Review: What determines the rate of progression in Huntington's disease?

Movement Disorders
doi: 10.1002/mds.23762

Authors: H. Diana Rosas MD, Martin Reuter PhD, Gheorghe Doros PhD, Stephanie Y. Lee BS, Tyler Triggs BS, Keith Malarick BS, Bruce Fischl PhD, David H. Salat PhD, Steven M. Hersch MD, PhD

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Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease.

We scanned 22 patients with Huntington's disease at approximately 1-year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex.

There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease.

© 2011 Movement Disorder Society

Summary and review by Dr. Ruth H. Walker, MB, ChB, PhD

In this retrospective study Rosenblatt and colleagues examined factors contributing to time to institutionalization in a large cohort of almost 800 patients with HD followed at the Johns Hopkins HD clinic. 88 of this cohort were institutionalized during the time they were followed by the clinic. The authors also compared institutionalized patients with a group they termed "long-survivors", who had avoided institutionalization for more than 15 years.

The authors studied a range of demographic and clinical factors using several statistical models - linear, survival analysis, and a Cox proportional hazards model. The factors examined included neurological, psychological, psychiatric, physiological, and functional measures.

23% of the cohort was black, evenly divided between gender. Black patients had a younger age of onset and worse symptoms at institutionalization. The authors attribute this finding to stronger social support for black patients, and also younger age masking effects of higher CAG repeat size due to overall better health.

CAG repeat size was associated with disease duration at time of institutionalization, but only after controlling for age of onset, and only explained 21% of the variation. The authors suggest that despite patients with lower CAG repeats having slower disease progression (which may be controversial), competing effects of aging are likely to contribute to institutionalization. However, given the ages of patients being in their late 40's-early 50's at exam, with mean age at institutionalization being 47.8, I would think this less of an influence than some other factor.

Recent falls were also correlated with institutionalization. Institutionalized patients had lower mean education attainment than those who were not institutionalized. This may be due to socioeconomic factors, e.g. the spouse having more resources to cope at home, but also may point to more intellectual reserve as in AD. The strongest predictors of institutionalization were scores indicating motor dysfunction, rather than psychiatric impairment. ADL and cognitive abilities, not surprisingly, were also important factors. This contrasts with findings in PD and AD, and may indicate the more disabling nature of the movement disorder in HD, although it is although possible that the psychiatric symptoms in advanced HD are less disruptive than in the other dementing disorders.

The authors note that they did not document caregiver factors. It is increasingly recognized that caregiver stress is an important factor in institutionalization in other dementing conditions. It is certainly possible that caregivers who were more burdened would be less likely to bring patients for follow-up care, and thus lost to follow-up. A prospective study would permit a more systematic examination of factors leading to institutionalization or enabling patients to stay at home.

About Dr. Ruth H. Walker, MB, ChB, PhD

Ruth H. Walker obtained her medical degree from the University of Edinburgh. Scotland, and went on to complete a PhD in basal ganglia neuroanatomy at the University of Edinburgh and MIT (USA). Following a neurology residency at New York University School of Medicine, she completed a fellowship in Movement Disorders at Mount Sinai School of Medicine.

She joined the James J. Peters Veterans' Affairs Medical Center (Bronx) as a staff neurologist and Director of the Movement Disorders Clinic, and is Associate Professor in the Department of Neurology at Mount Sinai School of Medicine, New York.

Dr. Walker's research focuses on the functional neuroanatomy of the basal ganglia and clinicopathologic correlations of neurogenetic disorders. She has a particular interest in rare causes of neurodegenerative chorea, and is the editor of a forthcoming book which comprehensively addresses the diagnostic and therapeutic aspects of this common movement disorder, "The Differential Diagnosis of Chorea" and the organizer of an NIH- and MDS-sponsored meeting entitled "Brain, Blood and Iron: Joint International Symposium on Neuroacanthocytosis and Neurodegeneration with Brain Iron Accumulation." Visit the website for more information. Dr. Walker may be reached by e-mail at