DENVER, CO – Huntington disease (HD) progression, clinical features, and treatment were the topics of several new studies presented at the AAN Annual Meeting. Among their findings are new data about presymptomatic abnormalities in white matter, the effect of the mode of disease onset on disease progression, and the potential use of genetic models for future treatments.
Presymptomatic gene carriers exhibit subtle neuropsychological and cognitive anomalies for years before the clinical diagnosis of HD is made. These early manifestations have been attributed to loss of cortical, cerebellum, and midbrain gray matter.
Christine Fennema-Notestine, PhD, and colleagues from University of California-San Diego (UCSD) presented new evidence, however, that white matter shows characteristic changes in presymptomatic patients. The investigators performed brain MRI and morphometric mapping of five gene-positive patients, five gene-negative family members, and 18 controls. The gene-positive patients showed the typical triplet repeat expansion in DNA analysis.
While gene-negative participants were not different from controls on any measure, white matter volume in gene-positive subjects was significantly reduced in subcortical, cerebellar, and cortical regions. The volume of cerebellar white matter in gene-positive patients was only 82 percent of controls, including participants within 10 years of expected clinical onset of disease, as determined by an algorithm based on cystosine-denine-guanine (CAG) repeat length and other factors. (The abnormal gene for HD, located on the tip of the short arm of chromosome 4 – 4p16.3 – contains extra copies of trinucleotide repeats of CAG.) Dr. Fennema-Notestine said these results indicate that “something is going on behind the scenes with white matter that we need to look into more carefully.”
Brain metabolic networks are also altered long before the onset overt symptoms of HD, according to a PET study performed by Andrew Feigin, MD, David Eidelberg, MD, and colleagues at the North Shore University Hospital in Manhasset, NY.
Ten presymptomatic gene carriers and eight controls had PET studies while learning two different motor tasks that required them to time movements with a tone. Areas of the brain that were activated during the learning process were analyzed. While patients were similar to controls in motor execution, they lagged in their sequence learning. This difference correlated with specific alterations in the networks of brain centers that were activated.
Learning in controls correlated with metabolic activity in the dorsolateral prefrontal cortex and premotor cortex, but there was no such correlation in presymptomatic HD subjects, who instead activated the anterior cingulate cortex significantly more than controls. The investigators suggested that this increased activity compensated for the abnormal caudate output in HD due to disease-related atrophy.
HD causes severe cognitive and psychiatric declines, and these are often more debilitating than the motor symptoms that classify the disease as a movement disorder. Any of these symptoms may come first, so the Huntington Study Group set out to determine whether the mode of onset influences the rate of progression. In short, it did not. A review of charts for 1,024 patients showed that the rate of decline was independent of the nature of the first symptom during the mean 2.3 year follow-up.
Additionally, younger patients were more likely to have cognitive or psychiatric symptoms at first, and progression of chorea and dystonia correlated poorly with disease duration and overall disability.
The prevalence of dementia in HD depends heavily on the criteria used to diagnose it, according to research by Guerry Peavy, MD, and colleagues at UCSD. They administered neuropsychological tests to quantify memory deficits, other cognitive impairment, and functional decline, which were used to evaluate patients for either a dementia diagnosis according to DSM-IV criteria or a dementia syndrome diagnosis according to Cummings & Benson criteria. (See box on criteria for dementia.)
Then they compared this to the clinician-rated impression of dementia, as recorded on the United Huntington Disease Rating Scale. While 58 percent satisfied Cummings & Benson criteria, and 42 percent DSM-IV criteria, only 29 percent were diagnosed with dementia by UHDRS clinical impression. Dr. Peavy said these results suggest the need for dementia criteria specifically targeted to HD patients.
REVERSING SYMPTOMS IN MICE
HD investigators say one of the most intriguing Huntington-related findings in the last two years has been the discovery that turning off the mutant gene leads to restoration of motor deficits, at least in mice. Ottavio Arancio, MD, PhD, René Hen, and colleagues at Columbia University College of Physicians and Surgeons have developed a transgenic HD mouse whose gene can be turned on or off with administration of tetracycline.
This molecular switch has allowed them to show that even after the development of significant symptoms, mice can recover most of their lost motor function if the mutant gene is turned off.
New research from this group now demonstrates that long-term potentiation is impaired in this model, and that change in electrical activity impairment can be reversed as well, implying that the functional declines in HD require continuous influx of mutant protein. Potentiation is the cellular process underlying learning, a long-term change in responsiveness of neurons as a result of exposure to stimuli of the correct type and in the correct sequence.
While the gene model itself cannot be applied to development of the treatments since the tetracycline regulatory system requires in vitro genetic engineering, the therapeutic implication is nonetheless encouraging, since it implies patients might recover if a way could be found to shut down the mutant gene.
Results from animal models can be misleading, though, as shown by a double-blind trial of the dietary supplement creatine. A study published in 2001 showed that daily oral creatine lessened brain atrophy, slowed motor decline, and increased survival in HD mice (Neurobiol Dis. 2001; 8 (3): 479–91).
To test its potential in humans, Patricia Verbessem, MD, and colleagues at Catholic University of Leuven in Belgium, gave either placebo or five grams of creatine per day to 41 HD patients. At the end of one year, there was no difference between the groups in cognitive decline, motor decline, muscle strength, or total functional capacity. This is the second negative result for this treatment in HD patients, casting doubt on the possible protective benefit of creatine, at least at doses normally used to improve muscle capacity in humans.