Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by a highly polymorphic CAG-repeat on the short arm of chromosome 4. Both, the function of the gene and the pathogenesis of HD are still unknown and there is a lack of biological markers for the natural history limiting the evaluation of new therapeutic approaches. In this project a number of methods are employed in order to investigate which is most sensitive in monitoring disease progression.
The Unified Huntington's Disease Rating Scale (UHDRS) is used to provide uniform assessment of the clinical features and course of HD. Investigations include molecular genetic testing, somatosensory evoked potentials (SSEP), magnetic cortex stimulation, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). 1 H-MRS is performed on a 1.5-T gyroscan S 15 (Philips). Based on a transversal T2-weighted imaging (TE=30 msec, TR=200 msec) we select a voxel volume of 20X20X40 mm in a frontoparietal area of the brain by a SPARS sequence. Water suppression is achieved by using selective inversion pulses. Spectra are obtained using a headcoil after shimming inhomogenities of the magnetic field. We use the following parameters: TE=136 msec, TR=200 msec, sample frequency 1KHz, 1024 samples, 256 measurements. In the standard processing of spectra zero filling 4 K, fourier transformation, and phase correction are used. Evaluation of the ratios phosphocholine (PCh)/phosphocreatine (PCr), N-acetylaspartate (NAA)/PCh and lactate/PCh by integral of the peaks allow a quantitative description of metabolic alterations. The spectroscopical data are obtained and processed without knowledge of the clinical characteristics of the patient.
In a study employing MRS so far 21 patients with HD have been investigated including four asymptomatic gene carriers. Using a clinical severity rating scale patients were divided into four groups: group 1 consisted of four asymptomatic gene carriers, group 2 consisted of six HD patients with mild handicap, group 3 of six patients with moderate severity and group 4 of six patients which were severely affected. In addition, a control group of nineteen healthy volunteers was also studied. In each of the asymptomatic gene carriers lactate in the frontal cortex was found but only in 47% of the symtomatic patients. No correlation with the clinical features was found.The PCh/PCr ratios did not show significant differences between the groups. A correlation between the NAA/PCh ratio and the clinical severity in our patients showed that there were no differences in asymptomatic gene carriers, patients of group 2 and controls. A decrease was seen in group 3 and 4 and the differences between group 2 and 3 were statistically significant. There was no correlation between the reductions of the NAA/PCh ratio and duration of the disease, age of patients and number of CAG repeats.
In each of the asymptomatic gene carriers and in 47% of the symptomatic patients lactate was detected in the frontal cortex. This study confirms in part the results reported by Jenkins et al. Neurology 1993;43:2689-2695 but at variance to those findings only a proportion of our symptomatic patients had increased lactate levels. Interestingly, our study shows that the neuronal marker NAA is reduced in severely affected patients with HD. Whether NAA can serve as a biological marker for the more severe stages of the condition must be shown in longitudinal studies.
This project is supported by a grant from the BMFT and by a BIOMED I grant of the European Union.