Functional neuropathology in Parkinson's disease.

The pathophysiology of akinesia and chorea involve disruption of the motor basal ganglia circuit. This circuit begins with cortical output to the striatum, followed by projections from striatum to pallidum, pallidum to thalamus, and finally thalamus to cortex. Abnormal thalamic output to the frontal cortex, particularly the supplementary motor cortex, is responsible for chorea and akinesia. The substantia nigra and subthalamic nucleus are also important parts of this circuit. Chemical or pathological changes in these nuclei that lead to reduced thalamic outflow to the cortex are associated with parkinsonism. Most disorders affect the nigrostriatal dopaminergic projection. The overall consequence of loss of nigrostriatal dopamine is a loss of inhibitory input to the striatum. This feeds through the circuit resulting in reduced thalamic outflow. Local factors that may affect symptoms are the degree of dopamine loss, the involvement of ventral or dorsal parts of substantia nigra, effect on direct and indirect pallidal pathways, topographical representation of the body in the striatum, and the presence of parallel basal ganglia circuits serving cognition and mood. Ageing, dopa-responsive dystonia, juvenile dystonia-Parkinson syndrome and Parkinson's disease have different effects on the nigrostriatal tract. In Parkinson's disease the speed and regional variation in nigrostriatal dopamine loss are associated with a significant pre-symptomatic period, steady rate of progression and a particular topography of L-dopa dyskinesias.

A prion disease with a novel 96-base pair insertional mutation in the prion protein gene.

There are coding mutations in the prion protein gene in familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease, and other phenotypes that make up the inherited prion diseases. Insertional mutations consisting of two, five, six, seven, eight, and nine additional octapeptide repeat elements are seen in the inherited prion diseases and usually present as atypical dementias with considerable intrafamilial phenotypic variability. A four-octarepeat insertion was reported previously in an individual without neurodegenerative disease who died of hepatic cirrhosis. Here we report a novel four-octarepeat insertional mutation in a case with classical clinical, electroencephalographic and histopathologic features of CJD with the unusual finding of pronounced prion protein immunoreactivity of the molecular layer of the cerebellum.

Dopa-responsive dystonia: pathological and biochemical observations in a case.

We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive dystonia.

Age-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The effect of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on juvenile (6-8 months), young adult (2-4 years) and aged (8-10 years) common marmosets were compared. Juvenile marmosets were more resistant to the actions of MPTP and required a greater cumulative dose over a longer period to induce the same degree of motor disability observed in older animals. Young adult and aged marmosets showed an equivalent motor recovery in the 4-5 weeks following cessation of MPTP treatment, but juvenile animals were less able to compensate for the motor impairments. Losses of putamen [3H]dopamine uptake and caudate nucleus dopamine content were equivalent in young adult and aged animals. However, juvenile animals showed a more marked degree of dopamine depletion and reduction in [3H]dopamine uptake. Histological analysis showed cell loss in the substantia nigra to be most prominent in juvenile animals although it was evident in all groups. No loss of cells in the locus coeruleus was apparent in any of the groups studied, and no intraneuronal eosinophilic inclusions were seen. Greater nigral cell loss and dopamine depletion were required in juvenile animals to impair motor function. The degree of behavioural recovery was less in juvenile animals than in young adult and aged marmosets. The extent of behavioural recovery appeared linked to the severity of cell loss and was not reduced in old age.

Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson's disease.

The anatomy of melanin-containing neurons and other midbrain structures was examined by tyrosine hydroxylase (TH), calbindin D28k, and substance P immunostaining. Greater than 95% of cells in the substantia nigra pars compacta contained melanin, but densely packed cells in a ventral tier had a low content of melanin and loosely packed cells in a dorsal tier had a high content of melanin. Approximately 60% in the gamma group and 40% in the retrorubral nucleus had a low content of melanin. TH immunostaining was moderate in both the ventral and dorsal tiers, but more intense in the gamma group and retrorubral nucleus. Calbindin D28k was absent from the ventral and dorsal tiers, but present in the gamma group and retrorubral nucleus. In the light of primate tracing studies these findings suggest that the ventral tier of the pars compacta projects to striosomes of the striatum and the dorsal tier, gamma group and retrorubral nucleus to the matrix compartment. The ventral tier is more vulnerable than the dorsal tier in Parkinson's disease, but the cells contain less melanin. Neither tier contains calbindin D28k. This differential vulnerability between the ventral and dorsal tiers cannot be explained by melanin or calbindin D28k.

Neuropathology of Parkinson's disease and related syndromes.

A progressive parkinsonian disorder predicts pathology in the substantia nigra and possibly elsewhere in the basal ganglia. Parkinson's disease is a manifestation of Lewy body disease, which is characterized by the association between Lewy bodies and cell degeneration in specific neuronal populations. Striatonigral degeneration is part of multiple system atrophy and is characterized by striatal and nigral degeneration without neuronal inclusion bodies, but glial inclusions have been described. Steele-Richardson-Olszewski disease is characterized by the globose neurofibrillary tangle and predominant brain stem pathology. Corticobasal degeneration shows similar midbrain pathology and a round, filamentous inclusion in the substantia nigra, not unlike the globose tangle, but there is also focal frontoparietal cortical atrophy. The combination of the distribution of degeneration and nerve cell morphology identify apparently distinct disorders, but most of the neuronal inclusions are not disease specific.

Severe generalised dystonia associated with a mosaic pattern of striatal gliosis.

A mosaic pattern of striatal pathology is described in a male who developed severe generalised dystonia from the age of 10 years, and died at the age of 18 years. There was no family history of dystonia, and extensive investigations during his life failed to identify a cause for the dystonia. The caudate nucleus and putamen showed a network of cell loss and gliosis surrounding islands of preserved striatum. Dorsal parts showed confluent gliosis, and ventral parts were spared. The pattern suggested a correlation with patch-matrix organisation, but there was no correlation with the distribution of calbindin immunoreactive cells, which are present in the matrix of the classical striosome-matrix organisation. The pathological findings were unlike those in status marmoratus, perinatal hypoxia-ischaemia, Huntington's disease, and neuroacanthocytosis, but similar to those reported in a 44-year-old man with predominantly cranial dystonia.

New pathologic observations in juvenile onset parkinsonism with dystonia.

A patient with hereditary juvenile onset parkinsonism with dystonia died at age 39. There were Lewy bodies and regionally selective neuronal damage in the substantia nigra pars compacta. These changes closely resemble those seen in Parkinson's disease, and emphasize the selective vulnerability of the ventral tier of the pars compacta in these degenerations.

Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease.

In six control subjects pars compacta nerve cells in the ventrolateral substantia nigra had a lower melanin content than nerve cells in the dorsomedial region. This coincides with a natural anatomical division into ventral and dorsal tiers, which represent functionally distinct populations. In six cases of Parkinson's disease (PD) the ventral tier showed very few surviving nerve cells compared with preservation of cells in the dorsal tier. In 13 subjects without PD, but with nigral Lewy bodies and cell loss, the degenerative process started in the ventral tier, and spread to the dorsal tier. This pattern of selective degeneration of nigrostriatal neurons is not seen in ageing or after acute administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

Neuropathology of the substantia nigra.

Neuronal subpopulations of the substantia nigra pars compacta can be separated into two functionally distinct nigrostriatal projections, the ventral tier which is poorly melanised, and the dorsal tier which is well melanised. In Parkinson's disease, juvenile-onset parkinsonism with dystonia and striatonigral degeneration the ventral tier is more vulnerable than the dorsal tier. The ventral tier mostly projects to the putamen, which is vulnerable in striatonigral degeneration and Huntington's disease. In Huntington's disease spiny neurons of the striatal matrix and neurons of the pars reticulata are particularly susceptible. Determining patterns of selective neuronal death may lead to identification of pathogenetic mechanisms.

Neuronal inclusions of Parkinson's disease.

Two distinct neuronal inclusions occur in Parkinson's disease. The Lewy body is the diagnostic hallmark and is recognized by its eosinophilic body and unstained halo. It can be found in specific regions of the nervous system, where its frequency, size, shape, and structure differ. Large neurons of the dorsal vagal nucleus and sympathetic ganglia often contain particularly large quantities of Lewy-body-like matter. It consists of filament in the outer part and electron dense material in the core, the outer part staining with silver and with antibodies to neurofilament and tubulin. The pale body is restricted to the substantia nigra and locus ceruleus. It does not react with conventional stains, silver, or neurofilament antibodies, and has a homogeneous structure with a granular and vesicular surface texture. It contains sparse granular matter, vacuoles, and filaments, surrounded by melanin. The Lewy body and pale body may be juxtaposed or contiguous in some cells, but their distinct appearances and structures indicate that they are separate inclusions.

1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) is less neurotoxic than MPTP in the common marmoset.

Four adult marmosets were treated with increasing doses of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in the range 0.23-4.3 mg/kg i.p. to give a cumulative dose of 11.0-11.6 mg/kg over a 6-10 day period. After 4 days of treatment, and as the dosage was gradually increased, the animals exhibited mild motor deficits. These abnormalities slowly declined over the following 1-6 week period. In contrast, similar treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 3-5 days in a cumulative dose of 6.9-9.2 mg/kg produced gross impairment of motor function which persisted throughout the 5 weeks period of observation. Administration of 2'-methyl-MPTP for 6-10 days caused some decrease in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) content in the caudate nucleus in animals 5-6 weeks after the start of treatment. There was a small decrease in [3H]dopamine uptake into putamen synaptosomes. This contrasted with the marked decreases in all these parameters observed after MPTP treatment of common marmosets. Histological examination of the substantia nigra from the four animals treated with 2'-methyl-MPTP did not show degeneration or loss of dopamine-containing cell bodies in the zona compacta. In contrast, MPTP caused severe destruction of these pigmented nigral neurones. In the common marmoset 2'-methyl-MPTP does not appear to show the same neurotoxic action as MPTP itself. This contrasts with findings in the mouse where 2'-methyl-MPTP is more toxic to dopamine-containing cells of substantia nigra than MPTP.