Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study

Abstract

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

“…Due to its pivotal importance in these domains, changes in striatal physiology can contribute to multiple neurological diseases, including Huntington's disease, Parkinson's disease, dystonia, and others. An increasing number of reports suggest that changes in striatal synaptic physiology, including changes at glutamatergic, dopaminergic, and cholinergic synapses, are evident beginning in the prediagnostic phase of HD (5,6,(8)(9)(10)(11)(12)(13)(14)(35)(36)(37). These changes may contribute to early motor, cognitive, and psychiatric abnormalities, and could set the stage for the extensive pathophysiological alterations appearing later in the striatum.…”

Verbal episodic memory declines prior to diagnosis in Huntington's disease

“…Several studies have documented structural and functional brain changes in CAG-expanded individuals who have not yet been diagnosed (Aylward et al, 1996;Aylward et al, 2000;Aylward et al, 2004;Kipps et al, 2005;Paulsen et al, 2006b;Reading et al, 2004). Although relatively few studies have investigated the association between cognition and brain changes in HD, a recent study showed that cognitive task performance correlated with cerebral white matter and striatal volumes in early HD (Beglinger et al, 2005).…”

Atrophy progression in semantic dementia with asymmetric temporal involvement: A tensor-based morphometry study

“…Both spatial pre-processing and statistical analysis were implemented in SPM2. Details regarding TBM image pre-processing are described in previous studies (Brambati et al, 2007;Kipps et al, 2005) (Fig. 1).…”

“…In TBM volume changes are inferred from the non-linear deformation field required to warp two serial MRI scans. This technique has proven useful for tracking progression of atrophy in various neurodegenerative diseases (Chan et al, 2001a,b;Fox et al, 2000Fox et al, , 2001Fox et al, , 1999Fox and Freeborough, 1997;Freeborough et al, 1996;Kipps et al, 2005;Leow et al, 2006;Studholme et al, 2001). A TBM-like approach has been applied to serial scans of classic SD patients and has shown progression of atrophy in the temporal lobes (Cardenas and Studholme, 2004;Whitwell et al, 2004), but longitudinal neuroimaging studies of patients with predominant right or left temporal atrophy are still lacking.…”