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: 9.2). 03/2013; 136(5). DOI: 10.1093/brain/awt065
Source: PubMed


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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    • "Further evidence in the literature of this shift from hyperactivation to hypoactivation comes from several imaging studies, all using different imaging modalities, applied to separate cohorts of individuals. A recent study by Ryan and colleagues demonstrated decreased mean diffusivity in the hippocampus in presymptomatic PSEN1 mutation carriers but increased hippocampal mean diffusivity in symptomatic carriers [30]. Another recent paper, in this case using FDG-PET, showed hypermetabolism in the precuneus/posterior cingulate in young mutation carriers , but hypometabolism in mutation carriers who were closer to the expected age of disease onset [31]. "
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    ABSTRACT: Background: Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer's disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. Objective: To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. Methods: Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. Results: PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus, parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. Conclusion: Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.
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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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    • "By association, the anterior thalamic nuclei are also implicated; given their dense, reciprocal connections with both structures [23,77]. It is, therefore, of note that pre-symptomatic familial cases of Alzheimer's disease show increased amyloid load in the thalamus [99] as well as evidence of thalamic atrophy, which was detected on average 5.6 years prior to expected symptom onset [100]. These results complement the reports of thalamic atrophy in mild cognitive impairment [97]. "
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    ABSTRACT: Although anterograde amnesia can occur after damage in various brain sites, hippocampal dysfunction is usually seen as the ultimate cause of the failure to learn new episodic information. This assumption is supported by anatomical evidence showing direct hippocampal connections with all other sites implicated in causing anterograde amnesia. Likewise, behavioural and clinical evidence would seem to strengthen the established notion of an episodic memory system emanating from the hippocampus. There is, however, growing evidence that key, interconnected sites may also regulate the hippocampus, reflecting a more balanced, integrated network that enables learning. Recent behavioural evidence strongly suggests that medial diencephalic structures have some mnemonic functions independent of the hippocampus, which can then act upon the hippocampus. Anatomical findings now reveal that nucleus reuniens and the retrosplenial cortex provide parallel, disynaptic routes for prefrontal control of hippocampal activity. There is also growing clinical evidence that retrosplenial cortex dysfunctions contribute to both anterograde amnesia and the earliest stages of Alzheimer's disease, revealing the potential significance of this area for clinical studies. This array of findings underlines the importance of redressing the balance and the value of looking beyond the hippocampus when seeking to explain failures in learning new episodic information.
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