Tracer Imaging in HD

The model disease in which the brunt of the pathological changes manifest, at least in the early stages of the disease, almost exclusively in the striatum, is HD. In this autosomal dominant disease the mutant gene leads to formation of an abnormal huntingtin protein resulting in malfunction and degeneration, in particular of the projection neurons of the striatum. Why this usually occurs after a delay of many years and why the disturbance mainly damages striatal neurons, is still a matter of speculation and investigation, but is undoubtedly of fundamental importance. HD can present clinically in various ways, but the most conspicuous neurological signs consist of movement disorders such as chorea, dystonia and bradykinesia [21]. In this sense HD is a typical example of a basal ganglia disorder. How exactly the abnormal movements characterized as chorea are generated by the altered regulation of cerebral motor networks remains to be elucidated. It appears that the altered final outflow pattern of the globus pallidus, due to the lesioned striatal projection neurons, projecting to the thalamus and cortex appears to be a necessary condition. It is intriguing, but as yet not clarified at a pathophysiological network level, that altered activity in the globus pallidus can lead to either chorea or to dystonia (and perhaps also to tics?).

The degeneration of the striatal neurons results at a certain stage in striatal atrophy, as has been shown many times in post mortem studies and during life in CT or MRI studies. When the disease has developed clinically, not only is structural atrophy detectable, but there is also markedly reduced local energy consumption and receptor loss, as shown, for example, by radiotracer PET studies. Changes in metabolism are demonstrated by regional glucose utilization studies using the tracer 18[F]-fluoro-deoxyglucose (FDG) and PET (Fig. 1)[25]. Dopamine D2 receptor binding (using for example [11C]-raclopride) indicates receptor binding on the cell membrane of striatal projection neurons [1, 5, 19].

Local biochemical alterations at the level of the striatum can be detected using the above-mentioned radiotracer methods many years before the disease becomes clinically manifest [2, 23]. This situation is currently being investigated in order to be able to predict the time course of the degenerative process. If local biochemical

Huntington Normal Sydenham

Fig. 1 Radiolabeled FDG ([18F]fluoro-deoxyglucose) uptake in the brain of a patient with Huntington's disease (left), a healthy volunteer (middle) and a patient with Sydenham's chorea (right). One plane cutting through the striatal regions is shown. The top of the images is the front of the brain. The Huntington patient shows a marked decrease of striatal glucose utilisation related to the severity of the neurodegeneration, whereas the Sydenham's chorea patient shows a marked increase in striatal glucose metabolism

Huntington Normal Sydenham

Fig. 1 Radiolabeled FDG ([18F]fluoro-deoxyglucose) uptake in the brain of a patient with Huntington's disease (left), a healthy volunteer (middle) and a patient with Sydenham's chorea (right). One plane cutting through the striatal regions is shown. The top of the images is the front of the brain. The Huntington patient shows a marked decrease of striatal glucose utilisation related to the severity of the neurodegeneration, whereas the Sydenham's chorea patient shows a marked increase in striatal glucose metabolism dysfunction is an early marker for disease progression then the appropriate patients could be selected to test potentially protective drugs.

It is interesting to realize that not only a loss of striatal projection neurons can cause chorea, but also selectively altered neuronal function, as apparently is the case in Sydenham's chorea (SC). Whereas in HD a loss of striatal synaptic activity results in lower local energy demands and altered functions, in SC a completely different pathophysiology results in local metabolic increases (Fig. 1), presumably due to aberrant immunologic activity towards striatal components in the context of a streptococcal infection. The disease process in SC apparently leads to almost identical network alterations as in HD as far as the generation of chorea is concerned. Usually SC is a self-limiting disease and the hypermetabolism disappears after some time [24]. This illustrates that chorea due to a striatal lesion must not automatically be associated with loss of local energy consumption.

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