Journal of Alzheimer's Disease - Volume 77, issue 4

Authors: Mathies, Franziska | Lange, Catharina | Mäurer, Anja | Apostolova, Ivayla | Klutmann, Susanne | Buchert, Ralph

Article Type: Research Article

Abstract: Background: Positron emission tomography (PET) of the brain with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) is widely used for the etiological diagnosis of clinically uncertain cognitive impairment (CUCI). Acute full-blown delirium can cause reversible alterations of FDG uptake that mimic neurodegenerative disease. Objective: This study tested whether delirium in remission affects the performance of FDG PET for differentiation between neurodegenerative and non-neurodegenerative etiology of CUCI. Methods: The study included 88 patients (82.0±5.7 y) with newly detected CUCI during hospitalization in a geriatric unit. Twenty-seven (31%) of the patients were diagnosed with delirium during their current hospital stay, which, however, at time …of enrollment was in remission so that delirium was not considered the primary cause of the CUCI. Cases were categorized as neurodegenerative or non-neurodegenerative etiology based on visual inspection of FDG PET. The diagnosis at clinical follow-up after ≥12 months served as ground truth to evaluate the diagnostic performance of FDG PET. Results: FDG PET was categorized as neurodegenerative in 51 (58%) of the patients. Follow-up after 16±3 months was obtained in 68 (77%) of the patients. The clinical follow-up diagnosis confirmed the FDG PET-based categorization in 60 patients (88%, 4 false negative and 4 false positive cases with respect to detection of neurodegeneration). The fraction of correct PET-based categorization did not differ between patients with delirium in remission and patients without delirium (86% versus 89%, p  = 0.666). Conclusion: Brain FDG PET is useful for the etiological diagnosis of CUCI in hospitalized geriatric patients, as well as in patients with delirium in remission. Show more

Keywords: Alzheimer’s disease, delirium, dementia, neuroimaging, positron-emission tomography

DOI: 10.3233/JAD-200530

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1609-1622, 2020

Authors: Ghoweri, Adam O. | Gagolewicz, Peter | Frazier, Hilaree N. | Gant, John C. | Andrew, R. David | Bennett, Brian M. | Thibault, Olivier

Article Type: Research Article

Abstract: Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. Objective: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures …associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2 –/– ) mice, a non-transgenic model of sporadic Alzheimer’s disease. Methods: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2 –/– mouse. Results: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2 –/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2 –/– animals compared to wild-type. Conclusion: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress. Show more

Keywords: Afterhyperpolarization, aging, calcium dysregulation, electrophysiology, hippocampus, HNE, intracellular, oxidative stress

DOI: 10.3233/JAD-200617

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1623-1637, 2020

Authors: Song, Ge | Yang, Haiqiang | Shen, Ning | Pham, Phillip | Brown, Breanna | Lin, Xiaoyang | Hong, Yuzhu | Sinu, Paul | Cai, Jianfeng | Li, Xiaopeng | Leon, Michael | Gordon, Marcia N. | Morgan, David | Zhang, Sai | Cao, Chuanhai

Article Type: Research Article

Abstract: Background: Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. Methods: Double transgenic APPswe /PS1Δ E9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of …antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC’s natural immunomodulatory properties. Conclusion: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody’s specificity for these “oligomeric” Aβ species could provide the opportunity to produce some clinical benefits in AD subjects. Show more

Keywords: Alzheimer’s disease, antibody, dendritic cells, T cell epitope, vaccine

DOI: 10.3233/JAD-200413

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1639-1653, 2020

Authors: Sible, Isabel J. | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Elevated blood pressure is linked to cognitive impairment and Alzheimer’s disease (AD) biomarker abnormality. However, blood pressure levels vary over time. Less is known about the role of long-term blood pressure variability in cognitive impairment and AD pathophysiology. Objective: Determine whether long-term blood pressure variability is elevated across the clinical and biomarker spectrum of AD. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (cognitively normal, mild cognitive impairment, AD [n  = 1,421]) underwent baseline exam, including blood pressure measurement at 0, 6, and 12 months. A subset (n  = 318) underwent baseline lumbar puncture to determine cerebrospinal fluid amyloid-β …and phosphorylated tau levels. Clinical groups and biomarker-confirmed AD groups were compared on blood pressure variability over 12 months. Results: Systolic blood pressure variability was elevated in clinically diagnosed AD dementia (VIM: F 2,1195  = 6.657, p  = 0.001, η 2  = 0.01) compared to cognitively normal participants (p  = 0.001), and in mild cognitive impairment relative to cognitively normal participants (p  = 0.01). Findings were maintained in biomarker-confirmed AD (VIM: F 2,850  = 5.216, p  = 0.006, η 2  = 0.01), such that systolic blood pressure variability was elevated in biomarker-confirmed dementia due to AD relative to cognitively normal participants (p  = 0.005) and in biomarker-confirmed mild cognitive impairment due to AD compared to cognitively normal participants (p  = 0.04). Conclusion: Long-term systolic blood pressure variability is elevated in cognitive impairment due to AD. Blood pressure variability may represent an understudied aspect of vascular dysfunction in AD with potential clinical implications. Show more

Keywords: Alzheimer’s disease, amyloid, blood pressure, cognitive dysfunction, tau proteins

DOI: 10.3233/JAD-200221

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1655-1669, 2020

Authors: He, Fan | Tang, James J. | Zhang, Tao | Lin, Junfen | Li, Fudong | Gu, Xue | Chen, Ruoling

Article Type: Research Article

Abstract: Background: The impact of air pollution on cognitive impairment in older people has not been fully understood. It is unclear which air pollutants are the culprit. Objective: We assessed the associations of six air pollutants and air quality index (AQI) with cognitive impairment. Methods: We examined 7,311 participants aged ≥60 years from the ZJMPHS cohort in China. They were interviewed for baseline socio-demographic and disease risk factors in 2014, and re-interviewed in 2015 and 2016, respectively. The presence of cognitive impairment was determined by the Chinese version of the Mini-Mental State Examination. Daily area-level data monitored …for air pollution during 2013-2015 was then examined for associations with cognitive impairment in logistic regression models. Results: Over the two years follow-up, 1,652 participants developed cognitive impairment, of which 917 were severe cases. Continuous air pollution data showed the risk of cognitive impairment increased with exposure to PM2.5 (fully adjusted odds ratio [aOR] 1.04, 95% CI 1.01–1.08), PM10 (1.03, 1.001–1.06), and SO2 (1.04, 1.01–1.08), but not with NO2 , CO, O3 , and AQI. Categorized data analysis for low, middle, and high level exposure demonstrated that the aOR increased with PM2.5 and AQI, somehow with PM10 and CO, but not significantly with SO2 and NO2 , and decreased with O3 . The patterns for these associations with severe cognitive impairment were stronger. Conclusion: Lowering PM2.5 , PM10 , SO2 , and CO level could reduce the risk of cognitive impairment in older Chinese. Strategies to target most important air pollutants should be an integral component of cognitive interventions. Show more

Keywords: Air pollution, air quality index, China, cognitive impairment, cohort study

DOI: 10.3233/JAD-200587

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1671-1679, 2020

Authors: Chae, Soohyun | Park, Jinsick | Byun, Min Soo | Yi, Dahyun | Lee, Jun Ho | Byeon, Gi Hwan | Suk, Hye Won | Choi, Hongyoon | Park, Jee Eun | Lee, Dong Young

Article Type: Research Article

Abstract: Background: The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer’s disease (AD) dementia. Objective: We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD. Methods: Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N  = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18 F]florbetaben positron emission tomography …assessment, the participants were divided into Aβ+ (N  = 70) and Aβ- (N  = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed. Results: A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F  = 5.987, p  = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F  = 3.984, p  = 0.048). Conclusion: Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ 4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD. Show more

Keywords: Aged, alpha rhythms, electroencephalography, eyes-closed resting state, eyes-open resting state

DOI: 10.3233/JAD-200442

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1681-1692, 2020

Authors: de Vent, Nathalie R. | Agelink van Rentergem, Joost A. | Huizenga, Hilde M. | van der Flier, Wiesje M. | Sikkes, Sieske A.M. | Murre, Jaap M.J. | van den Bosch, Karlijn A. | Scheltens, Philip | Schmand, Ben A.

Article Type: Research Article

Abstract: Background: In neuropsychology and neurology, there is no consensus on the definition of abnormal cognition. Objective: To operationally define ‘abnormal cognition’ for optimally predicting progression to dementia in a memory clinic sample, and to test whether multivariate profile analysis of cognitive test results improves this prediction compared to standard clinical evaluation. Methods: We used longitudinal data from 835 non-demented patients of the Amsterdam Dementia Cohort. For 10 cognitive measures at baseline, we determined which number of abnormal tests and which magnitude of score deviations best predicted progression. Results: Predictive ability for progression to dementia …of one, two, and three abnormal test scores out of 10 is highly similar (Cox hazard ratios: 3.7–4.1) provided cut-off values are adapted appropriately. Cut-offs have to be less stringent if the number of abnormal tests required increases: the optimal cut-off is z  < –1.45 when one deviating score is required, z  < –1.15 when two abnormal tests are required, and z  < –0.70 when three abnormal tests are required. The profile analysis has similar predictive ability at the cut-off of p  < 0.22 (hazard ratio 3.8). A likelihood ratio test showed that this analysis improves prediction of progression to dementia when added to standard clinical evaluation (p  < 0.001). Conclusion: Abnormal cognition may be defined as one, two, or three abnormal test scores out of 10 if the magnitude of score deviations is adapted accordingly. An abnormal score profile predicts decline to dementia equally well, and improves the prediction when used complimentary to standard clinical evaluation. Show more

Keywords: Cognition, dementia, mild cognitive impairment, multivariate normative comparison, profile analysis

DOI: 10.3233/JAD-200811

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1693-1703, 2020

Authors: Beauchamp, Leah C. | Liu, Xiang M. | Sedjahtera, Amelia | Bogeski, Mirjana | Vella, Laura J. | Bush, Ashley I. | Adlard, Paul A. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Background: Alterations in the methionine cycle and abnormal tau phosphorylation are implicated in many neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. rTg4510 mice express mutant human P301L tau and are a model of tau hyperphosphorylation. The cognitive deficit seen in these animals correlates with a burden of hyperphosphorylated tau and is a model to test therapies aimed at lowering phosphorylated tau. Objective: This study aimed to increase protein phosphatase 2A activity through supplementation of S-adenosylmethionine and analyze the effect on spatial memory and tau in treated animals. Methods: 6-month-old rTg4510 mice were treated with 100 mg/kg …S-adenosylmethionine by oral gavage for 3 weeks. Spatial recognition memory was tested in the Y-maze. Alterations to phosphorylated tau and protein phosphatase 2A were explored using immunohistochemistry, western blot, and enzyme-linked immunosorbent assays. Results: Treatment with S-adenosylmethionine increased the Y-maze novel arm exploration time and increased both the expression and activity of protein phosphatase 2A. Furthermore, treatment reduced the number of AT8 positive neurons and reduced the expression of phosphorylated tau (Ser202/Thr205). S-adenosylmethionine contributes to multiple pathways in neuronal homeostasis and neurodegeneration. Conclusion: This study shows that supplementation with S-adenosylmethionine stabilizes the heterotrimeric form of PP2A resulting in an increase the enzymatic activity, a reduced level of pathological tau, and improved cognition. Show more

Keywords: Cognition, phosphatase, phosphorylation, PP2A, S-adenosylmethionine, tau, tauopathy

DOI: 10.3233/JAD-200756

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1705-1715, 2020

Authors: Dai, MingRui | Feng, XueJian | Mo, ZengShuo | Sun, Yao | Fu, Lu | Zhang, Yong | Wu, Jiaxin | Yu, Bin | Zhang, Haihong | Yu, Xianghui | Wu, Hui | Kong, Wei

Article Type: Research Article

Abstract: Background: Adjuvants are important components of vaccines and effectively enhance the immune response of specific antigens. However, the role of adjuvants or combinations of adjuvants in stimulating immunogenicity of the amyloid-β (Aβ) vaccine, as well as molecular mechanisms underlying such stimulation still remain unclear. A previous study of ours developed a norovirus P particle-based active Aβ epitope vaccine, PP-3copy-Aβ1-6-loop123, which stimulates a high titer of Aβ-specific antibodies in mouse Alzheimer’s disease (AD) models. Objective: The most effective and safe adjuvant that maximizes the immunogenicity of our protein vaccine was determined. Methods: We investigated four adjuvants (CpG, …AS02, AS03, and MF59), and combinations of those, for capacity to enhance immunogenicity, and performed transcriptome analysis to explore mechanisms underlying the role of these in AD immunotherapy. Results: Addition of the adjuvant, AS02, remarkably improved the immunogenicity of the PP-3copy-Aβ1-6-loop123 vaccine without triggering an Aβ-specific T-cell response. Combinations of adjuvants, particularly CpG +  AS02 and CpG + AS03, elicited a significantly elevated and prolonged Aβ-specific antibody response. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that a combination of two adjuvants was more effective in activating immune-related pathways, thereby enhancing the immunogenicity of PP-3copy-Aβ1-6-loop123. Conclusion: These findings demonstrated that adjuvants can be used as enhancers in AD protein vaccination, and that a combination of CpG and AS-related adjuvants may be a very effective adjuvant candidate suitable for further clinical trials of the PP-3copy-Aβ1-6-loop123 vaccine. Our studies also revealed potential mechanisms underlying the stimulation of immune response of protein vaccines by adjuvants. Show more

Keywords: Adjuvant, Alzheimer’s disease, amyloid-β, immunogenicity, mechanisms, vaccine

DOI: 10.3233/JAD-200351

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1717-1732, 2020

Authors: Osuka, Yosuke | Kojima, Narumi | Sasai, Hiroyuki | Ohara, Yuki | Watanabe, Yutaka | Hirano, Hirohiko | Kim, Hunkyung

Article Type: Research Article

Abstract: Background: Participation in exercise may be useful for dementia prevention; however, the specific exercise types which may best to reduce the risk of developing cognitive decline have remained unidentified in the literature. Objective: To examine the relationships of specific exercise types with the risk of developing cognitive decline in older women. Methods: This 1- to 2-year population-based cohort study included 687 community-dwelling older Japanese women without disability, neurological disease, dementia, or cognitive impairment assessed as <24 points on the Mini-Mental State Examination (MMSE) at the baseline survey. Developing cognitive decline was defined as a decrease of …≥3 points in the participant’s MMSE score during the follow-up. We classified individuals into participation (≥3 months) and non-participation (<3 months) groups for 17 different exercise types. Log-binominal regression analyses were applied to compare risk ratios and confidence intervals of developing cognitive decline between the two groups. Results: Thirty-nine participants (5.7%) developed cognitive decline during the follow-up period. After adjusting for confounders (age, MMSE score, depressive symptoms, body mass index, heart disease, hypertension, diabetes, smoking, low educational level, and the follow-up period in the baseline survey), those who participated in calisthenics demonstrated a significantly lower risk of developing cognitive decline than those who did not participate in calisthenics. No significant relationships between other exercise types and the risk of developing cognitive decline were found. Conclusion: Participation in calisthenics significantly reduced the risk of cognitive decline in community-dwelling older Japanese women, indicating that calisthenics may be a useful type of exercise for promoting dementia prevention. Show more

Keywords: Aging, calisthenics, cognitive decline, dementia

DOI: 10.3233/JAD-200867

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1733-1742, 2020

Authors: Vila-Castelar, Clara | Guzmán-Vélez, Edmarie | Pardilla-Delgado, Enmanuelle | Buckley, Rachel F. | Bocanegra, Yamile | Baena, Ana | Fox-Fuller, Joshua T. | Tirado, Victoria | Muñoz, Claudia | Giraldo, Margarita | Acosta-Baena, Natalia | Rios-Romenets, Silvia | Langbaum, Jessica B. | Tariot, Pierre N. | Lopera, Francisco | Reiman, Eric M. | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer’s disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1 ) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20–44; 11 females), 11 symptomatic carriers (age range …42–56; 8 females), and 23 matched non-carriers family members (age range 20–50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. Results: There were no differential associations between age, CERAD Total Score, CERAD Word List–Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers. Show more

Keywords: Alzheimer’s disease, atrophy, cognition, familial Alzheimer’s disease, memory, sex

DOI: 10.3233/JAD-200723

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1743-1753, 2020

Authors: Pisano, Francesca | Caltagirone, Carlo | Satriano, Federica | Perri, Roberta | Fadda, Lucia | Marangolo, Paola

Article Type: Research Article

Abstract: Background: Recently, a growing body of evidence has shown that, from the early stage of impairment, Alzheimer’s patients (AD) present difficulties on a variety of tasks mostly relying on executive functions. These strongly impact their daily life activities causing a severe loss of independency and autonomy. Objective: To evaluate the efficacy of transpinal direct current stimulation (tsDCS) combined with cognitive trainings for improving attentional and executive function abilities in a group of AD patients. Methods: In a randomized-double blind design, sixteen AD patients underwent different cognitive trainings combined with tsDCS. During the treatment, each subject received …tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: 1) anodal, and 2) sham while performing three computerized tasks: alertness, selective attention, and executive functions. Each experimental condition was run in ten consecutive daily sessions over two weeks. Results: After anodal tsDCS, a greater improvement in executive functions compared to sham condition was found. More importantly, the follow-up testing revealed that these effects lasted over 1 month after the intervention and generalized to the different neuropsychological tests administered before, after the treatment and at one month after the end of the intervention. This generalization was present also in the attentional domain. Conclusion: This evidence emphasizes, for the first time, that tsDCS combined with cognitive training results efficacious for AD patients. We hypothesize that enhancing activity into the spinal sensorimotor pathways through stimulation improved cognitive abilities which rely on premotor activity, such as attention and executive functions. Show more

Keywords: Alzheimer’s disease, cognitive training, neuromodulation, transpinal stimulation, tsDCS

DOI: 10.3233/JAD-200695

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1755-1764, 2020

Authors: Holloway, Olivia G. | King, Anna E. | Ziebell, Jenna M.

Article Type: Research Article

Abstract: Background: Microglia are traditionally described as the immune cells of the brain and have an inflammatory role in Alzheimer’s disease (AD). Microglial morphological and phenotypic shifts in AD have not been fully characterized; however, microglia are often described as either pro- or anti-inflammatory. Objective: To determine microglial if microglial morphology and phenotype changes with disease status. Methods: This study observed morphology through Iba1 immunohistochemistry on tissue sections encompassing the primary motor cortex and somatosensory barrel fields. Immunohistochemistry for pro-inflammatory markers: CD14 and CD40; and anti-inflammatory markers: CD16 and TREM2, was performed at 3, 6, and 12 …months of age which correlated with pre-plaque, onset, and significant plaque load in APP/PS1 brains (n  = 6) and compared to age-matched littermate controls (n  = 6). Results: Microglia demonstrated a defined morphological shift with time. Deramified morphologies increased in the APP/PS1, at both 6 months (p  < 0.0001) and 12 months (p  < 0.0001). At 12 months, there were significantly lower numbers of ramified microglia (p  < 0.001). Results indicated that microglia have a heterogenic marker immunoreactivity as CD16, TREM2, and CD40 were associated with an activated morphology at the same time points. All inflammatory markers were significantly upregulated at 12 months in the APP/PS1 mice (TREM2 (F (2,30)   = 10.75, p  = 0.0003), CD40 (F (2,30)   = 15.86, p  < 0.0001), CD14 (F (2,30)   = 6.84, p  = 0.0036), and CD16 (F (2,30)   = 3.026, p  = 0.0635)). Conclusion: Our data indicate that pro- and anti-inflammatory factors of microglia occur in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, anti-inflammatory, microglia, morphology, phenotype, pro-inflammatory

DOI: 10.3233/JAD-200098

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1765-1781, 2020

Authors: Hulme, Bethany | Didikoglu, Altug | Bradburn, Steven | Robinson, Andrew | Canal, Maria | Payton, Antony | Pendleton, Neil | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1 , a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N  = 96). DNA methylation at six CpG sites at the promoter of BMAL1 , determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes …in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p  = 0.015) and CERAD (t(94), p  = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r  = 0.20, p  = 0.05) and CpG4 (r  = 0.20, p  = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r  = 0.20 p  = 0.05) and vocabulary (r  = 0.22 p  = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B  = 0.03, 95% CI, p  = 0.03) and CpG5 (B  = 0.04, 95% CI, p  = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B  = –0.27, 95% CI, p  = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle. Show more

Keywords: Alzheimer’s disease, BMAL1, circadian cycle, cognition, depressive symptoms, sleep quality

DOI: 10.3233/JAD-200634

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1783-1792, 2020

Authors: Smith, Patrick J. | Mabe, Stephanie M. | Sherwood, Andrew | Doraiswamy, P. Murali | Welsh-Bohmer, Kathleen A. | Burke, James R. | Kraus, William E. | Lin, Pao-Hwa | Browndyke, Jeffrey N. | Babyak, Michael A. | Hinderliter, Alan L. | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. Objective: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. Methods: ENLIGHTEN participants were randomized …using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). Results: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d  = 0.48, p  = 0.015) and DASH improved metabolic function (d  = 0.37, p  = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = –2.3 [–4.3, –0.2], p  = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7 ], p  = 0.004), associated with increases in Executive Function. Conclusion: Changes in neurocognition after lifestyle modification are associated with improved metabolic function. Show more

Keywords: Aerobic exercise, CIND, DASH diet, executive function, lifestyle modification, metabolic function, vascular risk factors

DOI: 10.3233/JAD-200374

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1793-1803, 2020

Authors: Abdelnour, Carla | Esteban de Antonio, Ester | Pérez-Cordón, Alba | Lafuente, Asunción | Buendía, Mar | Pancho, Ana | Jofresa, Sara | Aguilera, Nuria | Ibarria, Marta | Cuevas, Rosario | Cañada, Laia | Calvet, Anna | Diego, Susana | González-Pérez, Antonio | Orellana, Adela | Montrreal, Laura | de Jorge, Laura | Marquié, Marta | Benaque, Alba | Gurruchaga, Miren | Tárraga, Lluís | Ruiz, Agustín | Boada, Mercè | For the Research Center and Memory Clinic, Fundació ACE

Collaborators: Isabel, Hernández | Montserrat, Alegret | Pilar, Cañabate | Isabel, Rodríguez | Maitee, Rosende-Roca | Juan Pablo, Tartari | Rogelio, López | Silvia, Gil | Liliana, Vargas | Ana, Mauleón | Ana, Espinosa | Gemma, Ortega | Angela, Sanabria | Emilio, Alarcón | Mariola, Moreno | Silvia, Preckler | Natalia, Roberto | Sergi, Valero | Itziar, de Rojas | Sonia, Moreno-Grau | Elvira, Martín

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries. Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes. Methods: We describe participants’ clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests …to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period. Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19. Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trials, coronavirus, pandemics, telemedicine

DOI: 10.3233/JAD-200750

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1805-1813, 2020