Authors: Adam Rosenblatt MD, Brahma V. Kumar, Russell L. Margolis MD, Claire S. Welsh, Christopher A. Ross MD, PhD
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The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety-nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow-up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and Χ² or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R² = 0.203, P < .001), Huntington's disease Activities of Daily Living Scale (R² = 0.259, P < .001), and Motor Impairment Score (R² = 0.173, P < .001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R² = 0.248, P < .001) was significantly associated with disease duration at institutionalization, when controlling for age at onset.
In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini-Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long-term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias.
© 2011 Movement Disorder Society
Summary and review by Ruth H. Walker, MB, ChB, PhD
It is important to understand what factors influence disease progression in HD, both for prognostication in individual patients, and to be able to determine effects of potential disease-modifying therapies. The large variability in rate of progression in individuals, even with identical CAG repeat sizes, is a major confounding factor in studies of potential disease-modifying therapies, requiring very large numbers to demonstrate statistical significance. Apart from the size of the CAG repeats, other factors which determine rate of disease progression have yet to be clearly determined.
Rosas and colleagues studied rates of cortical atrophy as determined by quantitative MRI in a relatively small group of 22 HD patients. All patients were at similar disease stage as determined by total functional capacity and other neuropsychological measures, and had CAG repeat sizes in the middle of the pathogenic range (40-55) to avoid the effects of extremely long or short repeat sizes. They divided the group into 3, based upon the age of motor symptom onset (Young<40 ; Mid=40-55 ; Old>55 ). The mean CAG repeat size in each group was Young, 52.2; Mid, 43.6; Old, 42.1. The authors compared rates of atrophy of cortex using sophisticated MRI volumetry with scans performed approximately 1 year apart.
The rates by which the cortex thinned between the 2 scans differed most strikingly between the Young and the Old groups. In a few, but not all, cortical regions, rates of atrophy were significantly different, e.g. twice as fast in the Young group as compared with Old and Mid aged subjects. Rates of atrophy varied considerably between regions. Significant differences were not seen in all regions, but only in specific cortical regions, e.g. right precentral, right posterior frontal, cortex. There were differences in the rates of atrophy in different regions in the different groups. Correlation of rates of atrophy with CAG repeat size was found for certain cortical regions, e.g. right precentral, right caudal middle frontal, etc. but surprisingly this was only true for 11% of cortical regions. There were significant differences between rates of thinning in certain regions between Mid and Old subjects which did not correlate at all with differences in CAG repeat size.
Atrophy of the corpus callosum followed a similar pattern. Interestingly, there was no difference in rates of atrophy of the basal ganglia. In fact the rate of atrophy of the caudate was slower in the Young as compared with the Old group, and the investigators suggest this may be due to a floor effect, i.e. atrophy has already happened in the Young group.
Clinically, the change in the TFC in the Young group was twice that in the older groups at rescanning. Other details of changes in rating scales are not reported. Although these rating scales are unlikely to have been specific, it would be intriguing to correlate detailed neuropsychological and neurological testing with involvement of specific cortical or subcortical regions.
The authors conclude that the rates of progression and the anatomical distribution of cortical atrophy were influenced more by the clinically-defined age of onset than by CAG repeat size. Of course, as development of motor symptoms is related to neurodegeneration (mainly of basal ganglia structures, but secondarily of cortex) it is more likely that a third factor is influencing the rate of cortical atrophy and hence manifestation of motor symptoms at a younger age.
It is striking that, given the small numbers in each group, and the variability in the cortical regions showing atrophy, between and within groups, that statistically significant differences in rates of atrophy, should have emerged. This clearly indicates that other factors, epigenetic or environmental, can have very specific effects upon neuronal vulnerability. The authors propose variable transcriptional regulation, oxidative stress or other metabolic factors as potential causes for regional variation in neuronal loss.
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 www.naadvocacy.org/ for more information. Dr. Walker may be reached by e-mail at email@example.com.