Progressive supranuclear palsy: Postmortem chemical analysis

Over the past two decades, the postmortem analysis of brain neurotransmitters, neurohormones, metabolites, and neurotransmitter-related enzymes has yielded important information about the pathophysiological basis of human neurodegenerative disorders such as Parkinson’s, Huntington’s, and Alzheimer’s diseases. Such studies have led to the investigation of new and more specific therapies for these degenerative diseases. Following in this issue, two independent groups of investigators report their findings on the postmortem neurochemistry of progressive supranuclear palsy (PSP). These studies by Kish‘s and Ruberg’s groups shed light on the pathophysiological characteristics of PSP as well as on Parkinson’s and Alzheimer’s diseases. PSP was first described clinically in 1904 [l] but was only defined as a specific clinicopathological entity in 1964 by Steele, Richardson, and Olszewski [ 2 , 3 J. PSP is uncommon and accounts for about 4% of patients who manifest parkinsonian symptoms 111. The onset of the disease is usually in the sixth decade, and it is somewhat more common in men than in women. The average duration of the disease is less than 10 years. This is similar to untreated Parkinson’s disease, which has an average duration of about 7 to 10 years. The classic features of PSP are supranuclear ophthalmoparesis, bradykinesia, axial rigidity, postural instability, and pseudobulbar affect. Vertical-gaze paresis, especially down-gaze paresis, is the most common oculomotor sign. Bradykinesia and rigidity often develop early and can lead to an initial diagnosis of Parkinson’s disease. In contrast to Parkinson’s disease, however, tremor is unusual. Depression and irritability are common features, and dementia is frequently seen as the disease progresses. The neurochemical abnormalities reported by Ruberg’s and Kish‘s groups are in close agreement with each other. Their findings should enhance our understanding of basal gangha function in general and of PSP in particular. Ruberg’s group studied 9 cases of PSP, and Kish‘s group studied 5 cases. The most striking finding of both groups was a marked reduction in the concentrations of dopamine (80 to 90%) and homovanillic acid (HVA) (45 to 50%) in the caudate and putamen. Furthermore, the more marked reduction in dopamine concentrations as compared to HVA levels suggests an increased turnover of dopamine in the remaining dopamine terminals in the caudate and putamen. These observed reductions in dopamine and HVA concentrations are somewhat less marked than, but otherwise similar to, those seen in Parkinson’s disease and provide a probable explanation for the axial rigidity and bradykinesia seen clinically in PSP. In contrast to Parkinson’s disease, however, both groups found normal dopamine and HVA levels in the nucleus accumbens. Kish and co-workers also measured norepinephrine and serotonin levels, which were generally normal. In Parkinson’s disease, the loss of dopamine in the nucleus accumbens and limbic cortex has been hypothesized as a cause of depressive symptoms. This hypothesis is now in question because depression and dementia are common in PSP while dopaminergic function in mesolimbic and mesocortical pathways is normal. One would have to postulate either that there is a difference in the type or cause of depression seen in PSP versus Parkinson’s disease or that the involvement of noniimbic areas such as the caudate nucleus must be considered as an alternate explanation for the depression seen in these two diseases. In this regard, it is of interest that in Huntington’s disease, depression is also very common, but, again, the nucleus accumbens is relatively spared. Both groups of investigators measured choline acetyltransferase (CAT) activity in several brain regions. Ruberg and co-workers found a mild (approximately 20%) decrease of CAT activity in the cerebral cortex; moderate decreases (40 to 60%) in the caudate, putamen, and nucleus accumbens; and an even larger decrease (70%) in the substantia innominata (the presumed source of a large number of cholinergic cortical afferents). In contrast, Kish and colleagues found no significant changes in CAT activity in the cerebral cortex or basal gangha, even in 2 of the 5 PSP patients with documented severe dementia. This discrepancy must be resolved in further studies. Reported pathologic findings in the substantia innominata in PSP, although not as marked as those in Alzheimer’s disease, are most consistent with the existence of at least some cholinergic deficits [4]. Neither group, however, found changes approaching the decreases in cerebral cortical CAT that have been found in Alzheimer’s disease (85 to 95%). Thus, it is unlikely that the dementia in PSP is caused primarily by cortical cholinergic deficits. Ruberg and colleagues suggest that the decreases in CAT activity in the substantia innominata are likely caused by a loss of cholinergic af-