Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease

Abstract

Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3 T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity. Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy. Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.

Introduction

Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG repeat length expansion mutation in the Huntingtin Gene [20], [21]. After an initial prodromal phase, HD manifests with a characteristic triad of progressive motor-, cognitive and behavioral symptoms [39]. HD motor-symptoms are characterized early by chorea, incoordination and motor impersistence and later by dystonia, bradykinesia and rigidity [37], [45].

Neuropathological studies show damage of cortico-striatal components with neuronal loss in the cortex and the caudate nucleus in particular [44]. Neuroimaging studies using magnetic resonance imaging (MRI) are consistent with these data, indicating early characteristic structural alterations of striatal and cortical structures already in the prodromal phase [2], [33]. Particularly volume loss of the caudate and putamen have been demonstrated to be valid markers of disease progression [3], [4], [5], which is characterized by a general impairment of neural circuits linking basal ganglia and cortex [1], [11], [13]. This may be consistent with functional MRI (fMRI) data, demonstrating significant changes in neuronal activity in prodromal-HD [32], [36] involving distinct alterations of the motor system [25]. Functional connectivity is defined as synchronous blood oxygen level dependent (BOLD) activity of spatially segregated brain regions [19], [42] and distinct patterns of both positive and negative BOLD correlation are active at rest [7], [10], [12], [24]. In this context spontaneous fluctuations in the BOLD signal of resting state fMRI has been suggested to reflect basal neuronal activity within various networks involved in intrinsic brain function [18], [35]. In addition, altered interactions of neuronal populations measurable based on intrinsic functional connectivity may be a physiological correlate of various neuropsychiatric disorders [17], [43]. Altered functional connectivity has been reported for prodromal HD [46] and cortico-striatal BOLD synchrony in particular has been suggested to reflect early HD related pathology [28]. Functional connectivity analysis at rest appears particularly promising in HD, as it remains a central question whether there is independent degeneration in different brain regions or system degeneration due to functional connections [39]. However, at this point most fMRI studies on HD were performed during activation and to our knowledge no resting-state data have been published on functional integrity of cortico-striatal motor circuits.

We hypothesize that measuring functional connectivity at rest will reveal impaired interaction between the caudate nucleus and cortical regions in prodromal-HD versus unaffected healthy controls as a reflection of earliest disease related brain alterations. This study therefore focuses on probing functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD and will assess its relationship with striatal atrophy.