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α-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibres or glial cells. While small amounts of these α-synuclein pathologies can occur in some neurologically normal individuals who do not have associated neurodegeneration, the absence of neurodegeneration in such individuals precludes them from having a degenerative α-synucleinopathy, and it has yet to be established whether such individuals have a form of preclinical disease. There are three main types of α-synucleinopathy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with other rare disorders also having α-synuclein pathologies, such as various neuroaxonal dystrophies. Multiple clinical phenotypes exist for each of the three main α-synucleinopathies, with these phenotypes differing in the dynamic distribution of their underlying neuropathologies. Identifying the factors involved in causing different α-synuclein phenotypes may ultimately lead to more targeted therapeutics as well as more accurate clinical prognosis.

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 (

Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits.

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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.

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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