Journal of Alzheimer's Disease - Volume 94, issue 2

Authors: Curtis, Mary Elizabeth | Smith, Tiffany | Nenov, Miroslav | Blass, Benjamin E. | Praticò, Domenico

Article Type: Research Article

Abstract: Background: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer’s disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. Objective: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. Methods: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. …To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. Results: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. Conclusion: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome. Show more

Keywords: Alzheimer’s disease, Down syndrome, retromer, Ts65dn mice

DOI: 10.3233/JAD-230205

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 513-518, 2023

Authors: Zhang, Xiaoyu | Liu, Yan | Huang, Ming | Gunewardena, Sumedha | Haeri, Mohammad | Swerdlow, Russell H. | Wang, Ning

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear. Objective: To map genome-wide DSB distributions in AD and age-matched control brains. Methods: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γ H2AX, a marker of DSB formation. γ H2AX-enriched chromatins were …purified and analyzed via high-throughput genomic sequencing. Results: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression. Conclusion: Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression. Show more

Keywords: Alzheimer’s disease, DNA damage, double-strand DNA breaks, expression regulation, gene, genome instability

DOI: 10.3233/JAD-230316

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 519-535, 2023

Authors: Xu, Guang-Yu | Liu, Yu-Hao | Zeng, Xiao-Qin | Chen, Dong-Wan | Zeng, Gui-Hua | Fan, Dong-Yu | Liu, Yu-Hui | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: The profile of naturally occurring antibodies to amyloid-β (NAbs-Aβ) is altered in patients with Alzheimer’s disease (AD). However, the diagnostic potential of NAbs-Aβ for AD is not clear yet. Objective: This study aims to investigate the diagnostic capacities of NAbs-Aβ for AD. Methods: A total of 40 AD patients and 40 cognitively normal (CN) controls were enrolled in this study. Levels of NAbs-Aβ were detected by ELISA. The correlations of NAbs-Aβ levels with cognitive function and AD-associated biomarkers were examined by Spearman correlation analysis. Diagnostic abilities of NAbs-Aβ were evaluated by the receiver operating characteristic …(ROC) curve analyses. The integrative diagnostic models were established by logistic regression models. Results: We found that NAbs-Aβ7-18 had the highest diagnostic capability (AUC = 0.72) among all single NAbs-Aβ. The combined model (NAbs-Aβ7-18, NAbs-Aβ19-30, and NAbs-Aβ25-36) had a noticeable improvement (AUC = 0.84) in the diagnostic capacity compared with each single NAbs-Aβ. Conclusion: NAbs-Aβs are promising in the diagnosis of AD. Further investigations are needed to confirm the translational potential of this diagnostic strategy. Show more

Keywords: Alzheimer’s disease, amyloid-β, autoantibodies, biomarkers, diagnosis

DOI: 10.3233/JAD-230252

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 537-546, 2023

Authors: Chou, Oscar Hou In | Zhou, Jiandong | Li, Lifang | Chan, Jeffrey Shi Kai | Satti, Danish Iltaf | Chou, Vanessa Hou Cheng | Wong, Wing Tak | Lee, Sharen | Cheung, Bernard Man Yung | Tse, Gary | Chang, Carlin | Liu, Tong

Article Type: Research Article

Abstract: Background: Previous studies identified that neutrophil-to-lymphocyte ratio (NLR) may be a predictor of dementia. However, the associations between NLR and dementia at the population level were less explored. Objective: This retrospective population-based cohort study was designed to identify the associations between NLR and dementia among patients visiting for family medicine consultation in Hong Kong. Methods: The patients were recruited from January 1, 2000, to December 31, 2003, and followed up until December 31, 2019. The demographics, prior comorbidities, medications, and laboratory results were collected. The primary outcomes were Alzheimer’s disease and related dementia and non-Alzheimer’s dementia. …Cox regression and restricted cubic spline were applied to identify associations between NLR and dementia. Results: A cohort of 9,760 patients (male: 41.08% ; baseline age median: 70.2; median follow-up duration: 4756.5 days) with complete NLR were included. Multivariable Cox regression identified that patients with NLR >5.44 had higher risks of developing Alzheimer’s disease and related dementia (hazard ratio [HR]: 1.50, 95% Confidence interval [CI]: 1.17–1.93) but not non-Alzheimer’s dementia (HR: 1.33; 95% CI: 0.60–2.95). The restricted cubic splines demonstrated that higher NLR was associated with Alzheimer’s disease and related dementia. The relationship between the NLR variability and dementia was also explored; of all the NLR variability measures, only the coefficient of variation was predictive of non-Alzheimer’s dementia (HR: 4.93; 95% CI: 1.03–23.61). Conclusion: In this population-based cohort, the baseline NLR predicts the risks of developing dementia. Utilizing the baseline NLR during family medicine consultation may help predict the risks of dementia. Show more

Keywords: Alzheimer’s disease, dementia, inflammation, neuro-inflammation, non-Alzheimer’s dementia

DOI: 10.3233/JAD-220111

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 547-557, 2023

Authors: Mäurer, Anja | Himmel, Gudrun | Lange, Catharina | Mathies, Franziska | Apostolova, Ivayla | Peters, Oliver | Buchert, Ralph

Article Type: Research Article

Abstract: Background: Neuropsychological testing (NPT) of geriatric inpatients can be affected by the acute illness and/or the hospitalization. Objective: To test individualized interpretation of detailed NPT for the differentiation between primary ‘neurodegenerative’ etiologies (predominantly Alzheimer’s disease) and ‘other’ etiologies (including cerebrovascular disease) of newly detected cognitive impairment in geriatric inpatients without and with delirium in remission. Methods: 96 geriatric inpatients (81.9±5.6 years, 64.6% females) with clinically uncertain cognitive impairment were included. 31.3% had delirium in remission that was not considered the primary cause of the cognitive impairment. Categorization of the most likely etiology as ‘neurodegenerative’ or ‘other’ …was established retrospectively by a study neuropsychologist based on individualized summary assessment of detailed NPT compiled in a standardized vignette. The etiological diagnosis based on FDG-PET served as gold standard (54.2% ‘neurodegenerative’, 45.8% ‘other’). Results: Individualized summary assessment by the study neuropsychologist was correct in 80 patients (83.3%, 8 false positive, 8 false negative). The impact of delirium in remission was not significant (p  = 0.237). Individualized summary assessment by an independent neuropsychologist resulted in more false positive cases (n  = 22) at the same rate of false negative cases (n  = 8). Automatic categorization with a decision tree model based on the most discriminative NPT scores was correct in 68 patients (70.8%, 14 false positive, 14 false negative). Conclusion: Individualized summary assessment of detailed NPT in the context of relevant clinical information might be useful for the etiological diagnosis of newly detected cognitive impairment in hospitalized geriatric patients, also in patients with delirium in remission, but requires task-specific expertise. Show more

Keywords: Alzheimer’s disease, delirium, dementia, etiological diagnosis, hospitalized geriatric patients, neuropsychological testing

DOI: 10.3233/JAD-221273

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 559-584, 2023

Authors: Dintica, Christina S. | Calderón-Larrañaga, Amaia | Vetrano, Davide Liborio | Xu, Weili

Article Type: Research Article

Abstract: Background: Evidence suggests that sensory impairment is linked to dementia; however, the role of social network and leisure activity in this relationship is unclear. Objective: Examine the association of hearing and visual impairment with dementia, and whether a rich social network and leisure activity moderates this association. Methods: Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (n  = 2,579) were followed up for up for a median of 10 years (interquartile range = 6). Visual impairment was assessed with a reading acuity test, and hearing impairment was ascertained via self-report and medical records. …Dementia was diagnosed following international criteria. Data on social network and leisure activity was collected via self-report. Hazard ratios (HRs) of dementia risk were derived from Cox regression models. Results: Dual impairment, but not single impairment in hearing and vision was associated with a higher risk of dementia (HR: 1.62, 95% CI: 1.16 to 2.27). Compared to participants with no sensory impairment and a moderate-to-rich social network, those with dual impairment and low social network or leisure activity had higher dementia risk (HR: 2.08, 95% CI: 1.43 to 3.22; HR: 2.08, 95% CI: 1.43 to 3.22, respectively), whereas participants with dual impairment with a moderate-to-rich social network or leisure activity did not have significantly higher dementia risk (HR; 1.42, 95% CI: 0.87 to 2.33; HR; 1.42, 95% CI: 0.87 to 2.33, respectively). Conclusion: A richer social network and participation in stimulating activities may mitigate the higher dementia risk in older adults with dual impairment in vision and hearing. Show more

Keywords: Alzheimer’s disease, dementia, hearing impairment, sensory impairment, vision impairment

DOI: 10.3233/JAD-230041

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 585-595, 2023

Authors: Loughrey, David G. | Leroi, Iracema

Article Type: Article Commentary

Abstract: Recent epidemiological research has linked decline in multiple sensory functions with an increased risk of dementia. However, the pathways linking such factors with neurodegenerative disorders remain unclear. Studies that assess this are crucial for guiding the distribution of public health resources and the development of clinical trials aiming to delay or prevent dementia. This commentary examines the contribution of a study by Dintica and colleagues to the field of sensory-cognitive research.

Keywords: Alzheimer’s disease, dementia, hearing loss, mechanisms, sensory loss, vision loss

DOI: 10.3233/JAD-230472

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 597-599, 2023

Authors: Toccaceli Blasi, Marco | Valletta, Martina | Trebbastoni, Alessandro | D’Antonio, Fabrizia | Talarico, Giuseppina | Campanelli, Alessandra | Sepe Monti, Micaela | Salati, Emanuela | Gasparini, Marina | Buscarnera, Simona | Salzillo, Martina | Canevelli, Marco | Bruno, Giuseppe

Article Type: Research Article

Abstract: Background: The term sundowning is used to describe the emergence or worsening of neuropsychiatric symptoms in late afternoon or early evening in people with dementia. Objective: Our aim was to evaluate sundowning’s prevalence and clinical manifestations among patients attending a tertiary memory clinic and to investigate its clinical and neuropsychological correlates. Methods: Patients with dementia attending our memory clinic were enrolled in the study. Sundowning was identified through a specifically designed questionnaire. Sociodemographic and clinical features of sundowners and non-sundowners were compared, and a logistic regression was performed to identify the variables associated with the phenomenon. …A subgroup of patients underwent a complete neuropsychological assessment. Results: Among 184 recruited patients, 39 (21.2%) exhibited sundowning, mostly expressed as agitation (56.4%), irritability (53.8%), and anxiety (46.2%). Sundowners were significantly older, had a later dementia onset, exhibited more severe cognitive and functional impairment, more frequent nocturnal awakenings, and hearing loss relative to non-sundowners. They were also more likely to use anticholinergic medications and antipsychotics, and less likely to use memantine. In a multi-adjusted model, the factors significantly associated with sundowning were the Clinical Dementia Rating score (OR 3.88; 95% CI 1.39–10.90) and the use of memantine (OR 0.20; 95% CI 0.05–0.74). Participants with and without sundowning obtained similar results in single domain neuropsychological tests. Conclusion: Sundowning is commonly experienced by patients with dementia and appears as a multiply determined condition. Its presence should always be evaluated in clinical practice and a multidimensional approach should be adopted to identify its predictors. Show more

Keywords: Alzheimer’s disease, dementia, neuropsychiatric symptoms, sundown syndrome, sundowning

DOI: 10.3233/JAD-230094

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 601-610, 2023

Authors: Milano, Chiara | Hoxhaj, Domeniko | Del Chicca, Marta | Pascazio, Alessia | Paoli, Davide | Tommasini, Luca | Vergallo, Andrea | Pizzanelli, Chiara | Tognoni, Gloria | Nuti, Angelo | Ceravolo, Roberto | Siciliano, Gabriele | Hampel, Harald | Baldacci, Filippo

Article Type: Research Article

Abstract: Background: Neurosyphilis-associated cognitive and behavioral impairment— historically coined as “general paralysis of the insane”— share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer’s disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging. Objective: To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy. Methods: We selected the studies comparing patients with AD and …with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases. Results: The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD. Conclusion: Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression. Show more

Keywords: Alzheimer’s disease, biomarkers, general paralysis, neurosyphilis, treatable dementia

DOI: 10.3233/JAD-230170

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 611-625, 2023

Authors: Li, Bingyu | Shi, Kening | Ren, Chao | Kong, Min | Ba, Maowen

Article Type: Research Article

Abstract: Background: The way to evaluate brain tau pathology in vivo is tau positron emission tomography (tau-PET) or cerebrospinal fluid (CSF) analysis. In the clinically diagnosed mild cognitive impairment (MCI), a proportion of tau-PET are negative. Interest in less expensive and convenient ways to detect tau pathology in Alzheimer’s disease has increased due to the high cost of tau-PET and the invasiveness of lumbar puncture, which typically slows down the cost and enrollment of clinical trials. Objective: We aimed to investigate one simple and effective method in predicting tau-PET status in MCI individuals. Methods: The sample …included 154 individuals which were dichotomized into tau-PET (+) and tau-PET (–) using a cut-off of >1.33. We used stepwise regression to select the unitary or combination of variables that best predicted tau-PET. The receiver operating characteristic curve was used to assess the accuracy of single and multiple clinical markers. Results: The combined performance of three variables [Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13), Mini-Mental State Examination (MMSE), ADNI-Memory summary score (ADNI-MEM)] in neurocognitive measures demonstrated good predictive accuracy of tau-PET status [accuracy = 85.7%, area under the curve (AUC) = 0.879]. The combination of clinical markers model (APOE ɛ 4, neurocognitive measures and structural MRI imaging of middle temporal) had the best discriminative power (AUC = 0.946). Conclusion: As a noninvasive test, the combination of APOE ɛ 4, neurocognitive measures and structural MRI imaging of middle temporal accurately predicts tau-PET status. The finding may provide a non-invasive, cost-effective tool for clinical application in predicting tau pathology among MCI individuals. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, magnetic resonance imaging, mild cognitive impairment, positron-emission tomography

DOI: 10.3233/JAD-230180

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 627-640, 2023