Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease

BackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data.ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011.ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.     

Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

Introduction

The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.

Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort: The ABIDE project

IntroductionThe objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort.MethodsWe calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients.ResultsAlmost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%).DiscussionThe current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.     

The impact of automated hippocampal volumetry on diagnostic confidence in patients with suspected Alzheimer's disease: A European Alzheimer's Disease Consortium study

Introduction

Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear.

Comprehensive Management of Daily Living Activities,behavioral and Psychological Symptoms,and Cognitive Function in Patients with Alzheimer's Disease: A Chinese Consensus on the Comprehensive Management of Alzheimer's Disease

Alzheimer''s disease (AD) is the most common cognitive disorder in the elderly. Its main clinical manifestations are cognitive decline (C), behavioral and psychological symptoms (B), and a decline in the activities of daily living (A), also known as ABC symptoms. Early identification and evaluation of ABC symptoms are helpful for establishing the accurate diagnosis, comprehensive treatment, and prognosis of AD. To guide Chinese clinical practice for optimization of the comprehensive management of AD, in 2018, The Academy of Cognitive Disorder of China gathered 22 neurologists and gerontologists in China to build a consensus on the comprehensive management of AD. Based on a review of the evidence, the consensus summarizes the pathogenesis, pathological changes, clinical manifestations, evaluation, diagnosis, drug and non-drug treatment, and patient care for AD. Focus group discussion was used to establish a flowchart of comprehensive ABC management for AD patients. The new consensus provides a feasible AD management process for clinicians.     

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease

IntroductionVascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition.Methods433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/−) and tau status (T+/−). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition.ResultsThe absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline.DiscussionOur results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.     

Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory,accumulation of Aβ, and neurodegeneration in a prodromal stage of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre‐AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N‐methyl‐D‐aspartate receptor, subunit 2A (NR2A) and the low‐density lipoprotein receptor‐1 (LRP1). PSD95 and NR2A are involved in long‐term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta‐peptide (1‐42). Aβ (1‐42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD. © 2009 Wiley‐Liss, Inc.