Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Shojaie, Mehdi | Tabarestani, Solale | Cabrerizo, Mercedes | DeKosky, Steven T. | Vaillancourt, David E. | Loewenstein, David | Duara, Ranjan | Adjouadi, Malek

Article Type: Research Article

Abstract: Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to …capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition. Show more

Keywords: Alzheimer’s disease, amyloid-β , classification, feature selection, information theory, machine-learning, multimodal imaging, tau

DOI: 10.3233/JAD-210064

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Sun, Xiaoyan | Dong, Chuanhui | Levin, Bonnie E. | Caunca, Michelle | Zeki Al Hazzouri, Adina | DeRosa, Janet T. | Stern, Yaakov | Cheung, Ying Kuen | Elkind, Mitchell S.V. | Rundek, Tatjana | Wright, Clinton B. | Sacco, Ralph L.

Article Type: Correction

DOI: 10.3233/JAD-219015

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2021

Authors: Hin, Nhi | Newman, Morgan | Pederson, Stephen | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3′ or 5′ untranslated regions (UTRs) were identified in human, mouse, and …zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3′ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions. Show more

Keywords: Alzheimer’s disease, computational biology, familial Alzheimer’s disease, gene expression, iron homeostasis, iron responsive element, transcriptomics

DOI: 10.3233/JAD-210200

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-34, 2021

Authors: Chu, Min | Liu, Li | Wang, Jingjuan | Liu, Lin | Kong, Yu | Jing, Donglai | Xie, Kexin | Cui, Yue | Cui, Bo | Zhang, Jing | Ye, Hong | Li, Junjie | Wang, Lin | Rosa-Neto, Pedro | Gauthier, Serge | Wu, Liyong

Article Type: Research Article

Abstract: Background: The anterior cingulate cortex (ACC) seems to play an important role in behavioral deficits and executive dysfunctions in patients with behavior-variant frontotemporal dementia (bvFTD), while its specific and independent contribution requires clarification. Objective: To identify whether ACC abnormalities in gray matter (GM) volume and standardized uptake value ratio (SUVR) images are associated with disease severity of bvFTD, by analyzing hybrid T1 and 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET). Methods: We enrolled 21 bvFTD patients and 21 healthy controls in the study. Each subject underwent a hybrid PET/MRI study and a standardized neuropsychologic assessment …battery. GM volume and SUVR are voxel-wise calculated and compared. Then we estimate the mean value inside ACC for further partial Pearson’s correlation to explore the association between GM volume/SUVR of the ACC and severity of behavioral deficit as well as executive dysfunction. Results: ACC was shown to be involved in both atrophy and hypometabolism patterns. The partial Pearson’s correlation analysis showed that the SUVR of the ACC was strongly correlated with frontal behavior inventory total score (left r  = –0.85, right r  = –0.85, p  <  0.0001), disinhibition subscale score (left r  = –0.72, p  = 0.002; right = –0.75, p  <  0.0001), and apathy subscale score (left = –0.87, right = –0.85, p  <  0.0001). Conclusion: These findings demonstrated decreased ACC activity contributes to behavioral disturbances of both apathetic and disinhibition syndromes of bvFTD, which can be sensitively detected using 18 F-FDG PET. Show more

Keywords: Anterior cingulate cortex, atrophy, 18F-fluorodeoxyglucose positron emission tomography, frontotemporal dementia, hypometabolism, magnetic resonance imaging

DOI: 10.3233/JAD-215127

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Torres, Angie K. | Jara, Claudia | Park-Kang, Han S. | Polanco, Catalina M. | Tapia, Diego | Alarcón, Fabián | de la Peña, Adely | Llanquinao, Jesus | Vargas-Mardones, Gabriela | Indo, Javiera A. | Inestrosa, Nibaldo C. | Tapia-Rojas, Cheril

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones …or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, cognitive impairment, mitochondria, neurofibrillary tangles, synapses, synaptic mitochondria

DOI: 10.3233/JAD-215139

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Schultz, Bruna | Taday, Jéssica | Menezes, Leonardo | Cigerce, Anderson | Leite, Marina C. | Gonçalves, Carlos-Alberto

Article Type: Research Article

Abstract: One of the changes found in the brain in Alzheimer’s disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and …2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons. Show more

Keywords: Alzheimer’s disease, astrocyte, calcineurin, calpain, CDK5, GFAP, S100B

DOI: 10.3233/JAD-215182

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Upte, Jolanta | Brüning, Thomas | Möhle, Luisa | Brackhan, Mirjam | Bascuñana, Pablo | Jansone, Baiba | Pahnke, Jens

Article Type: Research Article

Abstract: Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET ® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision ® and Microsoft Excel ® software. For the proof of concept, intracerebral stereotactic surgery …was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET ® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds. Show more

Keywords: Alzheimer’s disease, amyloid-β, distributional activity, implantable infusion pump, histology, plaques, quantification, transgenic mice

DOI: 10.3233/JAD-215180

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Schneider, Julia | Miller, Jennifer | Teschauer, Winfried | Kruse, Andreas | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Entering the hospital via an emergency department (ED) is a pivotal moment in the life of people with dementia (PwD) and often starts an avoidable downward spiral. Therefore, it is required to further educate ED staff to raise awareness of the needs of PwD. Although there are many studies about existing dementia training programs for the hospital setting, empirical evidence for the ED setting and cross-level training evaluations are lacking. Objective: The study aims to evaluate a two-day dementia training course for ED staff on the outcome levels of learning, individual performance, and organizational performance. Furthermore, the …study examines whether the training fulfilled participants’ expectations. Methods: Mixed methods were used to assess data from head nurses, nursing, and administrative staff working in EDs. We conducted semi-structured interviews three weeks before (N  = 18) and eight months after (N  = 9) the training. Questionnaire data were assessed before the training, three months, and six months after the training (N  = 44). A qualitative content analysis was conducted to analyze qualitative data; quantitative data was described descriptively. Results: The intervention seems to be effective on both learning and individual performance levels. However, we did not observe any changes in the organizational performance. The training program met attendees’ expectations only partly. The working environment of EDs needs to be taken more into account. Conclusion: Hospital staffs’ expectations of a dementia training program depend on the work area in which they operate. Results support the implementation of intervention bundles to enable sustainable cross-level changes. Show more

Keywords: Education, health care facilities, health personnel, neurocognitive disorders, program evaluation

DOI: 10.3233/JAD-210505

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Rusanen, Minna | Selander, Tuomas | Kärkkäinen, Virve | Koivisto, Anne

Article Type: Research Article

Abstract: Background: Human-animal interactions are known to have many beneficial psychosocial and psychophysiological effects on persons with and without medical health conditions. There are no previous prospective studies with long follow-up times on the effects of domestic pets on the persons with Alzheimer’s disease (AD) living at home. Objective: To investigate the effects of pets on the activities of daily living (ADL), disease progression, and neuropsychiatric symptoms (NPS) during a five-year follow-up on the persons with AD. Methods: Altogether 223 home-dwelling persons (mean age 75.2 years) with very mild (CDR 0.5) or mild (CDR 1) AD at …baseline were included for this study. ADCS-ADL, NPI, MMSE, and CDR-SOB were measured at baseline, annually for three years and after five years. Results: Totally 40 (17.9%) participants had a pet. At the baseline, pet owners and non-pet owners had no significant differences in age, gender, or the ADCS-ADL, NPS, and CDR-SOB scores, while MMSE was lower in pet owners than non-pet owners (20.2 versus 21.7; p  = 0.009). Over the follow-up, pet owners had significantly better mean ADCS-ADL (57.5 versus 54.0; p  = 0.031), NPI (9.3 versus 13.0; p  = 0.038), and CDR-SOB scores (5.7 versus 6.6; p  = 0.004) compared to non-pet owners. The differences in the MMSE scores between the groups detected at baseline attenuated over time. Conclusion: Significant positive effects of the pets on ADL functions, NPS, and disease progression were detected over the whole follow-up suggesting that having a pet may support daily activity and slow the disease progression in AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive activity, dementia, neuropsychiatric symptoms, rating scales

DOI: 10.3233/JAD-210557

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Sundermann, Erin E. | Barnes, Lisa L. | Bondi, Mark W. | Bennett, David A. | Salmon, David P. | Maki, Pauline M.

Article Type: Research Article

Abstract: Background Despite a female advantage in verbal memory, normative data for verbal memory tests used to diagnose Alzheimer’s disease (AD) dementia and amnestic mild cognitive impairment (aMCI) often are not sex-adjusted. Objective To determine whether sex-adjusted norms improve aMCI diagnostic accuracy when accuracy was evaluated by progression to AD dementia over time. Methods Non-sex-specific and sex-specific verbal memory test norms were incorporated into Jak/Bondi aMCI criteria and applied to older (age 65–90) non-demented women (N  = 1,036) and men (N  = 355) from the Rush Memory and Aging Project. Using sex-specific aMCI diagnosis as the “true” condition versus …non-sex-specific aMCI diagnosis as the “predicted” condition, we identified True Positives, False Positives, True Negatives, and False Negatives and compared AD dementia risk over 10 years among groups. Results Rates of aMCI were higher in men versus women (χ 2  = 15.39, p  <  0.001) when determined based on typical diagnostic criteria, but this difference reversed when using sex-specific diagnostic criteria (χ 2  = 8.38, p  = 0.004). We identified 8%of women as False Negatives and 12%of men as False Positives. Risk of incident AD dementia in False Positive men was significantly lower than in True Positive men (HR = 0.26, 95%CI = 0.12–0.58, p  = 0.001). Risk of incident AD dementia in False Negative women was substantially higher than in True Negative women (HR = 3.11, 95%CI = 2.09–4.63, p  <  0.001). Conclusion Results suggest that previous reports of higher aMCI rates in men versus women may be an artifact of non-sex-adjusted norms/cut-scores. Incorporation of sex-specific norms/cut-scores for verbal memory impairment into aMCI diagnostic criteria may improve diagnostic accuracy and avoid diagnostic errors in approximately 20%. Show more

Keywords: Amnestic mild cognitive impairment, diagnosis, incident Alzheimer’s disease, sex differences, verbal memory

DOI: 10.3233/JAD-215260

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021