Tracking atrophy progression in familial Alzheimer's disease: A serial MRI study

Dementia Research Centre, University College London, Institute of Neurology, London, UK.
The Lancet Neurology (Impact Factor: 21.9). 11/2006; 5(10):828-34. DOI: 10.1016/S1474-4422(06)70550-6
Source: PubMed


Serial MRI scanning of autosomal dominant mutation carriers for Alzheimer's disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimer's disease progresses from the presymptomatic stage through to diagnosis.
Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimer's disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed.
Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimer's disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis.
Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimer's disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.

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    • "This suggests that acceleration of atrophy starts both some time after the build-up of significant amyloid load, and at least 18 months before symptom onset, in keeping with the current model of biomarker progression (Jack et al., 2013 ). Several longitudinal studies have demonstrated acceleration of brain atrophy in symptomatic familial Alzheimer's disease (Chan et al., 2003; Ridha et al., 2006), and sporadic MCI or Alzheimer's disease (Jack et al., 2008b; Leung et al., 2013; Schuff et al., 2009 ). Carlson and colleagues reported that rates of ventricular enlargement in healthy controls increased more than 2 years before the emergence of clinical cognitive impairment (Carlson et al., 2008). "
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    • "Mounting evidence suggests that there is considerable overlap of many key features between T2DM and the two leading types of dementia, including the aggregation of Ab proteins, increased tau phosphorylation, altered glycogen synthase kinase-3b activity (GSK-3b), increased oxidative stress, altered insulin signaling, and vascular abnormalities (Li and Holscher, 2007). The vast majority of transgenic AD models are based on a number of mutations that exist in three genes, the APP (amyloid precursor protein), presenilin-1 and presenilin-2, that lead to earlyonset (<60 years) AD, however, these mutations only account for 1% of AD cases (Ridha et al., 2006). The vast majority of AD cases are sporadic in origin (sporadic AD) and are less clearly influenced by a single mutation but rather some combination of many potential genetic and environmental risk factors (Pedersen et al., 2004 ), which includes T2DM and insulin perturbations. "
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    Full-text · Article · Aug 2015 · Neuropharmacology
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    • "immediately preceding diagnosis). Our results further correspond with the observation that the earliest pathological changes in AD usually occur in the medial temporal lobe regions, which are known to be critical for episodic memory functioning (Ridha et al. 2006; Sluimer et al. 2009). Moreover, our established multi-domain decline in pre-demented subjects also matches findings of spread pathology before AD diagnosis, indicating that multiple brains structures, like the parietal (Jacobs et al. 2011), and frontal cortex (Burgmans et al. 2009) are affected. "
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