Alzheimer's research & therapy
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Alzheimers Res Ther · Jan 2019
CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice.
The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury. ⋯ CHIMERA is a useful model to investigate the chronic consequences of rmTBI, including behavioural abnormalities consistent with features of post-traumatic stress disorder and inflammation of both white and grey matter. The presence of human Aβ greatly modified extinction of fear memory after rmTBI.
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Alzheimers Res Ther · Jan 2019
Measuring instrumental activities of daily living in non-demented elderly: a comparison of the new performance-based Harvard Automated Phone Task with other functional assessments.
Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer's disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants. ⋯ In this small pilot study, the Harvard APT, a brief, self-administered, objective measure of IADL performance, appears to correlate well with other sensitive measures of everyday functioning, providing good preliminary convergent validity for this new measure. Moreover, it appears to perform well across both CN and MCI participants, which suggests that it is a promising measure of early, clinically meaningful functional change. This may not be the case as suggested in our small sample for subjective IADL scales that may perform differentially depending on the reporter (self vs. study partner) across the clinical spectrum possibly due to diminishing awareness of IADL difficulties in individuals who become cognitively impaired. Secondary prevention trials in AD have a great need for such ecologically valid and reliable measures of early IADL changes.
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Alzheimers Res Ther · Oct 2018
ReviewSecondary prevention of Alzheimer's dementia: neuroimaging contributions.
In Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations. ⋯ We propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.
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Alzheimers Res Ther · Oct 2018
FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease.
Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. ⋯ AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1.
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Alzheimers Res Ther · Oct 2018
Randomized Controlled Trial Multicenter StudySafety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study.
PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. ⋯ The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study.