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

Authors: Boden, Kirsty A. | Barber, Imelda S. | Clement, Naomi | Patel, Tulsi | Guetta-Baranes, Tamar | Brookes, Keeley J. | Chappell, Sally | Craigon, Jim | Chapman, Natalie H. | ARUK Consortium | Morgan, Kevin | Seymour, Graham B. | Bottley, Andrew

Article Type: Research Article

Abstract: A number of genetic loci associate with early onset Alzheimer’s disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2β confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were …compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3’UTR of RIN3 (CpG1 p  = 0.019, CpG2 p  = 0.018, CpG3 p  = 0.012, CpG4 p  = 0.009, CpG5 p  = 0.002, CpG6 p  = 0.018, and CpG7 p  = 0.013, respectively; AD/Control n  = 22/26; Male/Female n  = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2 β, ABCA7 , SIRT1 , or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p  = 2.0E-10; Control n  = 26, AD n  = 25, Male/Female n  = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD. Show more

Keywords: Alzheimer’s disease, epigenetics, methylation, sporadic early onset

DOI: 10.3233/ADR-170015

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 97-108, 2017

Authors: Brendel, Matthias | Wagner, Leonie | Levin, Johannes | Zach, Christian | Lindner, Simon | Bartenstein, Peter | Okamura, Nobuyuki | Rominger, Axel

Article Type: Research Article

Abstract: We aimed to test if early, perfusion phase tau-PET imaging with [18 F]THK5351 might substitute for [18 F]FDG PET information on neurodegeneration, as has been previously shown for amyloid-tracers. A patient with cognitive impairment and positive amyloid-PET was examined by [18 F]THK5351 tau-PET and [18 F]FDG PET. The pattern of early phase of [18 F]THK5351 uptake was compared to [18 F]FDG visually and by the dice similarity coefficient. Visual inspection of axial slices and stereotactic-surface projection indicated a striking agreement between combined 0–2 min p.i. perfusion images of [18 F]THK5351 and standard [18 F]FDG 30–60 min p.i. A two-phase protocol of [18 …F]THK5351 PET might give information on neurodegeneration and tau pathology in a single session. Show more

Keywords: Alzheimer’s disease, [18F]FDG, [18F]THK5351, neurodegeneration, perfusion, PET

DOI: 10.3233/ADR-170023

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 109-113, 2017

Authors: Roberts, Rosebud O. | Kang, Yoo Na | Hu, Chunling | Moser, Catherine D. | Wang, Shaoqing | Moore, Michael J. | Graham, Rondell P. | Lai, Jin-Ping | Petersen, Ronald C. | Roberts, Lewis R.

Article Type: Research Article

Abstract: Background: The human sulfatase 1 (SULF1) and sulfatase 2 (SULF2) genes modulate cell signaling and homeostasis in many tissues. Gene expression analyses have implicated SULF2 in disease pathogenesis, including Alzheimer’s disease (AD), but changes in brain SULF2 expression have not been directly established. Objective: To investigate the expression of SULF1 and SULF2 in brain tissues from AD cases and cognitively normal controls. Methods: Autopsy tissue from AD cases (n  = 20) and age-and gender-matched cognitively normal controls (n  = 20) were identified from the Mayo Clinic Alzheimer’s Disease Patient Registry neuropathology database. Tissue slides were stained for SULF1 …and SULF2 protein expression in the hippocampus and frontal lobe and an expression score computed from the proportion of cells stained and the intensity of staining (range 0 [no expression] to 9 [marked expression]). Results: SULF2 expression was reduced in AD cases. Compared to cognitively normal controls, SULF2 expression in AD cases was significantly decreased in the hippocampal Cornu Ammonis (CA) (mean score of 6.5 in cases versus 8.3 in controls; p  = 0.003), in the gray matter of the parahippocampal gyrus (5.6 in cases versus 7.6 in controls; p  = 0.003), and in the frontal lobe gray matter (5.4 in cases versus 7.4 in controls; p  = 0.002). There was no difference in SULF1 expression in the hippocampus or frontal lobe of AD cases and controls. As expected there were no differences in SULF1 or SULF2 expression in white matter in AD cases compared to cognitively normal controls. Conclusion: Decreased SULF2 in specific regions of the brain occurs in AD. Show more

Keywords: Alzheimer’s disease, cognition, heparan sulfate proteoglycans, hSulf2, neuropathology, SULF2

DOI: 10.3233/ADR-170028

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 115-124, 2017

Authors: Carter, Chris J.

Article Type: Research Article

Abstract: Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans , Cryptococcus neoformans , Bornavirus, Borrelia burgdorferri , cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae , Porphyrymonas gingivalis , Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi ). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes …are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy. Show more

Keywords: Alzheimer’s disease, bacteria, blood-brain barrier, fungi, gene/environment, immune system, inflammation, microbes, virus

DOI: 10.3233/ADR-170017

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 125-157, 2017

Authors: Dordevic, Milos | Müller-Fotti, Alessa | Müller, Patrick | Schmicker, Marlen | Kaufmann, Jörn | Müller, Notger G.

Article Type: Research Article

Abstract: Background: Studies using neuromelanin-sensitive-MRI have established the locus coeruleus (LC)-to-pons intensity ratio as a biomarker for diagnosis of Parkinson’s and Alzheimer’s diseases. More detailed analysis is needed for exploiting the highest clinical potential of this technique. Objective: The aim is to determine the location of the highest LC-to-pons ratio within the LC and develop an easy-to-use tool for clinical application. Methods: Ten patients diagnosed with various stages of Alzheimer’s disease (74.1±3.9 years, range 68–80, 7 females) and ten healthy elderly subjects (72.4±3.1 years, range 68–77, 5 females) participated in the study. Five subsequent slices with a …thickness of 2.5 millimeters were analyzed using the image analysis tool FSL, starting with the first slice below inferior colliculus. The outcome variable was the intensity ratio between maximum values of LC and adjacent pontine region. Results: The section located 10 millimeters below the inferior colliculus has the highest potential in differentiating between healthy controls and patients, with the intensity-ratio difference between groups of 12.3% and effect size of 1.577. For the cut-off value of 1.09, the sensitivity and specificity values were 100% and 80%, respectively. Conclusion: We consider the method a promising clinical tool to aid AD diagnosis workup. Show more

Keywords: Alzheimer’s disease, biomarker, locus coeruleus, magnetic resonance imaging, neuromelanin

DOI: 10.3233/ADR-170021

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 159-167, 2017

Authors: Venzi, Marcello | Tóth, Miklós | Häggkvist, Jenny | Bogstedt, Anna | Rachalski, Adeline | Mattsson, Anna | Frumento, Paolo | Farde, Lars

Article Type: Research Article

Abstract: Background: The Apolipoprotein E (ApoE) alleles ɛ 2, ɛ 3, and ɛ 4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer’s disease (AD) via both amyloid-β (Aβ)-dependent and independent mechanisms. Objective: We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Aβ parenchymal deposits in APOE4-TR mice. Methods: Fludeoxyglucose ([18 F]FDG) positron emission tomography (PET) measures were performed longitudinally in homozygous APOE-TR mice (APOE2, APOE3, APOE4; n  = 10 for each group) at 3, 5, 11, and 15 …months. Results were quantified using standard uptake values and analyzed statistically using a linear mixed effects model. Levels of the Aβ40 and Aβ42 peptides were quantified ex vivo using enzyme-linked immunosorbent assay (ELISA) at 15 months in the same animals. Results: APOE2 mice (versus APOE3) showed a significant increase in glucose metabolism starting at 6 months, peaking at 9 months. No evidence of hypometabolism was apparent in any region or time point for APOE4 mice, which instead displayed a hypermetabolism at 15 months. Whole brain soluble Aβ40 and Aβ42 levels were not significantly different between genotypes at 15 months. Conclusions: Introduction of human APOE alleles ɛ 2 and ɛ 4 is sufficient to produce alterations in brain glucose metabolism in comparison to the control allele ɛ 3, without a concomitant alteration in Aβ40 and Aβ42 levels. These results suggest novel Aβ-independent metabolic phenotypes conferred by ɛ 2 and ɛ 4 alleles and have important implications for preclinical studies using TR-mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, [18F]FDG, glucose, mice, PET, preclinical

DOI: 10.3233/ADR-170006

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 169-180, 2017

Authors: Wong, Wee Ping | Coles, Jan | Chambers, Richard | Wu, David Bin-Chia | Hassed, Craig

Article Type: Research Article

Abstract: Background: The current lack of an effective cure for dementia would exacerbate its prevalence and incidence globally. Growing evidence has linked mindfulness to cognitive and psychological improvements that could be relevant for mild cognitive impairment (MCI). Objective: To investigate whether mindfulness practice can improve health outcomes of MCI. Methods: The study is the first longitudinal mixed-methods observational study with a one-year follow-up period, that customized an eight-week group-based mindfulness training program for older adults with MCI (n  = 14). Measures included cognitive function, psychological health, trait mindfulness, adherence to mindfulness practice, and everyday activities functioning as assessed …at pre-intervention, post-intervention, and one-year follow-up. Repeated measures ANOVAs, Pearson’s correlation analyses, and Mann-Whitney U tests were performed. Results: The MCI participants showed significant improvements in cognitive function (p  < 0.05) and trait mindfulness (p  < 0.05) after completing the intervention. Between program intervention and one-year follow-up (59 weeks), positive correlations were found between their cognitive function (p  < 0.05) and everyday activities functioning (p  < 0.05) with the duration of mindfulness meditation; and between trait mindfulness and the level of informal mindfulness practice (p  < 0.05). Those who meditated more during these 59 weeks, showed greater improvements in cognitive function (p  < 0.05) and everyday activities functioning (p  < 0.05), with large effect sizes at the one-year follow-up. Qualitative findings will be reported separately. Conclusion: Long-term mindfulness practice may be associated with cognitive and functional improvements for older adults with MCI. Mindfulness training could be a potential efficacious non-pharmacological therapeutic intervention for MCI. Show more

Keywords: Activities of daily living, Alzheimer’s disease, anxiety, cognition, dementia, depression, meditation, mild cognitive impairment, mindfulness

DOI: 10.3233/ADR-170031

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 181-193, 2017

Authors: Martins, Yandara Akamine | Tsuchida, Cristiane Jumko | Antoniassi, Patrícia | Demarchi, Izabel Galhardo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that does not have a proven cure; however, one of the most promising strategies for its treatment has been DNA vaccines. Objective: The present review is aimed to report the new developments of the efficacy and safety of DNA vaccines for AD in animal models. Method: The method PRISMA was used for this review. The article search was made in the electronic databases PubMed, LILACS, and Scopus using the descriptors ‘’Alzheimer disease” and ‘’Vaccine, DNA”. Articles published between January 2001 and September 2017 in English, Portuguese, and Spanish …were included. Results: Upon the consensus, the researchers identified 28 original articles. The studies showed satisfying results as for the decrease of amyloid plaques in mouse, rabbits, and monkeys brains using mostly the DNA Aβ42 vaccine, AV-1955, and AdPEDI-(Aβ1-6)11, mainly with a gene gun. In addition to a reduction in tau by the first DNA vaccine (AV-1980D) targeting this protein. The use of adjuvants and boosters also had positive results as they increased the destruction of the amyloid plaques and induced an anti-inflammatory response profile without side effects. Conclusion: The results of DNA vaccines targeting the amyloid-β and the tau protein with or without adjuvants and boosters were promising in reducing amyloid plaques and tau protein without side effects in animals. Although there are many vaccines being tested in animals, few reach clinical trials. Thus, as a future perspective, we suggest that clinical studies should be conducted with vaccines that have been promising in animal models (e.g., DNA Aβ42 vaccine, AV-1955, and AdPEDI-(Aβ1-6)11). Show more

Keywords: Alzheimer’s disease, animal models, DNA vaccine, immunization, mouse, side effects, therapeutic efficacy

DOI: 10.3233/ADR-170025

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 195-217, 2017

Authors: Sindi, Shireen | Kåreholt, Ingemar | Spulber, Gabriela | Soininen, Hilkka | Kivipelto, Miia | Solomon, Alina

Article Type: Research Article

Abstract: Background: Work-related stress has been associated with an increased dementia risk. However, less is known about the mechanisms that underlie these associations. Objective: The goal is to examine associations between midlife work-related stress and late-life structural brain alterations. Methods: The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50) in Finland. MRI measurements included gray matter (GM) volume, white matter lesions (WML) and medial temporal atrophy (MTA) (1st re-examination, n  = 102); and GM volume, hippocampal volume, WML volume, cortical thickness, and MTA (2nd re-examination, n  = 64). …Work-related stress comprised a score from two questions administered in midlife. Results: Higher levels of midlife work-related stress were associated with lower GM volume (β= –0.077, p  = 0.033) at the first re-examination, even after adjusting for several confounders. No significant associations were found with MTA, WML, or MRI measurements at the second re-examination. Conclusion: Previously shown associations of midlife work-related stress with dementia risk may be at least partly explained by associations with lower GM volume in late-life. The lack of associations at the second re-examination may indicate a critical time window for the effects of midlife work-related stress, and/or selective survival/participation. Show more

Keywords: Cortical thickness, gray matter volume, hippocampal volume, medial temporal lobe atrophy, stress, white matter lesions

DOI: 10.3233/ADR-170035

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 219-227, 2017

Authors: Ohsawa, Makoto | Tanaka, Yukiko | Ehara, Yoshito | Makita, Setsuko | Onaka, Kosuke

Article Type: Research Article

Abstract: A recent classification analysis of neuropsychiatric symptoms in patients with Alzheimer’s disease (AD) revealed a distinct cluster with apathy and eating problems including anorexia that exhibits frailty. The apathy and frailty are risk factors in the disease progresses. However, there is currently no effective drug for treating both anorexia and apathy in AD. Here, we conducted an open-label pilot study to determine whether ninjin’yoeito (NYT, TJ-108), a multicomponent drug, is effective for improving anorexia and apathy in patients with AD, and consequently their cognitive function. Trials were conducted at three sites in Japan. Twenty patients [4 men and 16 women, …average age = 82.6±7.7 (mean±SD) years old], including 19 AD and 1 mixed dementia with anorexia/apathy, were examined. NYT (6–9 g/day) was administered for 12 weeks. The changes in scores for “anorexia” using the Neuropsychiatric Inventory (NPI) subcategory for eating disturbance (primary outcome measure), NPI including “apathy”, the vitality index, Mini-Mental State Examination (MMSE), and physical and blood nutrition indices were evaluated at baseline (week 0), and weeks 4, 8 and 12. After week 4, significant improvements were observed in the scores for “anorexia” and “apathy” by NPI and meal ingestion amount. Vitality index and MMSE score were significantly improved by week 12. We propose that NYT, a multicomponent drug with several effects including dopamine modulation, is a new-type dementia therapeutic agent with low risk of adverse reactions that can improve simultaneously anorexia/apathy, as well as cognitive dysfunction in frail AD patients. Show more

Keywords: Alzheimer’s disease, anorexia, apathy, cognitive function, dementia, frailty, ninjin’yoeito

DOI: 10.3233/ADR-170026

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 229-235, 2017