Abstract
BackgroundThe heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain.MethodsStructural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach.ResultsAll AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient.ConclusionsThe cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype.Trial registrationClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010.
Highlights
The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of diseasemodifying treatments
We explored the effect of AD subtype on regional atrophy rates in AD patients with and without a cholinergic treatment consisting of encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain
NGF AD patients displayed younger age, less years of education, and lower MiniMental State Examination (MMSE) score compared with the Alzheimer’s Disease Neuroimaging Initiative (ADNI) AD patients (Table 1)
Summary
The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of diseasemodifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. Finding a cure for Alzheimer’s disease (AD) continues to be a major challenge. More than 200 AD clinical trials have failed to date [1], possibly due to the recruitment of heterogeneous populations. Murray et al [3] showed that AD patients often have balanced neurofibrillary tangle (NFT) counts in the hippocampus and association cortex, i.e., the typical AD subtype. Two other subtypes were identified, corresponding to limbic-predominant and hippocampus-sparing AD, with NFT counts predominantly in the hippocampus or the association cortex, respectively. Structural magnetic resonance imaging (sMRI) can reliably track these subtypes in vivo [4] and has consistently identified a fourth subtype with minimal atrophy, i.e., the minimal atrophy AD subtype [5,6,7,8,9]
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