Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinson's disease and age-matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Levels of iron, copper, zinc and manganese were measured by inductively coupled plasma spectroscopy in frozen postmortem brain tissue from patients with Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy with strionigral degeneration (MSA), and Huntington's disease (HD) compared with control subjects. Total iron levels were found to be elevated in the areas of basal ganglia showing pathological change in these disorders. In particular, total iron content was increased in substantia nigra in PD, PSP and MSA, but not in HD. Total iron levels in the striatum (putamen and/or caudate nucleus) were increased in PSP, MSA and HD but not in PD. Total iron levels were decreased in the globus pallidus in PD. There were no consistent alterations of manganese levels in basal ganglia structures in any of the diseases studied. Copper levels were decreased in the substantia nigra in PD, and in the cerebellum in PSP, and were elevated in the putamen and possibly substantia nigra in HD. Zinc levels were only increased in PD, in substantia nigra and in caudate nucleus and lateral putamen. Levels of the iron binding protein ferritin were measured in the same patient groups using a radio-immunoassay technique. Increased iron levels in basal ganglia were generally associated with normal or elevated levels of ferritin immunoreactivity, for example, the substantia nigra in PSP and possibly MSA, and in putamen in MSA. The exception was PD where there was a generalized reduction in brain ferritin immunoreactivity, even in the substantia nigra. An increase in total iron content appears to be a response to neurodegeneration in affected basal ganglia regions in a number of movement disorders. However, only in PD was there an increased total iron level, decreased ferritin content, decreased copper content, and an increased zinc concentration in substantia nigra. These findings suggest an alteration of iron handling in the substantia nigra in PD. Depending on the form in which the excess iron load exists in nigra in PD, it may contribute to the neurodegenerative process.

Reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were measured in various brain areas (substantia nigra, putamen, caudate nucleus, globus pallidus, and cerebral cortex) from patients dying with Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, and Huntington's disease and from control subjects with no neuropathological changes in substantia nigra. GSH levels were reduced in substantia nigra in Parkinson's disease patients (40% compared to control subjects) and GSSG levels were marginally (29%) but insignificantly elevated; there were no changes in other brain areas. The only significant change in multiple-system atrophy was an increase of GSH (196%) coupled with a reduction of GSSG (60%) in the globus pallidus. The only change in progressive supranuclear palsy was a reduced level of GSH in the caudate nucleus (51%). The only change in Huntington's disease was a reduction of GSSG in the caudate nucleus (50%). Despite profound nigral cell loss in the substantia nigra in Parkinson's disease, multiple-system atrophy, and progressive supranuclear palsy, the level of GSH in the substantia nigra was significantly reduced only in Parkinson's disease. This suggests that the change in GSH in Parkinson's disease is not solely due to nigral cell death, or entirely explained by drug therapy, for multiple-system atrophy patients were also treated with levodopa. The altered GSH/GSSG ratio in the substantia nigra in Parkinson's disease is consistent with the concept of oxidative stress as a major component in the pathogenesis of nigral cell death in Parkinson's disease.

References 1. Courchesne E, Yeung-Courchesne R, Press GA, et al. Hypoplasia of cerebellar vermal lobules VI md VII in autism. N Engl J Med 1988;318:1349-1354 2. Mirakanii JW, Courchesne E, Press GA. et al. Keduced cerehellar hemisphere size and its relationship to neural hypoplasia in autism. Arch Neurol 1989;46:689-694 3 . Courchesne E. Neuroanatomic imaging in autism. Pediatrics 1991;87:781-790 4. Courchesne E, Saitoh 0. Yeung-Courchesne R, et al. Abnormality of crrebellar vernii;in lobules V1 and VII in patients with infantile autism: identification of hypoplastic and hyperplasric subgroups with MR imaging. Am J Radio1 1994;162:123-130 5. Ritvo ER, Garber HJ. Cerebellar hypoplasia and autism. N Engl J Med 1988;3 19: 1 152 6. Kleiman MD, Neff S. liosinan NP. The brain in infantile autism: are posterior fotsa structures abnormal? Neurology 1992: 42:753-760 7. Piven J. Nehme E. Simon J, et RI. Magnetic resonance imaging in autism: measurement of the cerebellum. pons, and fourth ventriclr. Biol Psychiatry 1992;31:491-504 8. Schaefer GB. Thompson J N Jr. Bodensteiner JB. et al. Agerelated changes in rhe relative growth of the posterior fossa. J Child

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In the brains of humans and other mammals, there are two principal groups of cholinergic nuclei aside from those forming the cranial motor nuclei. One group lies in the forebrain and includes the nucleus basalis of Meynert. The second group lies in the hindbrain and includes the nucleus tegmenti pedunculopontinus (NPP) group Ch5. The basal forebrain cholinergic cell groups, which innervate widespread areas of the neocortex, undergo degeneration in Alzheimer disease and also in parkinsonism associated with dementia. We here report that the hindbrain NPP Ch5 cell group, thought to innervate many nuclei of the extrapyramidal motor system, the superior colliculus, and the substantia innominata, undergoes degeneration in idiopathic Parkinson disease and in the parkinsonian syndrome of progressive supranuclear palsy. These findings strongly suggest that degeneration in the brainstem in Parkinson disease is not confined to catecholamine-containing neurons, but that cholinergic neurons of the NPP are also vulnerable. The findings further raise the possibility that certain symptoms of Parkinson disease and progressive supranuclear palsy have their genesis in pathology of these cholinergic neurons.,The cardinal neuropathologic characteristics of Parkinson disease (PD) are massive cell loss in the dopamine-containing substantia nigra pars compacta (1, 2), with variable degeneration in other aminergic nuclei of the brainstem, and the appearance of intracellular Lewy bodies in neurons of both the hindbrain and forebrain (3). It is now recognized that in some if not most parkinsonian brains there is further a cholinergic defect and loss of neurons in the nucleus basalis of Meynert, the principal cholinergic nucleus of the forebrain (4-6). A matter of particularly active study in the past 5 years has been the possibility that cell loss in the nucleus basalis could underlie the dementia exhibited by some parkinsonian patients (5, 6).A second major set of cholinergic nuclei exists in the hindbrain (7-11), and one of these nuclei, the Ch5 group of Mesulam et al. (7), corresponds in location to one of the principal nuclei associated with the basal ganglia: the nucleus tegmenti pedunculopontinus (NPP) (11-13). Given the close association of the NPP with the extrapyramidal motor system (8, 14-18), we undertook a study of the NPP in autopsy material from the brains of persons who died with a diagnosis of idiopathic PD. We also determined the status of the nucleus in progressive supranuclear palsy (PSP), a parkinsonian syndrome associated with severe intellectual impairment (19 METHODSHistochemistry. Observations were made on postmortem specimens from the brains of four control individuals who died without known neurologic or psychiatric deficit, six patients who had suffered from PD, and three patients who had suffered from PSP. The diagnoses were confirmed postmortem on the basis of neuropathological examination and retrospective examination of clinical records. The mean ages were 85 ± 3 years (range 83-90 years) for the co...

The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls. In control brains, only iron, potassium, silicum, sodium, sulfur, and zinc were within the limit of detection of the technique. The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance. In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values. Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy. Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum. Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death. This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration.

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