Whilst many reports mention neurofibrillary tangle pathology in the thalamus in progressive supranuclear palsy, there has been little detailed regional analysis of the distribution and density of thalamic pathology in this disease or in other parkinsonian syndromes. The caudal intralaminar thalamic nuclei are the major thalamic regulators of the caudate nucleus and putamen, areas known to be dysfunctional in progressive supranuclear palsy and Parkinson's disease. We investigated whether these thalamic nuclei degenerate in patients with these disorders compared with age-matched, neurologically normal controls. Neurofibrillary tangle and Lewy body pathology was assessed and unbiased optical disector methods were used to quantify total neuronal number. Despite different thalamic pathology, there was a dramatic reduction in the total neuronal number in the caudal intralaminar nuclei in both progressive supranuclear palsy and Parkinson's disease (40-55% loss). In contrast, there was no loss of volume or total neuronal number in the limbic thalamic nuclei in either disease group, indicating selective degeneration of the caudal intralaminar nuclei. In Parkinson's disease, Lewy bodies were found in these regions, while in progressive supranuclear palsy abundant intracellular neurofibrillary tangles and glial tangles concentrated in the caudal intralaminar nuclei. However, tangle formation accounted for only a small proportion of cell loss (=10%) in the thalamus in progressive supranuclear palsy. These findings have several implications. The caudal intralaminar thalamus appears to be one of three basal ganglia sites commonly affected in both progressive supranuclear palsy and Parkinson's disease. These sites are the dopaminergic substantia nigra, the cholinergic pedunculopontine tegmental nucleus and, from our results, the glutamatergic caudal intralaminar thalamus. In both diseases these sites contain characteristic but different pathologies, indicating disease-specific mechanisms of neurodegeneration. Interestingly, the proportion of remaining neurons affected by these pathologies is low. This may indicate additional (possibly common) cellular mechanisms responsible for the degeneration in these regions. Both the dopaminergic nigra and the glutamatergic caudal intralaminar thalamus are the major regulators of basal ganglia function via the caudate nucleus and putamen. The pedunculopontine tegmental nucleus has major projections to both of these regulators. These findings indicate that dysregulation of two neurotransmitter systems within the basal ganglia may underlie common parkinsonian symptoms in these disorders. For patients with Parkinson's disease, this loss of glutamate regulation may help explain some problems with dopamine replacement therapies, particularly over time. For patients with progressive supranuclear palsy, more widespread degeneration of basal ganglia structures would contribute to poor treatment outcomes.
Two major noncortical inputs to the striatum originate from the substantia nigra and the thalamic centré median–parafascicular complex. Although it is established that in Parkinson's disease there is degeneration of the nigral dopaminergic neurons, there has been little analysis of the glutamatergic centré median–parafascicular complex. We therefore evaluated these and neighboring thalamic nuclei (for specificity of any changes) in 9 Parkinson's disease patients and 8 age‐matched controls. Degeneration in the substantia nigra and centré median–parafascicular complex was estimated by using quantitative neuronal counts. On average, 70% of the pigmented nigral neurons degenerated and there was 30% to 40% neuronal loss in the centré median–parafascicular complex in Parkinson's disease. Thalamic degeneration was marked in neuronal subpopulations (50% loss of parvalbumin‐positive neurons in the parafascicular, and 70% loss of non–parvalbumin‐positive neurons in the centré median nuclei). In contrast, adjacent thalamic nuclei did not degenerate, which supports a selective neurodegeneration of the centré median–parafascicular complex. Our results show that the thalamic centré median–parafascicular complex is an additional nondopaminergic site of neurodegeneration in Parkinson's disease. Because this thalamic region provides important sensorimotor feedback to the striatum, degeneration of this region is likely to exacerbate the clinical signs and symptoms of Parkinson's disease. Ann Neurol 2000;47:345–352
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