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: 21.82). 11/2006; 5(10):828-34. DOI: 10.1016/S1474-4422(06)70550-6
Source: PubMed

ABSTRACT 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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    • "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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    Psychological Medicine 11/2014; 45(07):1-11. DOI:10.1017/S0033291714002645 · 5.43 Impact Factor
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    • "Reiman et al. [8] reported a different pattern in their study with an increase in CSF A␤ 42 and reduced gray matter volume in the right parietal lobe on MRI 20 years before onset. Finally, a longitudinal study by Ridha et al. [12] showed differences between mutation carriers and controls in hippocampal and whole brain atrophy rates 5.5 and 3.5 years, respectively, before AD diagnosis. Despite the discrepancies described above, the results from the studies in different FAD populations seem to be more consistent than inconsistent, with abnormalities in CSF biomarkers and on MRI generally being observed in preclinical FAD. "
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    ABSTRACT: Objective: To compare cerebrospinal fluid (CSF) biomarkers and brain structure in preclinical mutation carriers (MC) and non-carriers (NC) from families with familial Alzheimer disease (FAD). Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 MC and 20 NC and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC and analyzed for Aβ42, tau-protein and phospho-tau. Results: The MC had significantly lower levels of CSF Aβ42 and higher levels tau-protein and phospho-tau than the NC. There was a trend showing a decrease in Aβ42 15 – 20 years before expected onset of clinical symptoms, while a trend of increasing tau-protein and phospho-tau was observed closer to expected onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical FAD, several years before the expected onset of clinical symptoms.
    Journal of Alzheimer's disease: JAD 08/2014; In-press. · 3.61 Impact Factor
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    • "The hippocampus is one of the earliest site of pathological changes (Braak and Braak 1991) and atrophy (Jack et al. 1999; Ridha et al. 2006) in Alzheimer's disease (AD). Magnetic resonance imaging (MRI) based measurement of volume and volume change in the hippocampus may be useful markers for AD diagnosis and tracking progression (Dubois et al. 2010; Henneman et al. 2009; Jack et al. 2005, 2008b; Wang et al. 2009). "
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    Neuroinformatics 07/2014; 12(3). DOI:10.1007/s12021-013-9217-y · 3.10 Impact Factor
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