Journal of Alzheimer's Disease - Volume 64, issue 3

Authors: Zusso, Morena | Barbierato, Massimo | Facci, Laura | Skaper, Stephen D. | Giusti, Pietro

Article Type: Review Article

Abstract: Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence—a change in phenotype without a change in genotype—which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone …modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer’s disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD. Show more

Keywords: Alzheimer’s disease, amyloid, DNA methylation, epigenetics, histone, neuroinflammation, phosphorylation, SUMOylation, tau, ubiquitylation

DOI: 10.3233/JAD-180259

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 671-688, 2018

Authors: Salloway, Stephen P. | Sperling, Reisa | Fox, Nick C. | Sabbagh, Marwan N. | Honig, Lawrence S. | Porsteinsson, Anton P. | Rofael, Hany | Ketter, Nzeera | Wang, Daniel | Liu, Enchi | Carr, Stephen | Black, Ronald S. | Brashear, H. Robert

Article Type: Research Article

Abstract: Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer’s disease dementia (apolipoprotein (APOE ) ɛ 4 carriers and noncarriers) is summarized. Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab …or placebo in the parent studies. Results: A total of 1,462 (688 were APOE ɛ 4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies. Show more

Keywords: Alzheimer’s disease, amyloid-related imaging abnormality with edema/effusions, bapineuzumab, long-term safety

DOI: 10.3233/JAD-171157

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 689-707, 2018

Authors: Hu, Wen | Tung, Yunn Chyn | Zhang, Yanchong | Liu, Fei | Iqbal, Khalid

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer’s disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation …of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2 PP2A ) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2 PP2A -PP2A-ptau pathway in tau pathology in TBI. Show more

Keywords: 3xTg-AD mice, asparaginyl endopeptidase, chronic traumatic encephalopathy, tau hyperphosphorylation, traumatic brain injury

DOI: 10.3233/JAD-180177

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 709-722, 2018

Authors: Madsen, Jes Buster | Folke, Jonas | Pakkenberg, Bente

Article Type: Research Article

Abstract: We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer’s disease (AD), age-matched female subjects with severe vascular dementia (VaD), and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles …in the entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with VaD, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.1% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume. Show more

Keywords: Neurofibrillary tangles, quantification, senile plaques, stereology, volume fraction

DOI: 10.3233/JAD-180105

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 723-734, 2018

Authors: Lehmann, Jana | Michalowsky, Bernhard | Kaczynski, Anika | Thyrian, Jochen René | Schenk, Nele Sophie | Esser, Alexander | Zwingmann, Ina | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: People with dementia (PwD) are at a high risk of hospitalization. Hospitals are often not adequately equipped for PwD and discharges often come unexpected. Therefore, PwD are at a risk of adverse outcomes. However, information about those outcomes is rare but crucial for the development of preventive strategies. Objectives: To conduct a quantitative systematic review and meta-analyses on the impact of a hospitalization on readmission, institutionalization, and mortality in PwD. To identify factors associated with these outcomes. Methods: PubMed, CENTRAL, and ScienceDirect were searched for studies including terms for dementia, hospital, readmission, institutionalization, and …mortality. Relevant were assessed by a quality criteria sheet. Results were summarized in a table. Meta-analysis was conducted with Review Manager 5.3. Results: The search yielded 1,108 studies; 20 fulfilled the inclusion criteria and 10 studies were eligible for meta-analyses. The incidence and relative risk (RR) of mortality (RR 1.74 CI95 % 1.50, 2.05) and institutionalization (RR: 2.16 CI95 % 1.31, 3.56) of PwD was significantly higher when compared to people without dementia. Results according to readmission rate were inconsistent. Factors significantly associated with the examined adverse outcomes were severity of dementia, number of medications, and deficits in daily living activities. Conclusion: Hospitalization of PwD lead to adverse outcomes. An improvement in the identification of and care for PwD in the acute setting as well as in after care in the community setting, especially in the interface between both settings, is required to prevent adverse outcomes in hospitalized PwD. Show more

Keywords: Dementia, institutionalization, mortality, prevention strategies, readmission

DOI: 10.3233/JAD-171128

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 735-749, 2018

Authors: Bartos, Ales | Fialová, Lenka | Švarcová, Jana

Article Type: Research Article

Abstract: Background: Unlike antibodies against amyloid-β, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer's disease (AD). Objective: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time. Methods: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations …over 1-2 years in a subset of individuals. Results: The AD patients had lower levels of anti-tau antibodies (p  = 0.03) and even lower anti-NFH antibodies (p  = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p  = 0.03). Conclusions: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD. Show more

Keywords: Alzheimer’s disease, autoantibody, cytoskeleton, immunity, neurofilament proteins, serum, tau proteins

DOI: 10.3233/JAD-180039

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 751-760, 2018

Authors: Giil, Lasse M. | Aarsland, Dag | Hellton, Kristoffer | Lund, Anders | Heidecke, Harald | Schulze-Forster, Kai | Riemekasten, Gabriela | Vik-Mo, Audun Osland | Kristoffersen, Einar K. | Vedeler, Christian A. | Nordrehaug, Jan Erik

Article Type: Research Article

Abstract: Background: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer’s disease (AD). Objectives: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes. Methods: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: “psychosis” (item 1 + 2), “mood” (item 4 + 5 + 7), and “agitation” (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to …principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p -values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg). Results: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β – 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline. Conclusion: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required. Show more

Keywords: Dopaminergic, naturally occurring antibodies, neuropsychiatric inventory, neuropsychiatric symptoms, physiological antibodies, serotonergic

DOI: 10.3233/JAD-170882

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 761-774, 2018

Authors: O’Regan, Niamh A. | Fitzgerald, James | Adamis, Dimitrios | Molloy, David William | Meagher, David | Timmons, Suzanne

Article Type: Research Article

Abstract: Background: Identifying patients at high risk of delirium is crucial to facilitate prevention. Although dementia is the most consistent risk factor across populations, it remains under-diagnosed. Hence understanding other markers of delirium vulnerability on admission is important. Objective: We aimed to identify predictors of incident delirium development in older medical inpatients that were readily identifiable at presentation to the emergency department. Methods: Medical inpatients of ≥70 years were assessed on admission for delirium using the Revised Delirium Rating Scale (DRS-R98) and those with prevalent delirium were excluded. Consenting non-delirious patients were then assessed daily using …the DRS-R98. Data pertaining to multiple baseline delirium risk factors were collected, including pre-morbid dementia. Multivariable logistic regression was used to examine which factors predicted the development of incident delirium. Results: Of 555 patients approached, 184 (33.1%) had prevalent delirium. Following other exclusions, 191 were included in the study and 61 developed incident delirium. Predictors of incident delirium on multivariable analysis, controlling for confounders, were dementia (OR 2.54, 95% CI 1.01–6.43, p  = 0.048); Barthel Index score (OR 1.15 for each unit decrease in score, 95% CI 1.06–1.25, p  = 0.001), and Modified Cumulative Illness Rating Scale score (OR 1.13 for each unit increase in score, 95% CI 1.05–1.22, p  = 0.001). Conclusion: Dementia is a well-known risk factor for delirium; however, it too is under-recognized and on admission can be missed. Conversely, the Barthel Index is a simple and widely used measure of functional ability that may prove useful in stratifying those at risk of in-hospital delirium on admission. Show more

Keywords: Comorbidity, delirium, dementia, frail elderly, risk factor

DOI: 10.3233/JAD-180178

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 775-785, 2018

Authors: Chalatsa, Ioanna | Arvanitis, Demetrios A. | Mikropoulou, Eleni V. | Giagini, Athina | Papadopoulou-Daifoti, Zeta | Aligiannis, Nektarios | Halabalaki, Maria | Tsarbopoulos, Anthony | Skaltsounis, Leandros A. | Sanoudou, Despina

Article Type: Research Article

Abstract: Background: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer’s disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings. Objective: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet. Methods/Results: After the detailed characterization of the extracts’ composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the Aβ PP overexpressing SH-SY5Y-Aβ PP and the …hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on Aβ PP and tau processing pathways were investigated in the SH-SY5Y-Aβ PP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3β , ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote Aβ PP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms. Conclusions: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level. Show more

Keywords: Alzheimer’s disease, amyloid, amyloidosis, Cichorium spinosum , Mediterranean diet, mountain tea, neurodegenerative diseases, prevention, Sideritis scardica , tauopathies

DOI: 10.3233/JAD-170862

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 787-800, 2018

Authors: Teipel, Stefan J. | Metzger, Coraline D. | Brosseron, Frederic | Buerger, Katharina | Brueggen, Katharina | Catak, Cihan | Diesing, Dominik | Dobisch, Laura | Fliebach, Klaus | Franke, Christiana | Heneka, Michael T. | Kilimann, Ingo | Kofler, Barbara | Menne, Felix | Peters, Oliver | Polcher, Alexandra | Priller, Josef | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Thelen, Manuela | Thyrian, René J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: Background: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer’s disease (AD). Objective: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. Methods: We determined rs-fMRI functional connectivity based on Pearson’s correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. …We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. Results: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. Conclusion: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD. Show more

Keywords: diagnostic accuracy, functional MRI, multicenter, subjective cognitive decline, contstartabstract

DOI: 10.3233/JAD-180106

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 801-813, 2018