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

Authors: Albani, Diego | Marizzoni, Moira | Ferrari, Clarissa | Fusco, Federica | Boeri, Lucia | Raimondi, Ilaria | Jovicich, Jorge | Babiloni, Claudio | Soricelli, Andrea | Lizio, Roberta | Galluzzi, Samantha | Cavaliere, Libera | Didic, Mira | Schönknecht, Peter | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Bocchio, Luisella | Salvatore, Marco | Rossini, Paolo Maria | Tsolaki, Magda | Visser, Pieter Jelle | Richardson, Jill C. | Wiltfang, Jens | Bordet, Régis | Blin, Olivier | Forloni, Gianluigi | Frisoni, Giovanni B. | Consortium, PharmaCog

Article Type: Research Article

Abstract: It is an open issue whether blood biomarkers serve to diagnose Alzheimer’s disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as “positive” (i.e., “prodromal AD” n = 76) or “negative” (n = 52) based on a diagnostic cut-off of Aβ42 /P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at …two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42 , Aβ40 ) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the “positive” (i.e., prodromal AD) and “negative” groups at baseline. In contrast, plasma Aβ42 showed a greater reduction over time in the prodromal AD than the “negative” aMCI group (p = 0.048), while CLU and Aβ40 increased, but similarly in the two groups. Furthermore, plasma Aβ42 correlated with the ADAS-Cog13 score both in aMCI patients as a whole and the prodromal AD group alone. Finally, CLU correlated with the ADAS-Cog13 only in the whole aMCI group, and no association with ADAS-Cog13 was found for Aβ40 . In conclusion, plasma Aβ42 showed disease progression-related features in aMCI patients with prodromal AD. Show more

Keywords: Amnesic mild cognitive impairment, amyloid-beta peptide, biomarkers, clinical trial, clusterin, PharmaCog project, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-180321

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

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

Article Type: Research 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. Pre-press, no. Pre-press, pp. 1-18, 2018

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: Martinez Martinez, Pilar | Mielke, Michelle

Article Type: Editorial

DOI: 10.3233/JAD-170735

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2017