S. E. Daniel

We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.

Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), e.g., rises in the level of the DNA damage product, 8-hydroxy-2'-deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8-hydroxyguanine (8-OHG) tended to be elevated and levels of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (ONOO-) or hydroxyl radicals (OH.), or to be a prooxidant effect of treatment with L-Dopa. However, some or all of the rise in 8-OHG could be due to a change in 8-OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage.

We report the clinicopathological features of 203 cases of pathologically proven multiple system atrophy (MSA) from 108 publications up to February 1995. The majority of patients showed symptoms in their early fifties, and men were more commonly affected than women (ratio of 1.3:1). Most patients suffered from some degree of autonomic failure (74%). Parkinsonism was the most common motor disorder (87%), followed by cerebellar ataxia (54%) and pyramidal signs (49%). The response to levodopa was poor in most patients, but there was a subgroup with a good response, who also often developed axial levodopa-induced dyskinesias. Other characteristic features included severe dysarthria, stridor, and, in a few patients, contractures and dystonia (antecollis). Mild or moderate intellectual impairment occurred in some cases, but severe dementing illness was most unusual. The main pathological change comprised cell loss and gliosis in the putamen, caudate nucleus, external pallidum, substantia nigra, locus ceruleus, inferior olives, pontine nuclei, cerebellar Purkinje cells, and intermediolateral cell columns of the spinal cord. However, other neuronal populations were also involved to varying degrees, such as the thalamus, vestibular nucleus, dorsal vagal nucleus, corticospinal tracts, and anterior horn cells. Characteristic glial and/or neuronal cytoplasmic inclusions were identified in all cases in which they were sought, irrespective of clinical presentation. Akinesia correlated with the degree of nigral and putaminal cell loss, whereas rigidity was related only to the later. Tremor was unrelated to cell loss at any site. Ataxia correlated with the degree of olivopontocerebellar atrophy. Pyramidal signs were associated with pyramidal tract pallor. Our analysis also confirmed an association of postural hypotension with intermediolateral cell column degeneration.

The UK Parkinson's Disease Society Brain Bank receives tissue from patients with Parkinson's disease and a variety of different movement disorders. Half of the brain is used for full neuropathological examination prior to allocation for specific research projects. Clinical misdiagnosis occurs in a significant proportion of cases and clinico-pathological correlation provides valuable information for disease recognition. With the expanding number of other specialist brain banks there is a need for agreement on diagnostic criteria. Furthermore, awareness of different methods of tissue handling is essential.

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Pick's disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Pick's disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria.