in the II/III and V cortical layers. The synaptic release of uPA promotes the formation of synaptic contacts and the repair of synapses damaged by various forms of injury, and its abundance is decreased in the synapse of Alzheimer’s disease (AD) patients. Inactivation of the Wingless/Int1 (Wnt)-β-catenin pathway plays a central role in the pathogenesis of AD. Soluble amyloid-β (Aβ) prevents the phosphorylation of the low-density lipoprotein receptor-related protein-6 (LRP6), and the resultant inactivation of the Wnt-β-catenin pathway prompts the amyloidogenic processing of the amyloid-β protein …precursor (AβPP) and causes synaptic loss. Objective: To study the role of neuronal uPA in the pathogenesis of AD. Methods: We used in vitro cultures of murine cerebral cortical neurons, a murine neuroblastoma cell line transfected with the APP-695 Swedish mutation (N2asw), and mice deficient on either plasminogen, or uPA, or its receptor (uPAR). Results: We show that uPA activates the Wnt-β-catenin pathway in cerebral cortical neurons by triggering the phosphorylation of LRP6 via a plasmin-independent mechanism that does not require binding of Wnt ligands (Wnts). Our data indicate that uPA-induced activation of the Wnt-β-catenin pathway protects the synapse from the harmful effects of soluble Aβ and prevents the amyloidogenic processing of AβPP by inhibiting the expression of β-secretase 1 (BACE1) and the ensuing generation of Aβ40 and Aβ42 peptides. Conclusion: uPA protects the synapse and antagonizes the inhibitory effect of soluble Aβ on the Wnt-β-catenin pathway by providing an alternative pathway for LRP6 phosphorylation and β-catenin stabilization. Show more

Keywords: Amyloid-β protein precursor secretases, β-Catenin, plasmin, urokinase-type plasminogen activator

DOI: 10.3233/JAD-220320

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 877-891, 2022

Authors: Dong, Liling | Wang, Jie | Liu, Caiyan | Li, Jie | Mao, Chenhui | Huang, Xinying | Chu, Shanshan | Peng, Bin | Cui, Liying | Gao, Jing

Article Type: Research Article

Abstract: Background: There are relatively few data on the genetic spectrum of Chinese frontotemporal dementia (FTD) population. Objective: With the dementia cohort of Peking Union Medical College Hospital, we aim to illustrate the genetic spectrum of FTD patients, as well as the phenotypic heterogeneity of FTD-gene variant carriers. Methods: 204 unrelated, clinically diagnosed FTD patients of Chinese ancestry were enrolled. All the participants received demographic survey, history inquiry, physical examination, cognitive assessment, blood biochemical test, brain CT/MRI, and gene sequencing. Results: 56.4% (115/204) participants were clinically diagnosed with behavioral variant of FTD, 20.6% (42/204) with …nonfluent/agrammatic variant primary progressive aphasia (PPA), 20.1% (41/204) with semantic variant PPA, and 2.9% (6/204) with mixed variant PPA. 11.8% (24/204) subjects harbored the potential causative variants in FTD-related genes, including the MAPT (n  = 7), TBK1 (n  = 7), GRN (n  = 2), TBK1+GRN (n  = 1), VCP (n  = 1), TARDBP (n  = 1), UBQLN2 (n  = 1), SQSTM1 (n  = 1), DCTN1 (n  = 1), HNRNPA1 (n  = 1), and C9orf72 GGGGCC repeats (n  = 1). The TBK1 T31fs, T457fs, K622fs, c.359-1G>A, the VCP P188T, and the GRN P50fs, P439fs were novel pathogenic/likely pathogenic variants. The TBK1 carriers showed a later disease onset and a higher incidence of parietal atrophy relative to the MAPT carriers. Conclusion: There is genetic and clinical heterogeneity among Chinese FTD population. The TBK1 has a high mutation frequency in Chinese FTD patients. Show more

Keywords: Behavioral variant of frontotemporal dementia, frontotemporal dementia, primary progressive aphasia, TBK1

DOI: 10.3233/JAD-220594

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 893-901, 2022

Authors: Wan, Jingxuan | Zhang, Jingyuan | Zhang, Mengyuan | Li, Chunxiao | Zhang, Qing | Hou, Xin | Xuan, Gao | Lin, Jiangtao

Article Type: Research Article

Abstract: Background: Previous studies have shown that impaired pulmonary function may be associated with cognitive decline, posing the question of whether peak expiratory flow (PEF) % pred could present a modifiable risk factor. Objective: To assess the association between PEF% pred and future cognitive function among Chinese participants aged 45 years and above. Methods: Data came from four waves fielded by the China Health and Retirement Longitudinal Study. Cognitive function was assessed by a global cognition score. Multivariate linear regression models and generalized estimating equation (GEE) were used to investigate associations between PEF% pred and later cognitive …function. Results: A total of 2,950 participants were eligible for the final data analysis. After adjustment for baseline cognition and potential confounders, the association remained statistically significant (β = 0.0057, p  = 0.027). Domains with increases were focused on episodic memory (β= 0.0028, p  = 0.048) and figure drawing (β= 0.0040, p  = 0.028). But these associations were not found in women (β= 0.0027, p  = 0.379). However, GEE suggested that the rates of decline in global cognition decreased by 0.0096 (p  < 0.001) units per year as baseline PEF% pred increased by 1% in middle-aged and elderly individuals, regardless of sex. And higher baseline PEF% pred correlated with declined rates of decrease of in episodic memory, figure drawing, and Telephone Interview of Cognitive Status (TICS). Conclusion: Higher baseline PEF% pred was significantly associated with slower cognitive decline in global cognition, episodic memory, figure drawing, and TICS in middle aged and elderly Chinese adults. Show more

Keywords: Chinese, cognitive function, longitudinal study, peak expiratory flow

DOI: 10.3233/JAD-215407

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 903-911, 2022

Authors: Watts, Amber | Chalise, Prabhakar | Hu, Jinxiang | Hui, Dongwei | Pa, Judy | Andrews, Shea J. | Michaelis, Elias K. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Mitochondrial DNA (mtDNA) may play a role in Alzheimer’s disease (AD) and cognitive decline. A particular haplogroup of mtDNA, haplogroup J, has been observed more commonly in patients with AD than in cognitively normal controls. Objective: We used two mtDNA haplogroups, H and J, to predict change in cognitive performance over five years. We hypothesized that haplogroup J carriers would show less cognitive resilience. Methods: We analyzed data from 140 cognitively normal older adults who participated in the University of Kansas Alzheimer’s Disease Research Center clinical cohort between 2011 and 2020. We used factor analysis …to create three composite scores (verbal memory, attention, and executive function) from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change adjusting for age, sex, years of education, and APOE ɛ4 allele carrier status. We compared haplogroup H, the most common group, to haplogroup J, the potential risk group. Results: Haplogroup J carriers had significantly lower baseline performance and slower rates of improvement on tests of verbal memory compared to haplogroup H carriers. We did not observe differences in executive function or attention. Conclusion: Our results reinforce the role of mtDNA in changes to cognitive function in a domain associated with risk for dementia, verbal memory, but not with other cognitive domains. Future research should investigate the distinct mechanisms by which mtDNA might affect performance on verbal memory as compared to other cognitive domains across haplogroups. Show more

Keywords: Alzheimer’s disease, cognition, haplogroup, mitochondrial DNA, mtDNA

DOI: 10.3233/JAD-220298

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 913-922, 2022

Authors: Liu, Shuai | Liu, Chunyan | Hu, Wenzheng | Ji, Yong

Article Type: Research Article

Abstract: Background: Autonomic dysfunction is supportive clinical feature for diagnosis of prodromal dementia with Lewy bodies (DLB). Objective: To compare the features of autonomic symptoms in patients with mild cognitive impairment (MCI) due to Lewy bodies (MCI-LB) and Alzheimer’s disease (MCI-AD). Methods: Autonomic symptoms were evaluated in the MCI-LB and MCI-AD patients using the Scales for Outcomes in Parkinson’s disease for autonomic symptoms (SCOPA-AUT). Results: Thirty patients with MCI-LB and 90 patients with MCI-AD were recruited. The frequency of autonomic dysfunction was higher in patients with MCI-LB compared to the MCI-AD patients (80% versus 54.4%, …p  = 0.013) and the gastrointestinal symptoms were predominant (73.3% versus 35.6%, p  < 0.001). Salivation, constipation, incontinence, incomplete emptying, lightheadedness when standing up or standing for some times, diurnal or nocturnal hyperhidrosis, and sexual dysfunction were more severe and protracted in the MCI-LB group compared to the MCI-AD group. Conclusion: The MCI-LB patients showed higher frequency and severity, as well as longer duration of autonomic symptoms compared to the MCI-AD group. These symptoms can facilitate early diagnosis of patients with DLB. Show more

Keywords: Alzheimer’s disease, autonomic symptoms, dementia with Lewy bodies, early diagnosis, SCOPA-AUT

DOI: 10.3233/JAD-220275

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 923-929, 2022

Authors: Juarez-Cedillo, Teresa | Gonzelez-Figueroa, Evangelina | Gutierez-Gutierez, Lidia | Aguilar-Navarro, Sara G. | Garcia-Cruz, Juan Carlos | Escobedo de la Peña, Jorge | Suerna-Hernandez, Alan

Article Type: Research Article

Abstract: Background: Dementia is a priority public health issue due to its high prevalence worldwide and its economic, social, and health impact. However, there are few reports in Mexico based on formal tests and with a clinical approach based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Objective: This study estimates the prevalence of the main types of dementia among elderly people living in the community in Mexico City. Methods: A population-based, two-step study was conducted, including 6,204 elderly individuals aged 60 or above with in-home assessment. All participants were screened for cognitive …impairment; those who presented some cognitive problem underwent a standardized neurological examination. Each diagnosis was based on the criteria for dementia in the DSM-5, and the final consensus diagnosis of dementia was determined by an expert panel. Results: The global estimated prevalence of dementia in the Mexican population was 7.8% met the criteria for Alzheimer’s disease, 4.3% for vascular dementia, and 2.1% for mixed dementia. The prevalence of dementia was higher in women than in men (15.3% versus 12.5%, respectively). Conclusion: These results provide evidence to propose strategies for Latin American countries where dementia represents a challenge due to the heterogeneity of the populations and socioeconomic disparities, requiring early diagnosis and at the first levels of care. Show more

Keywords: Alzheimer’s disease, dementia, elderly people, Mexican people, prevalence, SADEM

DOI: 10.3233/JAD-220012

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 931-941, 2022

Authors: Vassilaki, Maria | Crowson, Cynthia S. | Davis III, John M. | Duong, Stephanie Q. | Jones, David T. | Nguyen, Aivi | Mielke, Michelle M. | Vemuri, Prashanthi | Myasoedova, Elena

Article Type: Research Article

Abstract: Background: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population. Objective: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer’s disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA). Methods: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and …FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years). Results: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n  = 33) and without RA (n  = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p  = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p  = 0.02). Conclusion: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA. Show more

Keywords: Cognitive decline, cognitive impairment, dementia, magnetic resonance imaging, rheumatoid arthritis

DOI: 10.3233/JAD-220368

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 943-954, 2022

Authors: Zhang, Shujuan | Wei, Dongfeng | Lv, Shuang | Wang, Lei | An, Haiting | Shao, Wen | Wang, Yun | Huang, Yaping | Peng, Dantao | Zhang, Zhanjun

Article Type: Research Article

Abstract: Background: Scutellarin, a flavonoid purified from the Chinese herb Erigeron breviscapus , has been reported to prevent Alzheimer’s disease (AD) by affecting Aβ assembly. Given the low brain uptake rate of scutellarin, we hypothesize that the microbiota-gut-brain axis may be a potential route by which scutellarin prevents AD. Objective: This study aimed to explore the microbiota-gut-brain mechanism by which scutellarin prevented AD. Methods: Scutellarin was administrated to APP/PS1 mouse model of AD for two months, and the behaviors, pathological changes as well as gut microbial changes in APP/PS1 mice were evaluated after scutellarin treatment. …Results: This study found that scutellarin improved Aβ pathology, neuroinflammation, and cognitive deficits in APP/PS1 mice. It elucidated the effects of scutellarin on the diversity and activity of gut microbiota in APP/PS1 mice and these findings promoted us to focus on inflammation-related bacteria and short-chain fatty acids (SCFAs). Cognitive behaviors were significantly associated with inflammatory cytokines and inflammation-related bacteria, suggesting that microbiota-gut-brain axis was involved in this model and that inflammatory pathway played a crucial role in this axis. Moreover, we observed that cAMP-PKA-CREB-HDAC3 pathway downstream of SCFAs was activated in microglia of AD and inactivated by scutellarin. Furthermore, by chromatin immunoprecipitation (ChIP) assays, we found that the increased association between acetylated histone 3 and interleukin-1β (IL-1β) promoter in AD mice was reversed by scutellarin, leading to a decreased level of IL-1β in scutellarin-treated AD mice. Conclusion: Scutellarin reverses neuroinflammation and cognitive impairment in APP/PS1 mice via beneficial regulation of gut microbiota and cAMP-PKA-CREB-HDAC3 signaling in microglia. Show more

Keywords: Alzheimer’s disease, cAMP-response element binding protein (CREB), cyclic adenosine monophosphate (cAMP), gut microbiota, histone deacetylase, interleukin, protein kinase, scutellarin

DOI: 10.3233/JAD-220532

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 955-975, 2022

Authors: Dartora, Caroline Machado | de Moura, Luís Vinicius | Koole, Michel | Marques da Silva, Ana Maria

Article Type: Research Article

Abstract: Background: The population aging increased the prevalence of brain diseases, like Alzheimer’s disease (AD). Early identification of individuals with higher odds of cognitive decline is essential to maintain quality of life. Imaging evaluation of individuals at risk of cognitive decline includes biomarkers extracted from brain positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Objective: We propose investigating ensemble models to classify groups in the aging cognitive decline spectrum by combining features extracted from single imaging modalities and combinations of imaging modalities (FDG+AMY+MRI, and a PET ensemble). Methods: We group imaging data of 131 individuals …into four classes related to the individuals’ cognitive assessment in baseline and follow-up: stable cognitive non-impaired; individuals converting to mild cognitive impairment (MCI) syndrome; stable MCI; and Alzheimer’s clinical syndrome. We assess the performance of four algorithms using leave-one-out cross-validation: decision tree classifier, random forest (RF), light gradient boosting machine (LGBM), and categorical boosting (CAT). The performance analysis of models is evaluated using balanced accuracy before and after using Shapley Additive exPlanations with recursive feature elimination (SHAP-RFECV) method. Results: Our results show that feature selection with CAT or RF algorithms have the best overall performance in discriminating early cognitive decline spectrum mainly using MRI imaging features. Conclusion: Use of CAT or RF algorithms with SHAP-RFECV shows good discrimination of early stages of aging cognitive decline, mainly using MRI image features. Further work is required to analyze the impact of selected brain regions and their correlation with cognitive decline spectrum. Show more

Keywords: Aging, amyloid, atrophy, fluorodeoxyglucose F18, machine learning, multimodal imaging

DOI: 10.3233/JAD-215164

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 977-991, 2022

Authors: Rosende-Roca, Maitée | Cañabate, Pilar | Moreno, Mariola | Preckler, Silvia | Seguer, Susana | Esteban, Ester | Tartari, Juan Pablo | Vargas, Liliana | Narvaiza, Leire | Pytel, Vanesa | Bojaryn, Urszula | Alarcon, Emilio | González-Pérez, Antonio | Gurruchaga, Miren Jone | Tárraga, Lluís | Ruiz, Agustín | Marquié, Marta | Boada, Mercè | Valero, Sergi

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) can be disruptive for patients and their families. Objective: We aimed to classify patients based on NPS and to explore the relationship of these classes with sex and with caregiver burden. Methods: The study cohort comprised individuals with AD dementia diagnosed at Ace Alzheimer Center in Barcelona, Spain, between 2011–2020. NPS were ascertained by using the Neuropsychiatric Inventory-Questionnaire. Latent class analysis was used to identify clusters of individuals sharing a similar NPS profile. We evaluated the caregiver burden using the Zarit Burden Interview. Multivariable regression models were used …to obtain adjusted estimates of the association between sex, NPS classes, and caregiver burden. Results: A total of 1,065 patients with AD dementia and their primary caregivers were included. We classified patients into five different classes according to their NPS profile: “Affective”, “High-behavioral-disturbance”, “Negative-affect”, “Affective/deliriant”, and “Apathy”. We found that age, sex, and type of AD diagnosis differed greatly across classes. We found that patients from the “High-behavioral-disturbance” (OR = 2.56, 95% CI: 1.00–6.56), “Negative-affect” (OR = 2.72, 95% CI: 1.26–3.64), and “Affective/deliriant” (OR = 2.14, 95% CI: 1.26–3.64) classes were over two times more likely to have a female caregiver than those in “Apathy” class. These three classes were also the ones associated to the greatest caregiver burden in the adjusted analyses, which seems to explain the increased burden observed among female caregivers. Conclusion: Caregiver burden is highly dependent on the patient’s NPS profiles. Female caregivers provide care to patients that pose a greater burden, which makes them more susceptible to become overwhelmed. Show more

Keywords: Alzheimer’s disease, caregiver burden, gender, neurobehavioral manifestations, sex, women

DOI: 10.3233/JAD-215648

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 993-1002, 2022

Authors: Kang, Dong Woo | Wang, Sheng-Min | Um, Yoo Hyun | Kim, Nak Young | Lee, Chang Uk | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: There has been renewed interest in the deteriorating effects of sub-threshold amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Despite evidence suggesting a synergistic interaction between the APOE ɛ4 allele and Aβ deposition in neurodegeneration, few studies have investigated the modulatory role of this allele in sub-threshold Aβ deposition during the preclinical phase. Objective: We aimed to explore the differential effect of the APOE ɛ4 carrier status on the association between sub-threshold Aβ deposition, cortical volume, and cognitive performance in cognitively normal older adults (CN). Methods: A total of 112 CN with sub-threshold Aβ …deposition was included in the study. Participants underwent structural magnetic resonance imaging, [18 F] flutemetamol PET-CT, and a neuropsychological battery. Potential interactions between APOE ɛ4 carrier status, Aβ accumulation, and cognitive function for cortical volume were assessed with whole-brain voxel-wise analysis. Results: We found that greater cortical volume was observed with higher regional Aβ deposition in the APOE ɛ4 carriers, which could be attributed to an interaction between the APOE ɛ4 carrier status and regional Aβ deposition in the posterior cingulate cortex/precuneus. Finally, the APOE ɛ4 carrier status-neuropsychological test score interaction demonstrated a significant effect on the gray matter volume of the left middle occipital gyrus. Conclusion: There might be a compensatory response to initiating Aβ in APOE ɛ4 carriers during the earliest AD stage. Despite its exploratory nature, this study offers some insight into recent interests concerning probabilistic AD modeling, focusing on the modulating role of the APOE ɛ4 carrier status during the preclinical period. Show more

Keywords: APOE ɛ4 allele, function, cognitively normal older adults, cortical volume, sub-threshold amyloid-β

DOI: 10.3233/JAD-220427

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1003-1016, 2022

Authors: Cavalli, Andrea | Lelli, Diana | Pedone, Claudio | Boccardi, Virginia | Mecocci, Patrizia | Antonelli Incalzi, Raffaele

Article Type: Research Article

Abstract: Background: Dementia is a risk factor for undernutrition. However, it is not clear if specific cognitive deficits have a higher risk of undernutrition and how much appetite/nutritional problems and caregiver stress mediate this association. Objective: To evaluate the relationship between nutritional status and severity of global and function-specific scores of cognitive dysfunctions, and to which extent this association is mediated by appetite/nutritional problems and caregiver stress. Methods: Cross-sectional analysis of the ReGAl study data, including 761 older adults attending a Memory Clinic. Nutritional status was evaluated with Mini Nutritional Assessment (MNA). The relationship between scores at …neuro-cognitive tests and risk of undernutrition was evaluated using logistic regression models adjusted for potential confounders. To allow comparison between different tests, all scores were standardized. Mediation analysis was used to evaluate how much appetite/nutritional problems and caregiver stress mediate this association. Results: Mean age was 77 years (SD: 9), 37.3% were women. Exploring different cognitive domains, a stronger association was documented for attentive matrices (OR:0.49, 95% CI: 0.34–0.72), the figure copy test (OR:0.63, 95% CI: 0.45–0.88), and the verbal judgement test (OR:0.61, 95% CI: 0.42–0.91). The proportion of the effect of cognition (MMSE) on nutritional status mediated by caregiver distress was 9.5% (95% CI: 0.002–0.27), the proportion mediated by appetite/nutritional problems was 11% (95% CI: –4.8–3.18). Conclusion: Risk of undernutrition is associated to cognitive decline; a stronger association was observed for attention, praxis, and reasoning. Caregiver distress is a mediator of this association. This information should be considered in the management plans of this population. Show more

Keywords: Appetite alteration, caregiver burden, dementia, malnutrition, Mini Nutritional Assessment

DOI: 10.3233/JAD-215732

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1017-1024, 2022

Authors: Chong, Terence W.H. | Curran, Eleanor | Southam, Jenny | Cox, Kay L. | Bryant, Christina | Goh, Anita M.Y. | You, Emily | Ellis, Kathryn A. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: Physical inactivity is a modifiable risk factor for dementia, but there remains a research translation gap in effective physical activity (PA) implementation, particularly in the longer-term. The INDIGO trial investigated the effectiveness of a six-month PA intervention for inactive older adults at risk of cognitive decline with subjective cognitive decline or mild cognitive impairment. Objective: This follow-up study aimed to collect feedback from INDIGO participants about their experience of involvement in the trial, including barriers and enablers to longer-term maintenance of PA. Methods: A qualitative study using semi-structured individual interviews was conducted and transcripts analyzed …thematically. All INDIGO trial completers were invited, with 29 participating (follow-up period 27–66 months post-baseline). Results: At long-term follow-up, participants described INDIGO trial participation as beneficial. The theme of “Motivation” (subthemes: structure and accountability, knowledge and expected benefits, preferences and motivation, tools) followed by “Situation” (subthemes: environment and time, social aspects, aging and physical health) appeared to be critical to PA “Action". Most participants had a positive view of goal-setting and peer mentoring/support, but there was some polarization of opinion. Key factors to longer-term “Maintenance” of PA were self-efficacy and perceived benefits, habit formation, and for some participants, enjoyment. Conclusion: PA interventions for older adults at risk of cognitive decline should include behavior change techniques tailored to the individual. Effective techniques should focus on “Motivation” (particularly structure and accountability) and “Situation” factors relevant to individuals with the aim of developing self-efficacy, habit formation, and enjoyment to increase the likelihood of longer-term PA maintenance. Show more

Keywords: Cognition, exercise, goal setting, late-life, older adults, peer mentors, physical activity

DOI: 10.3233/JAD-220202

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1025-1037, 2022

Authors: Piccarducci, Rebecca | Caselli, Maria Chiara | Zappelli, Elisa | Ulivi, Leonardo | Daniele, Simona | Siciliano, Gabriele | Ceravolo, Roberto | Mancuso, Michelangelo | Baldacci, Filippo | Martini, Claudia

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer’s disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids. Objective: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ1-40 , Aβ1-42 , tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers …for CAA. Methods: For this purpose, the proteins’ concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC. Results: The results highlighted a significant increase of Aβ1-40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ1-42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ1-42 /Aβ1-40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies. Conclusion: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs. Show more

Keywords: α-synuclein, amyloid-β, biomarkers, cerebral amyloid angiopathy, plasma, red blood cells, tau

DOI: 10.3233/JAD-220216

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1039-1049, 2022

Authors: Dietzel, Nikolas | Graessel, Elmar | Kürten, Lara | Meuer, Sebastian | Klaas-Ickler, Dorothee | Hladik, Markus | Chmelirsch, Christina | Kolominsky-Rabas, Peter L.

Article Type: Research Article

Abstract: Background: Dementia is one of the main triggers for care dependency among older adults who are predominantly cared for at home by relatives. To provide support in the care situation, health systems need valid information about the central needs of the affected people. Objective: The present study aimed to develop a research instrument to assess the most important needs of people with dementia and their family caregivers. Methods: The development of the ‘Dementia Assessment of Service Needs (DEMAND)’ took place within the project ‘Digital Dementia Registry Bavaria (digiDEM Bayern)’. A focus group and an online survey …with dementia experts were conducted to identify the most relevant support services and to develop the design of the instrument. The questionnaire was deployed in the digiDEM baseline data collection. Participants were asked to evaluate the comprehensibility of the questionnaire. Readability was assessed using the Flesch reading ease score. Results: Seventeen experts participated in the focus group and 59 people in the online survey. The final questionnaire included 13 support services. One hundred eighty-three participants (50 people with dementia and 133 family caregivers) completed the questionnaire at baseline. The mean comprehensibility score was 3.6 (SD = 2.3). The Flesch reading ease score result was 76. Conclusion: A research instrument could be developed, enabling people with dementia and family caregivers to directly express their individual needs for specific support services. Results show that the DEMAND is easy to understand and short in execution. Therefore, supply gaps can be identified and transformed into a specific health care plan. Show more

Keywords: Demand, dementia, digiDEM, health services research, needs, resource use

DOI: 10.3233/JAD-220363

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1051-1061, 2022

Authors: Ou, Ya-Nan | Zhao, Bing | Fu, Yan | Sheng, Ze-Hu | Gao, Pei-Yang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between serum uric acid (UA) and Alzheimer’s disease (AD) risk still remained ambiguous despite extensive attempts. Objective: Via the two-sample Mendelian randomization (MR) design, we aimed to examine the bidirectional causal relationships of serum UA, gout, and the risk of AD. Methods: Genetic variants of UA, gout, and AD were extracted from published genome-wide association summary statistics. The inverse-variance weighted (IVW, the primary method), and several sensitivity methods (MR-Egger, weighted median, and weighted mode) were used to calculate the effect estimates. Egger regression, MR-PRESSO and leave-one-SNP-out analysis were performed to identify potential violations. …Results: Genetic proxies for serum UA concentration [odds ratio (ORIVW ) = 1.09, 95% confidence interval (CI) = 1.01–1.19, p  = 0.031] were related with an increased risk of AD using 25 single nucleotide polymorphisms (SNPs). This causal effect was confirmed by sensitivity analyses including MR-Egger (1.22, 1.06–1.42, p  = 0.014), weighted median (1.18, 1.05–1.33, p  = 0.006), and weighted mode (1.20, 1.07–1.35, p  = 0.005) methods. No evidence of notable directional pleiotropy and heterogeneity were identified (p  > 0.05). Three SNPs (rs2078267, rs2231142, and rs11722228) significantly drove the observed causal effects. Supportive causal effect of genetically determined gout on AD risk was demonstrated using two SNPs (ORIVW  = 1.05, 95% CI = 1.00–1.11, p  = 0.057). No reverse causal effects of AD on serum UA levels and gout risk were found. Conclusion: The findings revealed a causal relationship between elevated serum UA level and AD risk. However, further research is still warranted to investigate whether serum UA could be a reliable biomarker and therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, gout, Mendelian randomization, uric acid

DOI: 10.3233/JAD-220649

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1063-1073, 2022

Authors: Kritikos, Minos | Huang, Chuan | Clouston, Sean A.P. | Pellecchia, Alison C. | Santiago-Michels, Stephanie | Carr, Melissa A. | Hagan, Thomas | Kotov, Roman | Gandy, Sam | Sano, Mary | Horton, Megan | Bromet, Evelyn J. | Lucchini, Roberto G. | Luft, Benjamin J.

Article Type: Research Article

Abstract: Background: More than 8% of responders who participated in the search and rescue efforts at the World Trade Center (WTC) following 9/11 developed early-onset cognitive impairment (CI). Approximately 23% were also diagnosed with chronic post-traumatic stress disorder (PTSD). Objective: To shed light on the pathophysiology of these WTC-related conditions, we examined diffusion connectometry to identify altered white matter tracts in WTC responders with CI and/or PTSD compared to unaffected responders. Methods: 99 WTC responders (mean age 56 years) consisting of CI-/PTSD- (n  = 27), CI+/PTSD- (n  = 25), CI-/PTSD+ (n  = 24), and CI+/PTSD+ (n  = 23) were matched on …age, sex, occupation, race, and education. Cognitive status was determined using the Montreal Cognitive Assessment and PTSD status was determined using the DSM-IV SCID. Diffusion tensor imaging was acquired on a 3T Siemens Biograph mMR scanner. Connectometry analysis was used to examine whole-brain tract-level differences in white matter integrity as reflected by fractional anisotropy (FA) values after adjusting for confounders. Results: Analyses identified that FA was negatively correlated with CI and PTSD status in the fornix, cingulum, forceps minor of the corpus callosum and the right uncinate fasciculus. Furthermore, FA was negatively correlated with PTSD status, regardless of CI status in the superior thalamic radiation and the cerebellum. Conclusion: This is the first connectometry study to examine altered white matter tracts in a sample of WTC responders with CI and/or PTSD. Results from this study suggest that WTC responders with early-onset CI may be experiencing an early neurodegenerative process characterized by decreased FA in white matter tracts. Show more

Keywords: Alzheimer’s disease, cognitive impairment, diffusion tensor imaging, midlife, post-traumatic stress disorder, white matter connectometry, World Trade Center Responders

DOI: 10.3233/JAD-220255

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1075-1089, 2022

Authors: Dufour, Isabelle | Vedel, Isabelle | Quesnel-Vallée, Amélie

Article Type: Research Article

Abstract: Background: The first imperative in producing the relevant and needed knowledge about major neurocognitive disorder (MNCD) is to identify people presenting with the condition adequately. To document potential disparities between administrative health databases and population-based surveys could help identify specific challenges in this population and methodological shortfalls. Objective: To describe and compare the characteristics of community-dwelling older adults according to four groups: 1) No MNCD; 2) Self-reported MNCD only; 3) MNCD in administrative health data only; 4) MNCD in both self-reported and administrative health data. Methods: This retrospective cohort study used the Care Trajectories-Enriched Data (TorSaDE) …cohort, a linkage between five waves of the Canadian Community Health Survey (CCHS) and health administrative health data. We included older adults living in the community who participated in at least one cycle of the CCHS. We reported on positive and negative MNCD in self-reported versus administrative health data. We then compared groups’ characteristics using chi-square tests and ANOVA. Results: The study cohort was composed of 25,125 older adults, of which 784 (3.1%) had MNCD. About 70% of people with an MNCD identified in administrative health data did not report it in the CCHS. The four groups present specific challenges related to the importance of perception, timely diagnosis, and the caregivers’ roles in reporting health information. Conclusion: To a certain degree, both data sources fail to consider subgroups experiencing issues related to MNCD; studies like ours provide insight to understand their characteristics and needs better. Show more

Keywords: Alzheimer’s disease, cross-sectional surveys, data accuracy, dementia, linked data, self-reported data

DOI: 10.3233/JAD-220327

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1091-1101, 2022

Authors: Levine, Deborah A. | Gross, Alden L. | Briceño, Emily M. | Tilton, Nicholas | Whitney, Rachael | Han, Dehua | Giordani, Bruno J. | Sussman, Jeremy B. | Hayward, Rodney A. | Burke, James F. | Elkind, Mitchell S.V. | Moran, Andrew E. | Tom, Sarah | Gottesman, Rebecca F. | Gaskin, Darrell J. | Sidney, Stephen | Yaffe, Kristine | Sacco, Ralph L. | Heckbert, Susan R. | Hughes, Timothy M. | Lopez, Oscar L. | Allen, Norrina Bai | Galecki, Andrzej T.

Article Type: Research Article

Abstract: Background: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. Objective: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. Methods: Pooled cohort study of individual participant data from six cohorts (1971–2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10 ]); a 1-point difference represents a 0.1 SD difference …in cognition. Median follow-up was 7.7 (Q1–Q3, 5.2–20.1) years. Results: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. Conclusion: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals. Show more

Keywords: Blood pressure, cognition, dementia, ethnic groups, Hispanic Americans

DOI: 10.3233/JAD-220366

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1103-1117, 2022

Authors: Ala, Tom | Bakir, Danah | Goel, Srishti | Feller, Nida | Botchway, Albert | Womack, Cindy

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) differ in their memory, attention, and visuoconstructional characteristics. The subscales of the well-known Mini-Mental State Examination (MMSE) provide an opportunity to assess these characteristics. Previous research has shown that analysis of the MMSE subscale performance of AD and DLB patients helps to differentiate them. Objective: Study the MMSE scores of AD and DLB patients to see if the ability of previously reported analyses to differentiate them could be improved. Include other dementia patients for perspective. Methods: We studied the MMSEs of all patients seen in our …clinics during an 18-month period. Different equations were studied, derived from the subscales of Memory (M, 3 points maximum), Attention (A, 5 points maximum), and Pentagon-copying (P, 1 point maximum). Results: We obtained 400 MMSEs, 136 from AD patients and 24 from DLB patients, scoring range 1–30. The equation P minus M provided the best discrimination between AD and DLB. Using a P-M score = 1 to identify AD, the positive predictive value was 0.97, negative predictive value 0.22, specificity 0.92, and sensitivity 0.43. As a secondary finding, the P-M = 1 equation was also helpful to differentiate AD from Parkinson’s disease dementia. Conclusion: Considering AD versus DLB in our clinic population, a demented patient who was unable to recall the three memory words on the MMSE but able to copy the intersecting pentagons had a 97% likelihood of having AD. Additional work is needed to improve the sensitivity of the P-M = 1 equation. Show more

Keywords: Alzheimer’s disease, dementia, Lewy body dementia, memory loss, Mini-Mental State Examination, neurocognitive tests, neuropsychology

DOI: 10.3233/JAD-220392

Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 1119-1129, 2022