Peter L. Lantos

The same prion strain causes vCJD and BSE

Epidemiological and clinicopathological studies, allied with pathological prion protein (PrPSc) analysis, strongly support the hypothesis that the human prion disease new variant Creutzfeldt-Jakob disease (vCJD) is causally related to bovine spongiform encephalopathy (BSE),, but considerable controversy remains. Distinct prion strains are distinguished by their biological properties on transmission to laboratory animals and by physical and chemical differences in PrPSc strains. We now find that the biological and molecular transmission characteristics of vCJD are consistent with it being the human counterpart of BSE.

Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome)

Glial cytoplasmic inclusions (GCIs) were demonstrated by silver staining, immunocytochemistry and by electron microscopy in the central nervous system (CNS) of 11 patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome. Although their configuration in light microscope can sometimes resemble neurofibrillary tangles, their cellular localisation, measurements, ultrastructure, immunocytochemical characteristics and regional distribution all differ from these Alzheimer type changes. The majority of GCIs were localized in the white matter and appeared to be accompanied by an increase in the number of interfascicular oligodendroglial cells and pallor or loss of myelin staining. Our histological, ultrastructural and immunocytochemical findings all indicate that the cells which contain GCIs are oligodendrocytes and the inclusions themselves are composed of tubular structures. The presence of the until now unknown GCIs in all the 11 CNS, but not in age- and sex-matched control brains, indicates that GCI is a cellular change characteristic of multiple system atrophy and the three syndromes are various manifestations of the same disease.

Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples

BACKGROUND Prion diseases are associated with the accumulation of an abnormal isoform of cellular prion protein (PrPSc), which is the principal constituent of prions. Prions replicate in lymphoreticular tissues before neuroinvasion, suggesting that lymphoreticular biopsy samples may allow early diagnosis by detection of PrPSc. Variant Creutzfeldt-Jakob disease (variant CJD) is difficult to distinguish from common psychiatric disorders in its early stages and definitive diagnosis has relied on neuropathology. We studied lymphoreticular tissues from a necropsy series and assessed tonsillar biopsy samples as a diagnostic investigation for human prion disease. METHODS Lymphoreticular tissues (68 tonsils, 64 spleens, and 40 lymph nodes) were obtained at necropsy from patients affected by prion disease and from neurological and normal controls. Tonsil biopsy sampling was done on 20 patients with suspected prion disease. Tissues were analysed by western blot to detect and type PrPSc, by PrP immunohistochemistry, or both. FINDINGS All lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD, but not from patients with other prion diseases or controls, were positive for PrPSc. In addition, PrPSc typing revealed a consistent pattern (designated type 4t) different from that seen in variant CJD brain (type 4) or in brain from other CJD subtypes (types 1-3). Tonsil biopsy tissue was positive in all eight patients with an adequate biopsy sample and whose subsequent course has confirmed, or is highly consistent with, a diagnosis of variant CJD and negative in all patients subsequently confirmed to have other diagnoses. INTERPRETATION We found that if, in the appropriate clinical context, a tonsil biopsy sample was positive for PrPSc, variant CJD could be diagnosed, which obviates the need for a brain biopsy sample to be taken. Our results also show that variant CJD has a different pathogenesis to sporadic CJD.

Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies

α-Synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinsons disease and dementia with Lewy bodies. Here we show that α-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that α-synucleinopathies constitute a major class of human neurodegenerative disorder.

Preliminary NINDS neuropathologic criteria for Steele‐Richardson‐Olszewski syndrome (progressive supranuclear palsy)

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 brainstem 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 Alzheimers 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.

Neuronal loss in the frontal cortex in HIV infection.

In an attempt to elucidate the cause and mechanism of the dementia and other neurological disorders that can occur in HIV-1 infection, we have quantitatively assessed neuronal populations, by means of a stereological technique (the disector), in the frontal cortex of patients with HIV infection. Eleven of sixty-five brains in the Medical Research Council Central AIDS Brain Bank were selected for study. The selected patients died without opportunistic infection or neoplasm affecting the brain; they had HIV encephalitis or minimal changes. We compared their neuronal counts with those of eight control subjects (seven died of systemic illness, one of pontine haemorrhage which did not affect the cerebral hemispheres). The neuronal numerical density was significantly lower in the HIV group than in the control group (mean [SD] 307 [46] vs 499 [113] x 10(2) per mm3; p less than 0.001). This difference represents a loss of about 38%. There was no significant difference between the HIV subgroups, which suggests that neuronal loss occurs in cases of minor pathology as well as in HIV encephalitis. This finding contributes to the understanding of dementia in AIDS patients and has important implications for their future treatment.

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders

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 Picks 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 Picks 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

Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease

Activity of the enzyme which synthesizes acetylcholine, choline acetyltransferase, was estimated in the neocortex of three series of control and demented cases. Clinically demented cases were divided into those with the classical neuropathological features of Alzheimers disease (numerous neocortical plaques and tangles) and those with Lewy bodies in the brain stem and cortex (together with plaques and variable neurofibrillary pathology). In the Lewy body cases neocortical choline acetyltransferase was consistently lower than in the classical Alzheimer-type cases. Two of the Lewy body cases with extremely low cholinergic activity were responders in therapeutic trials of the cholinesterase inhibitor, tacrine, and the combined data suggest that cholinergic therapy may be particularly relevant to patients with Lewy body type dementia.

Neuropathology of early HIV-1 infection

Early HIV‐1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV‐1 carriers remain neurologically unimpaired during the so called “asymptomatic” period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre‐AIDS stages are very few, and the natural history of central nervous system changes in HIV‐1 infection remains poorly understood. Examination of brains of asymptomatic HIV‐1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV‐1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T‐cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV‐1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV‐1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV‐1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV‐1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T‐lymphocytes, continuously inhibits viral replication at that stage.

Clinical and neuropathological correlates of depression in Alzheimer's disease.

Depressive symptoms have been reported in patients with mild to moderate Alzheimers disease (AD). Recent evidence suggests that a noradrenergic deficit originating from neuronal degeneration in brainstem nuclei may represent an organic correlate of these disturbances. We examined the neuropathological changes in the locus coeruleus (LC), substantia nigra (SN), basal nucleus of Meynert and cortex of 52 patients (12 male, 40 female, mean age 83.2 +/- 6.4 years) with pathologically verified AD. Fourteen patients (1 male, 13 female) showed signs of depression. The majority of these patients suffered from severe physical disability or sensory impairment and developed persistent delusions, but had less cognitive impairment. Neuronal counts in the LC were significantly lower than in the 38 patients without depression (36.9 +/- 14.0; 51.4 +/- 28.0 neuromelanin-pigmented cells per section per nucleus; F = 3.4, df = 1, 50, P = 0.04). Neuron counts were higher in the basal nucleus of Meynert in depressed AD patients and there were no differences of the neuron numbers in the SN. Depression (main effect; F = 4.5, P = 0.04) contributed significantly to the variance of neuronal counts in the LC, even when covarying for gender, age of onset, cognitive impairment and cortical Alzheimer pathology. The observed disproportionate loss of noradrenergic and cholinergic neurons in the LC and basal nucleus of Meynert may represent an important organic substrate of depression in AD.