Rick, there is low glucose metabolism in the PD brain. Don't know how that relates to your experiments. And I don't know what 'reversal learning' is (mentioned below)......

Resting regional cerebral glucose metabolism in advanced Parkinson's disease studied in the off and on conditions with [18F]FDG-PET

Movement Disorders
Volume 16, Issue 6, Pages 1014-1022

Published Online: 7 Nov 2001

Cerebral Glucose Metabolism in PD

We focused on brain glucose metabolism in advanced PD without dementia. A mean 21% reduction of global rCMRGlc was found in patients when on compared with controls. This result is in line with that of Eberling et and colleagues,[12] who reported a reduction of 23% for the same comparison.

Significant relative regional reductions of glucose metabolism in studies of nondemented PD patients with established disease (mean durations between 6 and 8 years) have been demonstrated in various association cortical regions: occipital,[11][12] parietal,[11-14] frontal,[13] and temporal.[14] In both early disease with a mean duration of 4 years, and in some studies with longer mean durations of disease (between 6 and 7 years), no significant reductions have been reported.[4][5][15][16]

The reason for this is likely to reflect inclusion of very early cases in these studies with 1 to 2 years duration of disease, where cortical hypometabolism is unlikely. Here, only cases with at least 10 years disease duration were selected and the mean duration (15 years) was considerably higher compared with previous studies.

Hypometabolism was widespread in the cortex. During on condition, hypometabolism was even more pronounced with increasing severity of clinical state. Combining our results with those reported in literature suggests that cortical hypometabolism in PD parallels disease duration even in the absence of dementia.

Widespread hypometabolism, which is a pathognomomic feature in PD with dementia,[6-8] also appears to be common in nondemented patients with advanced PD.

In particular, frontal hypometabolism seems to be a characteristic of advanced disease, as it was found only in the study[13] with the longest mean duration (8 years) mentioned above, and in our present study (mean duration 15 years).

Further evidence that frontal lobe dysfunction is a specific finding in advanced disease comes from PET studies of neurotransmission and neuropsychological data. In advanced PD, reduced dopamine D2/3 receptor binding has been demonstrated in the prefrontal cortex.[35]

Conversely, higher flurodopa uptake has been reported in the frontal cortex of PD patients with better performance in cognitive testing.[36] Neuropsychological testing also reveals that frontal lobe functions are specifically impaired at more advanced stages of disease.[37-39]

With respect to subcortical structures, relative increased metabolism in the lentiform nucleus contralateral to the clinically predominantly involved side is characteristically present.[4][5] In contrast, one study reported reduced striatal metabolism in advanced disease, in line with our present study which detected decreased metabolism in the caudate.[40]

This impairment of caudate metabolism in advanced PD is similar to that reported in progressive supranuclear palsy and differs from findings in early PD where there is no impairment in striatal metabolism.[4][16][41] Reductions in caudate metabolism during the course of PD probably reflect reduced frontal input due to direct pathological involvement.

Metabolic changes are paralleled by changes in striatal D2 receptor binding, which is increased in early, untreated disease and decreased in the advanced treated state.[42][43]

Influence of L-DOPA on Cerebral Glucose Metabolism

Relative decreases of glucose metabolism in PD patients on compared with off L-dopa were demonstrated symmetrically in the ventral/orbital frontal cortex and the thalamus. There is some correspondence with other PET studies investigating brain metabolism, reporting decreases, although not significant, between 2% and 9% in the nucleus lentiformis, thalamus, and occipital cortex,[17] or more generally in the basal ganglia and cerebral cortex.[18]

Our findings complement those of neuropsychological studies on the influence of L-dopa on frontal lobe function. Swainson and colleagues[23] demonstrated a negative effect of dopaminergic medication in PD patients on reversal learning; Gotham and associates[19] reported impaired performance on the Tower of London task after L-dopa; other investigators have found beneficial[44-47] and detrimental effects [20-22] of L-dopa on performance of various neuropsychological tasks.

The heterogeneity of results may in part be explained by the fact that patient groups in different stages of disease were examined, and that specific tasks require integrity of different areas of prefrontal cortex/neurochemical pathways.

Lesioning experiments in primates and neuropsychological studies in patients with dementia of the frontal type indicate that the ventral/orbital prefrontal cortex is relevant for reversal learning deficits.[48][49] Dysfunction of the ventral/orbital frontal cortex in PD after L-dopa was most evident in our [18F]FDG PET study.

It has been demonstrated in animal experiments that frontal lesions cause transneuronal degeneration in the thalamus.[50]

Conversely, thalamic infarctions can result in disconnection and reduced activation of the frontal cortex with associated cognitive deficits.[51][52] In this context, our finding of simultaneous hypometabolism in thalamus and prefrontal cortex following dopaminergic treatment suggests a depression of this functional system due to the medication.

This could result from an overdosage for the cognitive systems in contrast to the motor systems as suggested by Gotham and colleagues.[19] Further evidence that the thalamus is required for functions of the ventral/orbital frontal cortex comes from a study demonstrating a correlation between a lower radiodensity in the thalamus shown by cranial computed tomography and deficits in reversal learning.[53]

In conclusion, we have demonstrated that hypometabolism of association cortex and caudate nucleus is a common feature in nondemented PD patients with advanced disease.

Caution is mandatory if [18F]FDG PET is being used to exclude early dementia or progressive supranuclear palsy, e.g., in the selection of suitable candidates for new therapeutic strategies in PD.

In addition, the present study demonstrates that L-dopa treatment impairs the activity of ventral/orbital frontal cortex and thalamus required for specific behavioural tasks such as reversal learning, known to be impaired with this medication.

Consequently, to avoid confounding effects in the assessment of the metabolic state in PD, dopaminergic therapy should be withdrawn before [18F]FDG PET.

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