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

Authors: Dai, MingRui | Sun, Yao | Mo, ZengShuo | Feng, XueJian | 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. Pre-press, no. Pre-press, pp. 1-16, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-10, 2020

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. Pre-press, no. Pre-press, pp. 1-14, 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. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Dutt, Shubir | Li, Yanrong | Mather, Mara | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. Objective: The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with …variable clinical follow-up (6–120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n  = 814), MCI (n  = 542), and AD (n  = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n  = 203) and AD (n  = 160) participants. Results: MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Conclusion: Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD. Show more

Keywords: Alzheimer’s disease, biomarkers, brainstem, cognitive aging, locus coeruleus, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-200187

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 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. Pre-press, no. Pre-press, pp. 1-15, 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 | 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. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Blom, Kim | Koek, Huiberdina L. | Zwartbol, Maarten H.T. | Ghaznawi, Rashid | Kuijf, Hugo J. | Witkamp, Theo D. | Hendrikse, Jeroen | Biessels, Geert Jan | Geerlings, Mirjam I. | on behalf of the UCC-SMART Study Group

Article Type: Research Article

Abstract: Background: Vascular risk factors have been associated with risk of Alzheimer’s disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields …were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors. Show more

Keywords: Cornu ammonis, dentate gyrus, entorhinal cortex, hippocampal region, hippocampus, magnetic resonance imaging, risk factors

DOI: 10.3233/JAD-200159

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Al-Janahi, Eiman | Ponirakis, Georgios | Al Hamad, Hanadi | Vattoth, Surjith | Elsotouhy, Ahmed | Petropoulos, Ioannis N. | Khan, Adnan | Gad, Hoda | Chandran, Mani | Sankaranarayanan, Anoop | Ramadan, Marwan | Elorrabi, Marwa | Gadelseed, Masharig | Tosino, Rhia | Gawhale, Priya V. | Arasn, Anjum | Alobaidi, Maryam | Khan, Shafi | Manikoth, Pravija | Hamdi, Yasmin | Osman, Susan | Nadukkandiyil, Navas | AlSulaiti, Essa | Thodi, Noushad | Almuhannadi, Hamad | Mahfoud, Ziyad R. | Own, Ahmed | Shuaib, Ashfaq | Malik, Rayaz A.

Article Type: Research Article

Abstract: Background: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer’s disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders. Objective: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI. Methods: Subjects aged 60–85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI. Results: 182 subjects …with NCI (n  = 36), MCI (n  = 80), and dementia (n  = 66), including AD (n  = 19, 28.8%), VaD (n  = 13, 19.7%), and mixed AD (n  = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2 ) (32.0±7.5 versus 24.5±9.6 versus 20.8±9.3, p  < 0.0001), branch density (CNBD, branches/mm2 ) (90.9±46.5 versus 59.3±35.7 versus 53.9±38.7, p  < 0.0001), and fiber length (CNFL, mm/mm2 ) (22.9±6.1 versus 17.2±6.5 versus 15.8±7.4, p  < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67–90%), 82% (72–92%), 86% (77–95%) versus 53% (36–69%) and 40% (25–55%), respectively, and for dementia it was 85% (76–94%), 84% (75–93%), 85% (76–94%) versus 86% (76–96%) and 82% (72–92%), respectively. Conclusion: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI. Show more

Keywords: Corneal confocal microscopy, corneal nerve fibers, dementia, medial temporal lobe atrophy, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-200678

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020