No abstract

Huntington disease is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this paper, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through Large Deformation Diffeomorphic Metric Mapping of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. Based on the relation to cortico-basal-ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

The purpose of this study was to examine longitudinal change in gait and motor function in pre-manifest Huntington’s disease (HD).We examined ten pre-manifest subjects at baseline, one and five years. Quantitative gait data were collected with an electronic mat (GAITRite®). We analyzed measures related to speed (velocity, step length, cadence), asymmetry (step length difference), dynamic balance (percent time in double support, support base) and variability in stride length and swing time. Motor function was assessed with the motor component of the Unified Huntington’s Disease Rating Scale.Gait velocity decreased (p=0.001), whereas step length difference (p=0.006), stride length variability (p=0.0001) and swing time variability increased (p=0.0001) from baseline to year five. Step length difference (p<0.05) and swing time variability (p<0.05) increased marginally in one year from baseline. UHDRS Total motor score increased over five years (p=0.003), though the increase in one year was not significant (p=0.053). Of the individual motor domain scores (eye, hand movements, gait and balance, chorea) only dystonia worsened over five years (p=0.02). Total motor score (r2= 0.49, p<0.001) and swing time variability (r2= 0.22, p<0.009) were correlated with estimated years to diagnosis.Our results present the longest longitudinal follow up of gait in pre-manifest HD thus far. Despite the small sample size, quantitative gait analysis was able to detect changes in gait speed, symmetry and variability. Swing time variability was particularly important because it increased in one year from baseline and was correlated with estimated time to diagnosis. Our results highlight the importance of predictive outcomes such as gait variability using quantitative analysis.

Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife to affect specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls. In contrast to a region in the anterior caudate, in which dysfunction was linked to genotype independent of phenotype, a region in the posterior body of the caudate was differentially associated with disease phenotype. Guided by these observations, we harvested regions from the anterior and posterior body of the caudate in postmortem control and HD human brain tissue. Gene-expression profiling identified two molecules whose expression levels were most strongly correlated with regional vulnerability — protein phosphatase 1 regulatory subunit 7 (PPP1R7) and Wnt inhibitory factor-1 (WIF1). To verify and potentially extend these findings, we turned to the YAC128 (C57BL/6J) HD transgenic mice. By fMRI we longitudinally mapped CBV in transgenic and wildtype (WT) mice, and over time, abnormally low fMRI signal emerged selectively in the dorsal striatum. A relatively unaffected brain region, primary somatosensory cortex (S1), was used as a control. Both dorsal striatum and S1 were harvested from transgenic and WT mice and molecular analysis confirmed that PPP1R7 deficiency was strongly correlated with the phenotype. Together, converging findings in human HD patients and this HD mouse model suggest an anatomo/functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability.

Background. Impairments in postural control in Huntington disease (HD) have important consequences for daily functioning. This observational study systematically examined baseline postural control and the effect of sensory attenuation and sensory enhancement on postural control across the spectrum of HD. Methods. Participants (n = 39) included healthy controls and individuals in premanifest (pHD) and manifest stages (mHD) of HD. Using wearable sensors, postural control was assessed according to (1) postural set (sit vs stand), (2) sensory attenuation using clinical test of sensory integration, and (3) sensory enhancement with gaze fixation. Outcomes included sway smoothness, amplitude, and frequency. Results. Based on postural set, pHD reduced postural sway in sitting relative to standing, whereas mHD had pronounced sway in standing and sitting, highlighting a baseline postural deficit. During sensory attenuation, postural control in pHD deteriorated relative to controls when proprioceptive demands were high (eyes closed on foam), whereas mHD had significant deterioration of postural control when proprioception was attenuated (eyes open and closed on foam). Finally, gaze fixation improved sway smoothness, amplitude, and frequency in pHD; however, no benefit was observed in mHD. Conclusions. Systematic examination of postural control revealed a fundamental postural deficit in mHD, which further deteriorates when proprioception is challenged. Meanwhile, postural deficits in pHD are detectable when proprioceptive challenge is high. Sensory enhancing strategies using gaze fixation to benefit posture may be useful when introduced well before motor diagnosis. These findings encourage further examination of wearable sensors as part of routine clinical assessments in HD.