Article

Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease

1 Dementia Research Centre, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Brain (Impact Factor: 10.23). 03/2013; 136(5). DOI: 10.1093/brain/awt065
Source: PubMed

ABSTRACT Amyloid imaging studies of presymptomatic familial Alzheimer's disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer's disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer's disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.

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    • "More recently, several studies in APP mice have demonstrated both increased and decreased FA and MD, suggesting a more complex relationship between amyloid and white matter (Muller et al., 2013; Qin et al., 2013; Shu et al., 2013; Zerbi et al., 2013). In human subjects, one study found opposite effects in FA and MD in presymptomatic compared to symptomatic subjects who harbored genetic mutations for early onset AD known to have considerable amyloid deposition (Ryan et al., 2013). Another study on older adults, with and without Mild Cognitive Impairment (MCI) and enriched with multiple vascular risk factors, found an association between amyloid and lower FA in fornix and corpus callosum (Chao et al., 2013). "
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    ABSTRACT: Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ- in all three ROIs and in Aβi compared to Aβ- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
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    • "DTI indexes in white matter regions adjacent to brain structures affected early in AD have also been associated with high levels of total tau (t-tau) protein in healthy cognitive adults (Bendlin et al., 2012). Recently, a group of presymptomatic presenilin 1 mutation carriers showed reduced mean diffusivity in the right hippocampus and reduced mean and axial diffusivity in the right cingulum (Ryan et al., 2013). However, the degree of axonal injury present in CN_Ab42þ has not been well established. "
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    • "Thus, preferential accumulation of tau in the striatum of familial Alzheimer's disease detected by ELISA in this study may suggest evidence of increased striatal vulnerability to neuronal dysfunction and degeneration in familial Alzheimer's disease, compared to sporadic Alzheimer's disease. Of note, a recent MRI study reported volume loss in the striatum, but not hippocampus, in the presymptomatic stage of familial Alzheimer's disease with various PSEN1 mutations (Ryan et al., 2013). This finding also supports the notion that striatum is a preferential site of neuronal dysfunction and degeneration in familial Alzheimer's disease, accompanied with tau accumulation in the same area. "
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