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Structures outside the basal ganglia may compensate for dopamine loss in the presymptomatic stages of Parkinson’s disease¹

ERWAN BEZARD^*2, ALAN R. CROSSMAN^*, CHRISTIAN E. GROSS and JONATHAN M. BROTCHIE^*

^* Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, U.K.; and
Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 33076 Bordeaux Cedex, France

²Correspondence: Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. E-mail: erwan.bezard{at}umr5543.u-bordeaux2.fr

SPECIFIC AIMS

The widely held concept of basal ganglia-mediated compensation postulates that the appearance of Parkinson’s disease motor abnormalities closely reflects the breakdown of the striatal dopamine homeostasis. This view implies that the changes in basal ganglia activity responsible for the generation of symptoms occur together with the appearance of those later. So far, however, this hypothesis has not been tested experimentally. To identify the changes in neuronal metabolic activity that occur before and after the appearance of parkinsonian motor abnormalities, the present study assessed the changes in 2-deoxyglucose (2-DG) metabolic levels in the whole basal ganglia, the motor thalamic nuclei, and the supplementary motor area (SMA), which receives afferents from the basal ganglia, following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state.

PRINCIPAL FINDINGS

1. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys
Both the parkinsonian rating score and bradykinesia timed test showed that the monkeys were asymptomatic on day 12 of the protocol (parkinsonian score of 0) whereas the level of dopamine in their striatum was significantly reduced by 56.3%. Day 12 animals could be considered a presymptomatic animals. Full parkinsonian animals killed on day 25 exhibited a typical dopaminergic depletion of 97.9%.

2. Basal ganglia of asymptomatic lesioned monkeys exhibited significant changes in 2-DG uptake
Both MPTP-treated groups of animals showed dramatic changes in regional brain 2-DG uptake in comparison with the controls (Table 1 ). Results obtained in fully parkinsonian monkeys (day 25) are in total accord with our previous reports whatever the considered nucleus. In both presymptomatic and parkinsonian animals, similar changes compared to intact animals were seen in subregions of the basal ganglia, e.g., the subthalamic nucleus and the globus pallidus pars internalis and in the primary target of basal ganglia outputs the ventral thalamus. There was in no case a significant difference between the magnitudes of the change observed in presymptomatic compared to fully symptomatic animals (Table 1) . Thus, even though animals of these groups showed markedly different motor behavior, there was no apparent difference in global basal ganglia functioning.

3. 2-DG uptake in SMA of asymptomatic lesioned is normal
The SMA, in contrast, showed a significant decrease in 2-DG uptake only in the fully parkinsonian animals (Table 1) . Whereas the presymptomatic group displayed abnormalities in basal ganglia function that are generally associated with the production of parkinsonian symptoms, SMA activity was not different from controls. Accordingly, 2-DG uptake in the SMA of the presymptomatic and fully parkinsonian animals was significantly different (Table 1) .

CONCLUSIONS

The key finding of this study is that the changes in neural metabolic activity responsible for generating parkinsonian symptoms are already established within the basal ganglia of the presymptomatic group. Neural activity in SMA was normal in those presymptomatic animals. Symptoms appear only when SMA activity is decreased. Thus, these data demonstrate that the neural mechanisms responsible for suppressing the appearance of parkinsonian symptoms in the presymptomatic animals would also lie downstream of the basal ganglia and not only within the nigrostriatal pathway. It seems likely that mechanisms regulating the transfer of information from basal ganglia output to the SMA through the thalamus would participate to compensate for abnormalities in basal ganglia outflow and so prevent the appearance of symptoms in the presymptomatic state.

That the changes in basal ganglia 2-DG uptake were comparable between asymptomatic (day 12) and fully parkinsonian monkeys does not necessarily, however, imply that the firing neuronal activities were identical. 2-DG autoradiography integrates metabolic activity during the 45 min that 2-DG was circulating, not allowing us to discriminate between changes in firing frequency or in pattern of neuronal activity. Thus, the mean basal firing rate may not be abnormal in day 12 animals, contrary to parkinsonian animals, but changes in the firing pattern may occur in these asymptomatic animals. Although it is not possible to determine, the key finding of this study remains that the striatal dopaminergic homeostasis is already broken in the presymptomatic group and that transition from presymptomatic period to symptomatic period could no more be considered as reflecting this breakdown.

Whereas the whole basal ganglia and thalamic nuclei were studied in our previous studies, the measurement of changes in SMA metabolic activity was not the same as in the present study. Whereas loss of mesencephalic dopaminergic neurons must give rise to disordered activity of basal ganglia output structures, which obviously underlies the motor manifestations of the condition, impairment of SMA metabolic activity would be linked to the appearance of those later. The decrease in metabolic activity in SMA accompanying motor symptoms of fully parkinsonian animals (day 25) is similar to that reported in previous in vivo and ex vivo functional imaging studies in both humans and monkeys. This metabolic decrease is obviously correlated with both globus pallidus pars internalis and thalamic hypermetabolism in both MPTP-monkey and parkinsonian patients. In an attempt to develop an early diagnosis of Parkinson’s disease with fluorodeoxyglucose and positron emission tomography, Eidelberg et al. suggested that this technique may also be applicable to preclinical detection when using scaled subprofile model to analyze small side-to-side differences in basal ganglia function. To support their suggestion, they cited a personal communication by M. H. Mark reporting asymmetries in striatal fluorodopa uptake in preclinical subjects such as unaffected co-twins. Whereas their hypothesis was obviously difficult to test in human patients, the present study supports their preliminary observations.

It remains to be determined where this hitherto unknown off-basal ganglia compensation takes place. Four hypotheses can be proposed to explain why SMA activity is normal in presymptomatic animals with apparent major dysfunction of the basal ganglia: 1) abnormal GPi activity (firing rate and/or firing pattern) might be compensated for by opposing activity of other, excitatory, afferent inputs to the thalamic nuclei; 2) compensation could be due to specific intrinsic properties of thalamic neurons; 3) compensation could be the result of modifications of other hitherto-unidentified structures located outside the basal ganglia and projecting on SMA in order to counterbalance a putative pathological thalamic activity or 4) could be an emergent property of the network linking the thalamus and SMA, given the complex anatomy of reciprocal feedback loops and involvement of reticular thalamic connections such a proposition is appealing.

These results, which do not refute the within-basal ganglia compensation, would on the contrary reflect the sequential activation of two families of compensatory mechanisms, leading us to consider that presymptomatic period in Parkinson’s disease in fact comprises two stages (Fig. 1 ): 1) a first period during which ‘classical’ within-basal ganglia compensatory mechanisms are able to ‘mask’ the disease (Fig. 1) , 2) followed by a second, beginning with the breakdown of striatal dopaminergic homeostasis during which the off-basal ganglia compensation takes place (Fig. 1) . The appearance of parkinsonism with increasing dopamine depletion may result from the failure of these hitherto unidentified nonbasal ganglia compensatory mechanism(s) that counter the abnormal activity arising from the basal ganglia (Fig. 1) . Identification of these mechanisms will allow us to understand how the brain integrates the information arising from subcortical loops to control cortical activity in keeping with a clinical application; their enhancement, if feasible, would allow us to further delay the parkinsonian sign appearance (i.e., resulting in an increase of the presymptomatic period of Parkinson’s disease) or to at least postpone the beginning of levodopa therapy.

View larger version (29K): [in this window] [in a new window]   Figure 1. Schematic diagram of the hypothesized sequential activation of two families of compensatory mechanisms in relation with the gradual process of nigral degeneration in the course of Parkinson’s disease (adapted from Agid, Lancet, 1991, vol. 337, pp. 1321–1323). The key finding of the present study is to dissociate the breakdown of the striatal dopaminergic homeostasis from the appearance of parkinsonian motor abnormalities. The presymptomatic period may be divided into two periods. The threshold of the transition between the latter, however, remains to be defined as well as the nature of the off-basal ganglia compensatory mechanisms.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0637fje ; to cite this article, use FASEB J. (February 26, 2001) 10.1096/fj.00-0637fje

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