Journal of Alzheimer's Disease - Volume 79, issue 4

Authors: Castagna, Alberto | Fabbo, Andrea | Manzo, Ciro | Lacava, Roberto | Ruberto, Carmen | Ruotolo, Giovanni

Article Type: Research Article

Abstract: Background: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11%of men, mean …age 76,81±4.93 years): 48.8%treated with memantine and donepezil; 48.2%with memantine and rivastigmine; 2.9%with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p  = 0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p  = 0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, citicoline, combined treatment, memantine

DOI: 10.3233/JAD-201211

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1509-1515, 2021

Authors: Martínez-Maldonado, Alejandra | Ontiveros-Torres, Miguel Ángel | Harrington, Charles R. | Montiel-Sosa, José Francisco | Prandiz, Raúl García-Tapia | Bocanegra-López, Patricia | Sorsby-Vargas, Andrew Michael | Bravo-Muñoz, Marely | Florán-Garduño, Benjamín | Villanueva-Fierro, Ignacio | Perry, George | Garcés-Ramírez, Linda | de la Cruz, Fidel | Martínez-Robles, Sandra | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. …Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP. Show more

Keywords: Alzheimer’s disease, neurofibrillary tangle, progressive supranuclear palsy, tau protein, truncation

DOI: 10.3233/JAD-201139

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1517-1531, 2021

Authors: Prakash, Mithilesh | Abdelaziz, Mahmoud | Zhang, Linda | Strange, Bryan A. | Tohka, Jussi | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and …36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months = 4.1, 4.5, and 5.0, ρ12, 24 & 36 months = 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months = 3.5, 3.7, and 4.6, ρ12, 24 & 36 months = 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials. Show more

Keywords: Alzheimer’s disease, machine learning, magnetic resonance imaging, multi-modal imaging, neuropsychology

DOI: 10.3233/JAD-200906

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1533-1546, 2021

Authors: Mehder, Rasha H. | Bennett, Brian M. | Andrew, R. David

Article Type: Research Article

Abstract: Background: Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective: We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if …altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods: Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results: The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion: This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory. Show more

Keywords: CA1, dendrite, hippocampus, morphometry, oxidative stress, pyramidal neurons, spatial memory, spines

DOI: 10.3233/JAD-201024

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1547-1561, 2021

Authors: Lim, Yen Ying | Pase, Matthew P. | Buckley, Rachel F. | Yassi, Nawaf | Bransby, Lisa | Fowler, Christopher | Laws, Simon M. | Masters, Colin L. | Maruff, Paul

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ɛ 4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ɛ 4 heterozygotes; 50 ɛ 4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective …cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ 4 heterozygotes; 31 ɛ 4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ɛ 4 homozygotes compared with ɛ 4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ 4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ 4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ɛ 4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ 4 homozygosity increases with older age. APOE ɛ 4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, early detection, memory

DOI: 10.3233/JAD-201281

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1563-1573, 2021

Authors: Peng, Zhouyuan | Nishimoto, Hiroyuki | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological tests that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had …better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ = –0.707, p  < 0.01), BDT (ρ = –0.560, p  < 0.05), and ADAS (ρ = 0.758, p  < 0.01), “Forgetting to use turn signals” with the TMT-B score (ρ = 0.608, p  < 0.05), “Centerline crossings” with the scores of MMSE (ρ = –0.582, p  < 0.05) and ADAS (ρ = 0.538, p  < 0.05), and “Going the wrong way” was correlated with the score of CDT (ρ = –0.624, p  < 0.01). Conclusion: Different neuropsychological factors serve as predictors of different specific driving maneuvers segmented from driving performance. Show more

Keywords: Automobile driving, cognitive impairment, computer simulation, dementia, neuropsychological tests

DOI: 10.3233/JAD-201323

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1575-1587, 2021

Authors: Rodriguez, Francisca S. | Pabst, Alexander | Heser, Kathrin | Kleineidam, Luca | Hajek, Andre | Eisele, Marion | Röhr, Susanne | Löbner, Margrit | Wiese, Birgitt | Angermeyer, Matthias C. | Maier, Wolfgang | Scherer, Martin | Wagner, Michael | König, Hans-Helmut | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer’s disease and related dementias. Objectives: The aim of this study was to investigate the prevalence of disorientation in older age in association with the level of cognitive status, personal characteristics, and life events. Methods: Three longitudinal population-based cohort studies on cognitive health of elderly adults were harmonized (LEILA 75 + , AgeCoDe/AgeQualiDe, AgeMooDe). Participants who completed a baseline and at least one follow-up assessment of cognitive functioning and who did not have stroke, Parkinson’s disease, atherosclerosis, kidney disease, and/or alcoholism were included …in the analysis (n  = 2135, 72.6% female, mean age 80.2 years). Data was collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant’s general practitioner. Results: Making three errors in the MMSE other than in the questions on orientation (MMSEwo ) came with a probability of 7.8% for disorientation, making ten errors with a probability of 88.9%. A lower MMSEwo score (HR 0.75, CI 95 0.71–0.79, p  < 0.001), older age (HR 1.11, CI 95 1.08–1.14, p  < 0.001), and living in a nursing home (HR 1.64, CI 95 1.02–2.64, p  = 0.042) were associated with incident disorientation. Impairments in walking (OR 2.41, CI 95 1.16–4.99, p  = 0.018) were associated with a greater probability for prevalent disorientation. None of the life events were significant. Conclusion: Our findings suggest that disorientation is primarily associated with cognitive status. Regular walking activities might possibly reduce the risk for disorientation but further research is necessary. Show more

Keywords: Cognitive functioning, cognitive status, dementia, longitudinal cohort, orientation, symptoms

DOI: 10.3233/JAD-201008

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1589-1599, 2021

Authors: Arendt, Johan Frederik Håkonsen | Horváth-Puhó, Erzsébet | Sørensen, Henrik Toft | Nexø, Ebba | Pedersen, Lars | Ording, Anne Gulbech | Henderson, Victor W.

Article Type: Research Article

Abstract: Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients …with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia. Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. Conclusion: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia. Show more

Keywords: Alzheimer’s disease, cobalamin, cohort studies, clinical nutrition, registries

DOI: 10.3233/JAD-201096

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1601-1612, 2021

Authors: Li, Sen | Yi, Yushan | Cui, Ke | Zhang, Yanqiu | Chen, Yange | Han, Dou | Sun, Ling | Zhang, Xiaohui | Chen, Fei | Zhang, Yixin | Yang, Yufeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a common cause of dementia among elderly people. Hyperphosphorylation and aggregation of tau correlates with the clinical progression of AD; therefore, therapies targeting the aggregation of tau may have potential applications for anti-AD drug development. Several inhibitors of tau aggregation, including small molecules and antibodies, have been found to decrease the aggregation of tau and the corresponding pathology. Objective: To screen one kind of single-chain variable fragment (scFv) antibody which could inhibit the aggregation of tau and ameliorate its cytotoxicity. Methods/Results: Using phosphorylated tau (pTau) as an antigen, we obtained a …scFv antibody via the screening of a high-capacity phage antibody library. Biochemical analysis revealed that this scFv antibody (scFv T1) had a strong ability to inhibit pTau aggregation both in dilute solutions and under conditions of macromolecular crowding. ScFv T1 could also depolymerize preformed pTau aggregates in vitro . Furthermore, scFv T1 was found to be able to inhibit the cytotoxicity of extracellular pTau aggregates and ameliorate tau-mediated toxicity when coexpressed with a hTauR406W mutant in the eye of transgenic Drosophila flies. Conclusion: This scFv T1 antibody may be a potential new therapeutic agent against AD. Our methods can be used to develop novel strategies against protein aggregation for the treatment of neurodegenerative diseases. Show more

Keywords: Aggregation, Alzheimer’s disease, Drosophila , single-chain variable fragment antibody, tau, tauopathy, toxicity

DOI: 10.3233/JAD-191266

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1613-1629, 2021

Authors: Park, Jin-Hyuck | Lee, Sang Ah

Article Type: Research Article

Abstract: Background: Although episodic memory impairment is one of the hallmarks of Alzheimer’s disease (AD), the relative decline in the components of episodic memory (What, Where , and When ) and the effects of cognitive training on each of them are still unknown. Objective: We aimed to independently assess the impairment in each component of episodic memory in early to moderate AD and address whether it can be enhanced through active, spatiotemporal episodic training. Methods: A non-verbal scene-based episodic memory task was developed to assess the ability to remember What, Where, and When information. Experiment …1 tested whether this task can differentiate AD subjects (N = 16) from healthy controls (N = 16). In Experiment 2, 13 AD subjects underwent 16 training sessions, followed by a re-administration of the scene-based memory task. Experiment 3 tested 42 healthy older adults and 51 younger adults on the same task to investigate the effects of normal aging. Results: Of the three components, When memory had the highest predictive power in distinguishing AD from normal aging. Following training of AD subjects, only Where memory improved. Only What memory revealed a significant decline in healthy subjects from 65–85 years of age. Conclusion: These findings shed new light on the importance of the temporal component of episodic memory as a behavioral marker of AD. The selective improvement of spatial but not temporal memory through training further demonstrates the fragility of temporal memory even in early AD. Neuroscientific research is needed to distinguish whether the Where component was enhanced by improvements in hippocampal spatial representation or by other compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, cognitive training, episodic memory, temporal order memory, visual scene memory, What-Where-When memory

DOI: 10.3233/JAD-200892

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1631-1646, 2021