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

Authors: Marizzoni, Moira | Ferrari, Clarissa | Jovicich, Jorge | Albani, Diego | Babiloni, Claudio | Cavaliere, Libera | Didic, Mira | Forloni, Gianluigi | Galluzzi, Samantha | Hoffmann, Karl-Titus | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Ribaldi, Federica | Rossini, Paolo Maria | Schönknecht, Peter | Soricelli, Andrea | Hensch, Tilman | Tsolaki, Magda | Visser, Pieter Jelle | Wiltfang, Jens | Richardson, Jill C. | Bordet, Régis | Blin, Olivier | Frisoni, Giovanni B. | The PharmaCog Consortium

Article Type: Research Article

Abstract: Background: Early Alzheimer’s disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. Methods: APOE ɛ 4 specific CSF Aβ42 /P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42 /P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes …in ADAS-cog13, 2) with Aβ42 /P-tau status, time, and Aβ42 /P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p ≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs. Show more

Keywords: Alzheimer’s disease, biomarkers, clinical trial, magnetic resonance imaging, mild cognitive impairment, precision medicine

DOI: 10.3233/JAD-180152

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Teipel, Stefan J. | Metzger, Coraline | Brosseron, Frederic | Buerger, Katharina | Brueggen, Katharina | Catak, Cihan | Diesing, Dominik | Dobisch, Laura | Fliebach, Klaus | Franke, Christiana | Heneka, Michael | 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. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Lu, Hanna | Xi, Ni | Fung, Ada W.T. | Lam, Linda C.W.

Article Type: Research Article

Abstract: Background: Memory and learning, as the core brain function, shows controversial results across studies focusing on aging and dementia. One of the reasons is because of the multi-faceted nature of memory and learning. However, there is still a dearth of comparable proxies with psychometric and morphometric portrait in clinical and non-clinical populations. Objective: We aim to investigate the proxies of memory and learning function with direct and derived measures and examine their associations with morphometric features in senior adults with different cognitive status. Methods: Based on two modality-driven tests, we assessed the component-specific memory and learning …in the individuals with high performing (HP), normal aging, and neurocognitive disorders (NCD) (n = 488). Structural magnetic resonance imaging was used to measure the regional cortical thickness with surface-based morphometry analysis in a subsample (n = 52). Methods: Compared with HP elderly, the ones with normal aging and minor NCD showed declined recognition memory and working memory, whereas had better learning performance (derived scores). Meanwhile, major NCD patients showed more breakdowns of memory and learning function. The correlation between proxies of memory and learning and cortical thickness exhibited the overlapped and unique neural underpinnings. Conclusions: The proxies of memory and learning could be characterized by component-specific constructs with psychometric and morphometric bases. Overall, the constructs of memory are more likely related to the pathological changes, and the constructs of learning tend to reflect the cognitive abilities of compensation. Show more

Keywords: Capacity, cortical thickness, learning, retention, working memory

DOI: 10.3233/JAD-180225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Hutton, Craig P. | Lemon, Jennifer A. | Sakic, Boris | Rollo, C. David | Boreham, Douglas R. | Fahnestock, Margaret | Wojtowicz, J. Martin | Becker, Suzanna

Article Type: Research Article

Abstract: The increasing global burden of Alzheimer’s disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2–4 months of age. We hypothesized that the MDS …would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model. Show more

Keywords: Alzheimer’s disease, anhedonia, anxiety, dietary supplements, learning, memory, mice, mild cognitive impairment, reversal learning, transgenic, working memory

DOI: 10.3233/JAD-170921

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 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. Pre-press, no. Pre-press, pp. 1-14, 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, 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 …entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with vascular dementia, 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 0.01% 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-19, 2018

Authors: Bohlken, Jens | Jacob, Louis | van den Bussche, Hendrik | Kostev, Karel

Article Type: Research Article

Abstract: The goal of the present retrospective study was to focus on the potential influence of polypharmacy on the initiation of antidementia therapy in patients diagnosed with dementia in general practices in Germany. The current study sample included patients diagnosed with dementia in 1,217 general practices in Germany between 2014 and 2016 (index date). The primary outcome measure was the rate of prescription of anti-dementia drugs within one year following the index date. The explanatory variable was the number of different drugs prescribed at baseline per patient. Independent variables included age, sex, and type of dementia. Logistic regression analyses were conducted …to study the impact of the number of different drugs prescribed at baseline per participant on the odds of receiving anti-dementia therapy (in all patients and in patients diagnosed with Alzheimer’s disease). The study included 21,888 patients with all-cause-dementia. Mean age was 80.2 years (SD = 7.3 years) and 61.4% of the study population were women. Individuals receiving six drugs or more at baseline were significantly less likely to be prescribed anti-dementia treatment when compared to those without any drug at baseline (6– 9 drugs: odds ratio [OR] = 0.75;≥10 drugs: OR = 0.58). In the subgroup of patients with Alzheimer’s disease, the odds of being prescribed anti-dementia therapy were lower in individuals with four drugs or more, compared to patients who had not been prescribed any drugs at baseline (4– 5 drugs: OR = 0.60; 6– 9 drugs: OR = 0.49;≥10 drugs: OR = 0.36). There is a negative association between polypharmacy and antidementia therapy initiation in general practices in Germany. Show more

Keywords: Anti-dementia therapy initiation, dementia, Germany, polypharmacy, retrospective study

DOI: 10.3233/JAD-180382

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 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 asparaginylendopeptidase (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. Pre-press, no. Pre-press, pp. 1-14, 2018