Huntington's disease

Environmental Enrichment Slows Disease Progression in R6/2 Huntington's Disease Mice. Hockly E, Cordery PM, Woodman B. et al. Ann Neurol. 2002;51:235-242.

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive impairment, and personality changes. It is dominantly inherited with midlife onset and is a progressive condition leading to death within 20 years of onset. To date there is no effective then apy. Transgenic mice who recapitulate many of the features of human HD including poor coordination, motor impersistence, muscle strength impairment, and weight loss have been widely used in the testing of drug therapies. The authors wished to expand on a previous study that demonstrated delayed onset of symptoms in R6/1 mice when provided with an enriched environment. The purpose of this study was to confirm the delayed onset of symptoms in R6/2 mice and to determine the importance of environmental standardization in future therapeutic trials. R6/2 mice have an accelerated phenotype that allowed the authors to study the effects of environmental enrichment in much less time.

For the study, affected mice were herozygote R6/2 females and were identified by polymcrase chain reaction of tail-tip DNA. Control mice were wild-type female littermates. Littermates of the same genotype were randomized between treatment groups. Each treatment arm had 10 transgenic and 10 control mice. All mice had unlimited access to food and water. There were 3 levels of living conditions: no enrichment, minimal enrichment, and highly enriched. The non-enriched condition provided wtxxl shaving bedding. The minimal enrichment provided the same cage dimensions as the non-enriched, wood shavings, hut in addition, food pellets were placed on the cage floor and a cardboard tube was supplied. The highly enriched environment however, was supplied with additional bedding materials, running wheels, and a number of toys such as balls and wood objects. Three test areas were identified: behavioral tests which consisted of RotaRod analysis and grip strength analysis, weight loss, and histology and immunohistochemistry. Mice were tested at 3 time points established as standards for phenotype analysis in the authors' laboratory. Mice were tested at 4 weeks, 8 weeks, and 12 weeks.

Results of the test areas were as follows. In RotaRod performance, there was a significant difference in the magnitude of symptom progression between transgenic mice with different levels of enrichment and the non-enriched mice. In grip strength analysis, there was a borderline significant difference between the transgenic mice with different levels of enrichment. In weight loss analysis, there was no significant difference between the mice with different enrichment levels. Highly enriched controls showed a pattern of weight gain similar to less enriched wild-type littermates. There was, however, a significant relationship between grip strength and weight in transgenic mice hut not in the control mice. Histological analysis showed that the peristriatal cerebral volume was greater in the enriched transgenic mice than in the non-enriched group, whereas enrichment did not significantly affect the peristriatal cerebral volume of the control mice. This suggests that environmental enrichment delays degenerative loss of cerebral volume in the transgenic mice.

The authors concluded that RotaRod performance, grip strength, and weight loss are reliable measures of disease progression in R6/2 mice. To the surprise of the authors, maximal and minimal levels of enrichment ameliorated disease progression to a similar degree compared to the non-enriched level. It is unclear how enrichment exerts its effects on disease progression. The authors suggest that neuronal function may be improved and acts as a buffer against the effects of the HD mutation.

This study implies that increasing environmental stimulation could have a positive effect on the disease progression of humans with HD. It is thought that stimulation could be effective whether occurring before or after disease onset since transgenic mice with a high level of performance before the onset of symptoms outperform mice with a lower baseline performance. Therefore, people with HD performing highly before onset of the disease, could possibly continue to function at a level equivalent to average non affected individuals long alter the onset of neuronal decline.

Suzanne Imbriglio, PT

Director of Rehabilitation, Huntington's Disease Treatment

Program, Lowell, MA

Copyright Neurology Report Dec 2002
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