Journal of Alzheimer's Disease - Volume 85, issue 1

Authors: Macoir, Joël | Tremblay, Marie-Pier | Wilson, Maximiliano A. | Laforce, Robert | Hudon, Carol

Article Type: Research Article

Abstract: Background: The role of semantic knowledge in emotion recognition remains poorly understood. The semantic variant of primary progressive aphasia (svPPA) is a degenerative disorder characterized by progressive loss of semantic knowledge, while other cognitive abilities remain spared, at least in the early stages of the disease. The syndrome is therefore a reliable clinical model of semantic impairment allowing for testing the propositions made in theoretical models of emotion recognition. Objective: The main goal of this study was to investigate the role of semantic memory in the recognition of basic emotions conveyed by music in individuals with svPPA. …Methods: The performance of 9 individuals with svPPA was compared to that of 32 control participants in tasks designed to investigate the ability: a) to differentiate between familiar and non-familiar musical excerpts, b) to associate semantic concepts to musical excerpts, and c) to recognize basic emotions conveyed by music. Results: Results revealed that individuals with svPPA showed preserved abilities to recognize familiar musical excerpts but impaired performance on the two other tasks. Moreover, recognition of basic emotions and association of musical excerpts with semantic concepts was significantly better for familiar than non-familiar musical excerpts in participants with svPPA. Conclusion: Results of this study have important implications for theoretical models of emotion recognition and music processing. They suggest that impairment of semantic memory in svPPA affects both the activation of emotions and factual knowledge from music and that this impairment is modulated by familiarity with musical tunes. Show more

Keywords: Emotions, music, semantic variant of primary progressive aphasia, semantics

DOI: 10.3233/JAD-215083

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 115-128, 2022

Authors: Li, Yike | Guo, Jiajie | Yang, Peikai

Article Type: Research Article

Abstract: Background: The Pentagon Drawing Test (PDT) is a common assessment for visuospatial function. Evaluating the PDT by artificial intelligence can improve efficiency and reliability in the big data era. This study aimed to develop a deep learning (DL) framework for automatic scoring of the PDT based on image data. Methods: A total of 823 PDT photos were retrospectively collected and preprocessed into black-and-white, square-shape images. Stratified fivefold cross-validation was applied for training and testing. Two strategies based on convolutional neural networks were compared. The first strategy was to perform an image classification task using supervised transfer learning. The …second strategy was designed with an object detection model for recognizing the geometric shapes in the figure, followed by a predetermined algorithm to score based on their classes and positions. Results: On average, the first framework demonstrated 62%accuracy, 62%recall, 65%precision, 63%specificity, and 0.72 area under the receiver operating characteristic curve. This performance was substantially outperformed by the second framework, with averages of 94%, 95%, 93%, 93%, and 0.95, respectively. Conclusion: An image-based DL framework based on the object detection approach may be clinically applicable for automatic scoring of the PDT with high efficiency and reliability. With a limited sample size, transfer learning should be used with caution if the new images are distinct from the previous training data. Partitioning the problem-solving workflow into multiple simple tasks should facilitate model selection, improve performance, and allow comprehensible logic of the DL framework. Show more

Keywords: Computer vision, convolutional neural network, deep learning, image classification, object detection, Pentagon Drawing Test

DOI: 10.3233/JAD-210714

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 129-139, 2022

Authors: Fuller-Thomson, Esme | Ahlin, Katherine Marie

Article Type: Research Article

Abstract: Background: Numerous studies suggest the prevalence of dementia has decreased over the past several decades in Western countries. Less is known about whether these trends differ by gender or age cohort, and if generational differences in educational attainment explain these trajectories. Objective: 1) To detect temporal trends in the age-sex-race adjusted prevalence of serious cognitive problems among Americans aged 65+; 2) To establish if these temporal trends differ by gender and age cohort; 3) To examine if these temporal trends are attenuated by generational differences in educational attainment. Methods: Secondary analysis of 10 years of annual …nationally representative data from the American Community Survey with 5.4 million community-dwelling and institutionalized older adults aged 65+. The question on serious cognitive problems was, “Because of a physical, mental, or emotional condition, does this person have serious difficulty concentrating, remembering, or making decisions?” Results: The prevalence of serious cognitive problems in the US population aged 65 and older declined from 12.2% to 10.0% between 2008 and 2017. Had the prevalence remained at the 2008 levels, there would have been an additional 1.13 million older Americans with serious cognitive problems in 2017. The decline in memory problems across the decade was higher for women (23%) than for men (13%). Adjusting for education substantially attenuated the decline. Conclusion: Between 2008 and 2017, the prevalence of serious cognitive impairment among older Americans declined significantly, although these declines were partially attributable to generational differences in educational attainment. Show more

Keywords: Cognitive impairment, dementia, memory, temporal trends

DOI: 10.3233/JAD-210561

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 141-151, 2022

Authors: DiProspero, Natalie D. | Keator, David B. | Phelan, Michael | van Erp, Theo G.M. | Doran, Eric | Powell, David K. | Van Pelt, Kathryn L. | Schmitt, Frederick A. | Head, Elizabeth | Lott, Ira T. | Yassa, Michael A.

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is associated with increased risk for Alzheimer’s disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, …during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38–61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion. Show more

Keywords: Alzheimer’s disease, biomarkers, default mode network, dementia, Down syndrome, functional connectivity, resting state functional magnetic resonance imaging

DOI: 10.3233/JAD-210572

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 153-165, 2022

Authors: Song, Yizhi | Du, Zunshu | Chen, Xinyue | Zhang, Wanning | Zhang, Guitao | Li, Hui | Chang, Lirong | Wu, Yan

Article Type: Research Article

Abstract: Background: Soluble oligomeric amyloid-β (Aβ)-induced synaptic dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis. Mounting evidence has suggested N-methyl-D-aspartate receptors (NMDARs) play an important role in Aβ-induced synaptotoxicity. Originally NMDARs were believed to be expressed exclusively in neurons; however, recent two decades studies have demonstrated functional NMDARs present on astrocytes. Neuronal NMDARs are modulators of neurodegeneration, while our previous initial study found that astrocytic NMDARs mediated synaptoprotection and identified nerve growth factor (NGF) secreted by astrocytes, as a likely mediator, but how astrocytic NMDARs protect neurons against Aβ-induced synaptotoxicity through regulating NGF remains unclear. Objective: To …achieve further insight into the mechanism of astrocytic NMDARs oppose Aβ-induced synaptotoxicity through regulating NGF. Methods: With the primary hippocampal neuronal and astrocytic co-cultures, astrocytes were pretreated with agonist or antagonist of NMDARs before Aβ142 oligomers application to neuron-astrocyte co-cultures. Western blot, RT-PCR, etc., were used for the related proteins evaluation. Results: Activation of astrocytic NMDARs can significantly mitigate Aβ142 -induced loss of PSD-95 and synaptophysin through increasing NGF release. Blockade of astrocytic NMDARs inhibited Aβ-induced compensatory protective NGF increase in protein and mRNA levels through modulating NF-κB of astrocytes. Astrocytic NMDARs activation can enhance Aβ-induced Furin increase, and blockade of astrocytic NMDARs inhibited Aβ-induced immunofluorescent intensity elevation of vesicle trafficking protein VAMP3 and NGF double-staining. Conclusion: Astrocytic NMDARs oppose Aβ-induced synaptotoxicity through modulating the synthesis, maturation, and secretion of NGF in astrocytes. This new information may contribute to the quest for specific targeted strategy of intervention to delay the onset of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , astrocyte, N-methyl-D-aspartate receptors, nerve growth factor

DOI: 10.3233/JAD-210730

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 167-178, 2022

Authors: Hyun, Jinshil | Hall, Charles B. | Katz, Mindy J. | Derby, Carol A. | Lipnicki, Darren M. | Crawford, John D. | Guaita, Antonio | Vaccaro, Roberta | Davin, Annalisa | Kim, Ki Woong | Han, Ji Won | Bae, Jong Bin | Röhr, Susanne | Riedel-Heller, Steffi | Ganguli, Mary | Jacobsen, Erin | Hughes, Tiffany F. | Brodaty, Henry | Kochan, Nicole A. | Trollor, Julian | Lobo, Antonio | Santabarbara, Javier | Lopez-Anton, Raul | Sachdev, Perminder S. | Lipton, Richard B. | for Cohort Studies of Memory in an International Consortium (COSMIC)

Article Type: Research Article

Abstract: Background: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia. Objective: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts. Method: We used data from 10,195 participants (median baseline age = 74.1, range = 58∼103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated …failure time model was applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed. Result: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28%of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with ‘high school completion’ or ‘above high school’ compared to ‘middle school completion or below’. Conclusion: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course. Show more

Keywords: Cognitive reserve, coordinated analysis, education, occupational complexity

DOI: 10.3233/JAD-210627

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 179-196, 2022

Authors: Müller, Ebba Gløersen | Edwin, Trine Holt | Strand, Bjørn Heine | Stokke, Caroline | Revheim, Mona Elisabeth | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) show heterogeneity in clinical progression rate, and we have limited tools to predict prognosis. Amyloid burden from 18 F-Flutemetamol positron emission tomography (PET), as measured by standardized uptake value ratios (SUVR), might provide prognostic information. Objective: We investigate whether 18 F-Flutemetamol PET composite or regional SUVRs are associated with trajectories of clinical progression. Methods: This observational longitudinal study included 94 patients with clinical AD. PET images were semi-quantified with normalization to pons. Group-based trajectory modeling was applied to identify trajectory groups according to change in the Clinical Dementia Rating Scale …Sum of Boxes (CDR-SB) over time. Multinomial logistic regression models assessed the association of SUVRs with trajectory group membership. Results: Three trajectory groups were identified. In the regression models, neither composite nor regional SUVRs were associated with trajectory group membership. Conclusion: There were no associations between CDR progression and 18 F-Flutemetamol PET-derived composite SUVRs or regional SUVRs in clinical AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, clinical progression, Flutemetamol, PET-CT, trajectories

DOI: 10.3233/JAD-215046

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 197-205, 2022

Authors: Mani, Chinnadurai | Acharya, Ganesh | Kshirsagar, Sudhir | Vijayan, Murali | Khan, Hafiz | Reddy, P. Hemachandra | Palle, Komaraiah

Article Type: Research Article

Abstract: Background: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer’s disease. BRCA1 interacting protein 1 or BRIP1 is a 5’ to 3’ DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity. Objective: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases. Methods: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence …studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability. Results: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2 O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells. Conclusion: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress. Show more

Keywords: BRIP1, DNA damage, L-Glutamic acid, mitochondrial stress, R-loop

DOI: 10.3233/JAD-215305

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 207-221, 2022

Authors: Nihashi, Takashi | Sakurai, Keita | Kato, Takashi | Iwata, Kaori | Kimura, Yasuyuki | Ikenuma, Hiroshi | Yamaoka, Akiko | Takeda, Akinori | Arahata, Yutaka | Washimi, Yukihiko | Suzuki, Keisuke | Bundo, Masahiko | Sakurai, Takashi | Okamura, Nobuyuki | Yanai, Kazuhiko | Ito, Kengo | Nakamura, Akinori | MULNIAD Study Group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Objective: Using 18 F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18 F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. Methods: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with …structural magnetic resonance imaging, 11 C-Pittsburgh compound-B (PIB) and 18 F-THK5351 PET, and neuropsychological assessment. 18 F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. Results: On visual analysis, 18 F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18 F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18 F-THK5351 accumulation correlated positively with supratentorial 11 C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. Conclusion: The AD continuum showed an increase in 18 F-THK5351 with stage progression, suggesting that 18 F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum. Show more

Keywords: Alzheimer’s disease, amyloid, Braak stages, 18F-THK5351, positron emission tomography

DOI: 10.3233/JAD-215024

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 223-234, 2022

Authors: Noguchi-Shinohara, Moeko | Yuki-Nozaki, Sohshi | Abe, Chiemi | Mori, Ayaka | Horimoto, Mai | Yokogawa, Masami | Ishida, Natsuko | Suga, Yukio | Ishizaki, Junko | Ishimiya, Mai | Nakamura, Hiroyuki | Komai, Kiyonobu | Nakamura, Hiroyuki | Shibata, Mao | Ohara, Tomoyuki | Hata, Jun | Ninomiya, Toshiharu | Yamada, Masahito | on behalf of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) study group

Article Type: Research Article

Abstract: Background: Glucose dysmetabolism is an important risk factor for dementia. Objective: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. Methods: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c ), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer’s disease (AD) and vascular dementia (VaD) were investigated. Results: The multivariable-adjusted odds ratios …(ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08–1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %–6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19–2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00–1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. Conclusion: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level. Show more

Keywords: Alzheimer’s disease, diabetes mellitus, glycated albumin, hemoglobin A1c, vascular dementia

DOI: 10.3233/JAD-215153

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 235-247, 2022