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