Combining shape and connectivity analysis: An MRI study of thalamic degeneration in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is associated with neuronal loss not only in the hippocampus and amygdala but also in the thalamus. Anterodorsal, centromedial, and pulvinar nuclei are the main sites of degeneration in AD. Here we combined shape analysis and diffusion tensor imaging (DTI) tractography to study degeneration in AD in the thalamus and its connections.

Structural and diffusion tensor MRI scans were obtained from 16 AD patients and 22 demographically similar healthy volunteers. The thalamus, hippocampus, and amygdala were automatically segmented using our locally developed algorithm, and group comparisons were carried out for each surface vertex. We also employed probabilistic diffusion tractography to obtain connectivity measures between individual thalamic voxels and hippocampus/amygdala voxels and to segment the internal medullary lamina (IML).

Shape analysis showed significant bilateral regional atrophy in the dorsal–medial part of the thalamus in AD patients compared to controls. Probabilistic tractography demonstrated that these regions are mainly connected with the hippocampus, temporal, and prefrontal cortex. Intrathalamic FA comparisons showed reductions in the anterodorsal region of thalamus. Intrathalamic tractography from this region revealed that the IML was significantly smaller in AD patients than in controls. We suggest that these changes can be attributed to the degeneration of the anterodorsal and intralaminar nuclei, respectively. In addition, based on previous neuropathological reports, ventral and dorsal–medial shape change in the thalamus in AD patients is likely to be driven by IML atrophy. This combined shape and connectivity analysis provides MRI evidence of regional thalamic degeneration in AD.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological hallmarks of AD are neurofibrillary tangles, β-amyloid plaques, as well as neuronal and synaptic loss (Braak and Braak, 1991b, Mirra et al., 1991). These pathological findings occur initially and predominantly in the medial temporal lobe structures including hippocampus and amygdala (Braak and Braak, 1991a, Braak and Braak, 1991b). Hippocampal and, to a lesser extent, amydgalar atrophy in Alzheimer's disease have been well documented, whereas thalamic degeneration, particularly in the early stages of the disease, is controversial (Braak and Braak, 1991a, Paskavitz et al., 1995, Xuereb et al., 1991).

The thalamus is an important part of the Papez circuit. The hippocampus connects directly with the anterior thalamus via the fornix and to the pulvinar via the temporopulvinar tract. The hippocampus also indirectly connects with the anterior thalamus via the mammillary bodies. Integrity of these connections is essential for episodic memory (Aggleton and Brown, 1999), which is specifically impaired in Alzheimer's disease (Di Paola et al., 2007). In addition, some intralaminar nuclei, namely central medial, central lateral, and parafascicular nuclei, located within the internal medullar lamina (IML) were found to be involved at the early stages of AD (Rub et al., 2002, Xuereb et al., 1991). For this reason, we investigated the pattern of thalamic degeneration and its relation to the degeneration of the hippocampus and amygdala using a combination of structural MRI and diffusion tensor image analysis.

Analysis of the shape of subcortical structures provides useful information about the location and pattern of structural changes in neurological and psychiatric disorders. Using this method, several reports showed that CA1 is the primary site of degeneration of the hippocampus in AD (Qiu et al., 2008, Xu et al., 2008). Similar analyses have been done on the thalami of patients with schizophrenia (Coscia et al., 2009, Harms et al., 2007, Kang et al., 2008), obsessive–compulsive disorders (Kang et al., 2008), Parkinson's disease (McKeown et al., 2008) and Tourette's syndrome (Wang et al., 2007). Although there is only indirect evidence of regional thalamic atrophy in AD using shape analysis of cerebral ventricles (Ferrarini et al., 2008), postmortem pathological studies showed degeneration of pulvinar, intralaminar nuclei, and dorsolateral nuclei of the thalamus in AD (Xuereb et al., 1991). In addition, we have recently showed changes in the fractional anisotropy of white matter tracts in the proximity of the hippocampal formation in the temporal lobe using diffusion tensor imaging (Damoiseaux et al., 2008). An important feature of these tracts is the abundant connections between the medial temporal structures and the thalamus. Taken together, these findings provide a solid justification to use a combination of shape analysis and diffusion tensor tractography to study the pattern of degeneration of the thalamus in AD.