Journal of Alzheimer's Disease - Volume 84, issue 1

Authors: Zhang, Xiao-Qin | Xu, Le | Yang, Si-Yu | Hu, Lin-Bo | Dong, Fei-Yuan | Sun, Bing-Gui | Shen, Hao-Wei

Article Type: Research Article

Abstract: Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons …in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD. Show more

Keywords: Alzheimer’s disease, excitatory circuit, prefrontal cortex, pyramidal neurons

DOI: 10.3233/JAD-210585

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 129-140, 2021

Authors: Katzourou, Ioanna | Leonenko, Ganna | Ivanov, Dobril | Meggy, Alun | Marshall, Rachel | Sims, Rebecca | Williams, Julie | Holmans, Peter | Escott-Price, Valentina | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The rate of cognitive decline in Alzheimer’s disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity. Objective: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD. Methods: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used …in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE ) genotype. Results: No association was found between the number of APOE ɛ 2 or ɛ 4 alleles and the rate of cognitive decline in either of the datasets examined. Conclusion: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD. Show more

Keywords: Alzheimer’s disease, APOE , cognitive decline, dementia, genetics

DOI: 10.3233/JAD-210685

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 141-149, 2021

Authors: Pytel, Vanesa | Cabrera-Martín, María Nieves | Delgado-Álvarez, Alfonso | Ayala, José Luis | Balugo, Paloma | Delgado-Alonso, Cristina | Yus, Miguel | Carreras, María Teresa | Carreras, José Luis | Matías-Guiu, Jorge | Matías-Guiu, Jordi A

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. Objective: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting. Methods: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in …other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET. Results: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n  = 7), the group receiving active-site rTMS (n  = 20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally. Conclusion: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment. Trial registration : NCT03580954 (https://clinicaltrials.gov/ct2/show/NCT03580954 ) Show more

Keywords: Apraxia of speech, brain stimulation, frontotemporal dementia, neuromodulation, primary progressive aphasia, transcranial magnetic stimulation

DOI: 10.3233/JAD-210566

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 151-167, 2021

Authors: Cotton, Quinton D. | Kind, Amy J.H. | Kim, Alice J. | Block, Laura M. | Thyrian, Jochen René | Monsees, Jessica | Shah, Manish N. | Gilmore-Bykovskyi, Andrea

Article Type: Research Article

Abstract: Background: Family caregivers of people living with dementia benefit from supportive service use to address care needs associated with caregiving. Yet, research consistently demonstrates low rates of service use. Existing research has focused on barriers and facilitators to service use, with few studies examining the influence of caregivers’ environmental context which often patterns social advantage and health services accessibility. Objective: To describe the perspectives of caregivers residing in socially disadvantaged areas have in regards to utilizing supportive services. Methods: Ten informal caregivers residing in socially disadvantaged areas participated in in-depth interviews that were analyzed using thematic …analysis. Results: Across all interviews, caregivers spontaneously described common precedents of service use (crisis or accumulation of unmet needs) and a distinct sequence of stages (seeking, initiating, and utilizing) surrounding service engagement. Major themes characterizing caregivers’ experiences throughout service engagement highlight the varied influence of personal, familial, health, and social system-related factors. Findings demonstrate that caregivers may have different service needs as dementia progresses and that gerontological social work practice can facilitate service use. Conclusion: While preliminary, these findings provide important insights into new domains that can be further examined in future research and intervention efforts to improve supportive service use in socially disadvantaged and underserved communities. Show more

Keywords: Caregiving, dementia, health disparities, social support

DOI: 10.3233/JAD-210609

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 169-177, 2021

Authors: He, Fangmei | Zhang, Yuchen | Wu, Xiaofeng | Li, Youjun | Zhao, Jie | Fang, Peng | Fan, Liming | Li, Chenxi | Liu, Tian | Wang, Jue | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is the transitional stage between normal aging and Alzheimer’s disease (AD). Some aMCI patients will progress into AD eventually, whereas others will not. If the trajectory of aMCI can be predicted, it would enable early diagnosis and early therapy of AD. Objective: To explore the development trajectory of aMCI patients, we used diffusion tensor imaging to analyze the white matter microstructure changes of patients with different trajectories of aMCI. Methods: We included three groups of subjects:1) aMCI patients who convert to AD (MCI-P); 2) aMCI patients who remain in MCI …status (MCI-S); 3) normal controls (NC). We analyzed the fractional anisotropy and mean diffusion rate of brain regions, and we adopted logistic binomial regression model to predicate the development trajectory of aMCI. Results: The fraction anisotropy value is significantly reduced, the mean diffusivity value is significantly increased in the two aMCI patient groups, and the MCI-P patients presented greater changes. Significant changes are mainly located in the cingulum, fornix, hippocampus, and uncinate fasciculus. These changed brain regions significantly correlated with the patient’s Mini-Mental State Examination scores. Conclusion: The study predicted the disease trajectory of different types of aMCI patients based on the characteristic values of the above-mentioned brain regions. The prediction accuracy rate can reach 90.2%, and the microstructure characteristics of the right cingulate band and the right hippocampus may have potential clinical application value to predict the disease trajectory. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, diffusion tensor imaging, cognition, early microstructure changes

DOI: 10.3233/JAD-210495

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 179-192, 2021

Authors: DeFeis, Brittany | Ying, Gelan | Kurasz, Andrea M. | De Wit, Liselotte | Amofa Sr., Priscilla | Chandler, Melanie | Locke, Dona | Shandera-Ochsner, Anne | Phatak, Vaishali | Smith, Glenn

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease and related disorders (ADRD) research, common outcome measures include cognitive and functional impairment, as well as persons with mild cognitive impairment (pwMCI) and care partner self-reported mood and quality of life. Studies commonly analyze these measures separately, which potentially leads to issues of multiple comparisons and/or multicollinearity among measures while ignoring the latent constructs they may be measuring. Objective: This study sought to examine the latent factor structure of a battery of 12-13 measures of domains mentioned above, used in a multicomponent behavioral intervention (The HABIT® program) for pwMCI and their partners. …Methods: Exploratory factor analysis (EFA) involved 214 pwMCI-partner pairs. Subsequent Confirmatory factor analyses (CFA) used 730 pairs in both pre- and post-intervention conditions. Results: EFA generated a three-factor model. Factors could be characterized as partner adjustment (29.9%), pwMCI adjustment (18.1%), and pwMCI impairment (12.8%). The subsequent CFA confirmed our findings, and the goodness-of-fit for this model was adequate in both the pre- (CFI = 0.937; RMSEA = 0.057, p  = 0.089) and post-intervention (CFI = 0.942; RMSEA = 0.051, p  = 0.430) groups. Conclusion: Results demonstrated a stable factor structure across cohorts and intervention conditions suggesting that three broad factors may provide a straightforward and meaningful model to assess intervention outcome, at least during the MCI phase of ADRD. Show more

Keywords: Behavioral intervention, caregiver burden, factor analysis, functional status, mild cognitive impairment

DOI: 10.3233/JAD-210582

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 193-205, 2021

Authors: Cox, Kay L. | Clare, Linda | Cyarto, Elizabeth V. | Ellis, Kathryn A. | Etherton-Beer, Christopher | Southam, Jenny | Ames, David | Flicker, Leon | Almeida, Osvaldo P. | LoGiudice, Dina | Liew, Danny | Vlaskovsky, Philip | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: Increasing physical activity (PA) in those who have memory concerns requires innovative approaches. Objective: To compare in this randomized controlled trial (RCT) the effects on PA, adherence, and fitness of two approaches to deliver a 6-month home-based PA program in older, inactive individuals at risk of cognitive decline. Methods: Individuals (n  = 52) aged 60–85 years, inactive with mild cognitive impairment or subjective cognitive decline were recruited from the community and memory clinics. Randomization was to 6 months of 150 min/week moderate intensity PA with either: goal-setting with mentor support; or education and peer contact. A subset …of participants (n  = 36) continued for a further 6 months. PA, moderate and vigorous PA, and secondary outcomes, fitness, goal performance/satisfaction and self-efficacy were assessed at baseline, 6 and 12 months. Modelling of primary and secondary outcomes was conducted with linear mixed models. Results: Participants were mean age (±sd) 70.1 (6.4) years. Six-month retention was 88.5%(n  = 46). No significant between-group differences were observed for PA or fitness. Post-hoc combined group data showed a significant, moderate-large effect size increase in PA with time. PA increased by a mean 1,662 (943, 2383) steps/day (95%CI) and 1,320 (603, 2037) steps/day at 6 and 12 months (p  < 0.001). Median (quartiles Q1-Q3) 6 and 6–12 month combined group adherence was 88.9 (74.4–95.7)%and 84.6 (73.9–95.4)%respectively. Conclusion: In this target group, no differences were detected between groups both intervention strategies were highly effective in increasing PA and fitness. Show more

Keywords: Aged, cognitive dysfunction, exercise, goals, mentors, physical fitness, sedentary behavior, volunteers

DOI: 10.3233/JAD-210479

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 207-226, 2021

Authors: Haddad, Mohamed | Perrotte, Morgane | Ben Khedher, Mohamed Raâfet | Madec, Elise | Lepage, Aurelie | Fülöp, Tamás | Ramassamy, Charles

Article Type: Research Article

Abstract: Background: Growing evidence supports that receptor for advanced glycation end products (RAGE) and glyoxalase-1 (GLO-1) are implicated in the pathophysiology of Alzheimer’s disease (AD). Extracellular vesicles (EVs) are nanovesicles secreted by almost all cell types, contribute to cellular communication, and are implicated in AD pathology. Recently, EVs are considered as promising tools to identify reliable biomarkers in AD. Objective: The aim of our study was to determine the levels of RAGE and GLO-1 in circulating EVs from mild cognitive impairment (MCI) and AD patients and to analyze their correlation with the clinical Mini-Mental State Examination and Montreal Cognitive …Assessment scores. We have studied the possibility that neuronal cells could release and transfer GLO-1 through EVs. Methods: RAGE and GLO-1 levels were measured in circulating EVs, respectively, by Luminex assay and western blot. Released-EVs from SK-N-SH neuronal cells were isolated and GLO-1 levels were determined by western blot. Results: Our data showed higher levels of RAGE in EVs from late AD patients while GLO-1 levels in EVs from early AD were lower as compared to control and MCI patients. Interestingly, levels of RAGE and GLO-1 in EVs were correlated with the cognitive scores regardless of age. For the first time, we demonstrated that GLO-1 was released from neuronal cells through EVs. Conclusion: Although more samples will be needed, our preliminary results support the use of peripheral EVs cargo as new tools for the discovery of peripheral AD biomarkers. Show more

Keywords: Alzheimer’s disease, extracellular vesicles, glyoxalase-1, mild cognitive impairment, receptor for advanced glycation end products

DOI: 10.3233/JAD-210441

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 227-237, 2021

Authors: Xia, Lei | Pang, Yayan | Li, Junjie | Wu, Bin | Du, Yehong | Chen, Yuxin | Luo, Man | Wang, Yan | Dong, Zhifang

Article Type: Research Article

Abstract: Background: Tauopathies are a group of neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. Objective: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. Methods: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau ) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, …we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. Results: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. Conclusion: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology. Show more

Keywords: Dihydroartemisinin, learning and memory, long-term potentiation, O-GlcNAcylation, phosphorylation, tau

DOI: 10.3233/JAD-210643

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 239-248, 2021

Authors: Kolinko, Yaroslav | Marsalova, Lucie | Proskauer Pena, Stephanie | Kralickova, Milena | Mouton, Peter R.

Article Type: Research Article

Abstract: Background: Microcirculatory factors play an important role in amyloid-β (Aβ)-related neuropathology in Alzheimer’s disease (AD). Transgenic (Tg) rat models of mutant Aβ deposition can enhance our understanding of this microvascular pathology. Objective: Here we report stereology-based quantification and comparisons (between- and within-group) of microvessel length and number and associated parameters in hippocampal subregions in Tg model of AD in Fischer 344 rats and non-Tg littermates. Methods: Systematic-random samples of tissue sections were processed and laminin immunostained to visualize microvessels through the entire hippocampus in Tg and non-Tg rats. A computer-assisted stereology system was used to quantify …microvessel parameters including total number, total length, and associated densities in dentate gyrus (DG) and cornu ammonis (CA) subregions. Results: Thin hair-like capillaries are common near Aβ plaques in hippocampal subregions of Tg rats. There are a 53% significant increase in average length per capillary across entire hippocampus (p ≤0.04) in Tg compared to non-Tg rats; 49% reduction in capillary length in DG (p ≤0.02); and, higher microvessel density in principal cell layers (p ≤0.03). Furthermore, within-group comparisons confirm Tg but not non-Tg rats have significant increase in number density (p ≤0.01) and potential diffusion distance (p ≤0.04) of microvessels in principal cell layers of hippocampal subregions. Conclusion: We show the Tg deposition of human Aβ mutations in rats disrupts the wild-type microanatomy of hippocampal microvessels. Stereology-based microvascular parameters could promote the development of novel strategies for protection and the therapeutic management of AD. Show more

Keywords: Alzheimer’s disease, capillary, hippocampus, microvessels, stereology, TgF344-AD rat

DOI: 10.3233/JAD-210738

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 249-260, 2021