Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease
Highlights
► Dysfunction of cortico-striatal circuits may precede structural changes in prodromal HD. ► This is the first report on dysfunctional cortico-striatal connectivity at rest in HD. ► Particularly the caudate nucleus and the premotor cortex appear affected. ► These measures may serve as response markers for neuroprotective treatment approaches.
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.
Section snippets
Study population
Ten subjects CAG-expansion-positive for HD that were still in the prodromal phase of the disease, were recruited through the Huntington's Disease Center at Johns Hopkins University School of Medicine. All prodromal-HD subjects received standardized neurological examination, using Quantified Neurological Exam-scores [16]. Estimated time to onset of motor symptoms was calculated based on CAG-repeat length of the mutated HTT allele and age [26], disease burden score (DBS) was calculated as
Subject characteristics
Group demographics for the 20 individuals included in this study (ten unaffected controls, ten expansion positive individuals in the prodromal phase of HD) are displayed in Table 1. The mean total QNE and also chorea subscore reflect only non-HD specific neurological symptoms, subjects with manifest HD usually have total QNE scores significantly above 20 [9], [16].
Group comparisons of brain morphology between controls and HD subjects
Measures of brain morphology as assessed by cortical and subcortical segmentation indicate significantly reduced caudate (p = 0.01,
Discussion
Our data show significantly reduced BOLD synchrony between seeds representing the caudate nucleus and lateral premotor area, indicating impaired cortico-striatal functional connectivity as a correlate of brain changes in prodromal-HD.
To our knowledge this is the first study reporting impaired functional connectivity at rest between motor cortex and the caudate nucleus in prodromal-HD subjects. Relevance for motor circuits is indicated by the fact that functional connectivity between the caudate
Conclusion
By measuring BOLD-synchrony between the caudate nucleus and the motor cortex, we find evidence for impaired cortico-striatal functional connectivity in prodromal-HD subjects which shows similar effect size as striatal atrophy. Further longitudinal studies may help to elucidate temporal aspects of the relationship between functional and structural brain alterations in prodromal-HD.
Disclosure
The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Equipment used in the study is manufactured by Philips. Dr. van Zijl is a paid lecturer for Philips Medical Systems and the inventor of technology that is licensed to Philips. This arrangement has been approved by Johns Hopkins University in accordance with its conflict of interest policies. All authors have approved the final version of this article and have
Acknowledgments
This study was made possible by grant support from NINDS NS16375, NIH-NCRR P41-RR015241 and P50AG005146. Dr. Paul G. Unschuld is supported by NIH-T32MH015330. We thank Nadine Yoritomo and Morgan Writhenour of the Baltimore Huntington's Disease Center (BHDC) at Johns Hopkins Hospital for support in study organization. We thank Terri Brawner, Ivana Kusevic and Kathleen Kahl of the F.M.Kirby Research Center and Guillermo Verduzco of the Division of Psychiatric Neuroimaging for their technical
References (48)
Change in MRI striatal volumes as a biomarker in preclinical Huntington's disease
Brain Res. Bull.
(2007)- et al.
Caudate volume as an outcome measure in clinical trials for Huntington's disease: a pilot study
Brain Res. Bull.
(2003) - et al.
Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways
Neurobiol. Dis.
(2011) - et al.
The corticostriatal pathway in Huntington's disease
Prog. Neurobiol.
(2007) Functional imaging in Huntington's disease
Exp. Neurol.
(2009)- et al.
Brain structure in preclinical Huntington's disease
Biol. Psychiatry
(2006) Two views of brain function
Trends Cogn. Sci.
(2010)- et al.
Huntington's disease: from molecular pathogenesis to clinical treatment
Lancet Neurol
(2011) Huntington's disease
Lancet
(2007)- et al.
Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease
Exp. Neurol.
(2008)
Parallel organization of functionally segregated circuits linking basal ganglia and cortex
Annu. Rev. Neurosci.
Longitudinal change in basal ganglia volume in patients with Huntington's disease
Neurology
Longitudinal change in regional brain volumes in prodromal Huntington disease
J. Neurol. Neurosurg. Psychiatry
Topology-preserving tissue classification of magnetic resonance brain images
IEEE Trans. Med. Imaging
Functional connectivity in the motor cortex of resting human brain using echo-planar MRI
Magn. Reson. Med.
Trinucleotide repeat length and clinical progression in Huntington's disease
Neurology
Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease
J. Neurosci.
Consistent resting-state networks across healthy subjects
Proc. Natl. Acad. Sci. U.S.A.
Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington's disease
Hum. Brain Mapp.
Brain networks in Huntington disease
J. Clin. Invest.
Frequency distribution of the values of the correlation coefficient in samples from an indefinitely large population
Biometrika
The measurement of abnormal movement: methods developed for Huntington's disease
Neurobehav. Toxicol. Teratol.
Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging
Nat. Rev. Neurosci.
The human brain is intrinsically organized into dynamic, anticorrelated functional networks
Proc. Natl. Acad. Sci. U.S.A.
Cited by (87)
Selective vulnerability in Huntington's disease: From excitotoxicity, mitochondrial dysfunction, and transcription dysregulation to therapeutic opportunity
2024, Huntington's Disease: Pathogenic Mechanisms and Implications for TherapeuticsHuntington's disease: Clinical features, genetic diagnosis, and brain imaging
2024, Huntington's Disease: Pathogenic Mechanisms and Implications for Therapeutics