title: Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications.
abstract: 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.
authors.affiliation: Prince of Wales Medical Research Institute, High Street, Randwick, Australia. j.henderson@unsw.edu.au
authors.forename: J M
authors.initials: JM
authors.lastname: Henderson
authors.forename: K
authors.initials: K
authors.lastname: Carpenter
authors.forename: H
authors.initials: H
authors.lastname: Cartwright
authors.forename: G M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology; D002452:Cell Count; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020646:Intralaminar Thalamic Nuclei / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology* / Q000628:therapy; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D013787:Thalamic Nuclei; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins