Transmission of fatal familial insomnia to laboratory animals.
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Animals↗
Biomedical subjects
P Lantos
Publications and source records attributed to P Lantos.
Evidence for persistent enterovirus infection of the central nervous system in patients with previous paralytic poliomyelitis.
It has been suggested that late onset neurological deterioration after poliomyelitis may be due in some cases to persistent poliovirus infection of the central nervous system. In view of this, we decide to determine whether polioviruses and other enteroviruses can persist in the central nervous system. In a previous study, one of us (M.K.S.) reported serological evidence of persistent poliovirus infection of the central nervous system (CNS) in a proportion of these patients. We have now studied cerebrospinal fluid (CSF) from these patients for the presence of enterovirus RNA sequences using the polymerase chain reaction (PCR). Enteroviral RNA was detected in 3 of 24 patients with a clinical diagnosis of post-polio syndrome, but in none of 36 patients with stable poliomyelitis, and none of 36 patients with other neurological conditions of noninfective origin. All 3 patients in whom viral RNA was detected had high intrathecal levels of poliovirus-specific oligoclonal IgM bands. In a second study we examined formalin-fixed postmortem CNS tissue from 7 patients with a history of paralytic poliomyelitis. Enterovirus RNA was detected in tissue from the spinal cord from 3 patients, but not in the cerebral cortex. We are now conducting a larger prospective, blind study of patients with evidence of late deterioration. Analysis of the first 30 patients studied revealed the presence of enterovirus RNA in CSF of 1 of 4 patients with unexplained late-onset post-polio weakness, 1 of 6 with some evidence of clinical deterioration, but none of 20 without inexplicable signs of post-polio weakness. Enteroviral RNA was also detected in spinal cord from 2 of 3 patients who died from other causes during this study. These studies provide virological evidence that enteroviruses may persist in the CNS of man. Further study is required in order to understand fully the biological and clinical significance of these findings.
Adolescent↗
Clinical features of early onset, familial Alzheimer's disease linked to chromosome 14.
Early onset familial Alzheimer's disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the beta-amyloid precursor protein (beta APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with beta APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val-->Ile) or a valine to glycine (Val-->Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the beta APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the beta APP717 Val-->Ile and beta APP717 Val-->Gly encoded families that have been previously described.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Spatial data analysis in the quantitative assessment of cerebral white matter pathology on MRI in HIV infection.
This study was carried out using MRI (proton density--and T2-weighted) on 16 HIV-negative controls, 9 symptom-free HIV-positive patients and 25 with CDC IV HIV disease. The studies from this last group had previously been allocated by a radiologist to the following categories: 8 with focal mass lesions and normal-appearing white matter; 9 with diffuse encephalopathy (high signal on T2-weighted images, affecting most or all of the white matter) and 8 with patchy encephalopathy (high signal affecting only one or two areas within the white matter). Moran's I, a statistic of spatial autocorrelation, was calculated for the grey-scale values of a sampled pixel array from a central white matter region of each of the images. All values of Moran's I calculated in this study showed a large positive excess over the expected value under randomisation, indicating highly significant positive auto-correlation in the spatial arrangement of the grey-scale values. On T2-weighted images a statistically significant increase in the mean value of Moran's I, compared with controls, was found in the diffuse encephalopathy group, indicating that quantifiable changes in the spatial autocorrelation of pixel data can be related to recognised qualitative changes in the appearance of white matter in subjects with HIV disease. A lesser, but significant, rise in the mean value of Moran's I was also found in the focal mass lesion group, suggesting that changes in spatial autocorrelation may indicate pathological change in advance of qualitative MRI changes.
AIDS Dementia Complex↗
Decreased expression of AMPA receptor messenger RNA and protein in AIDS: a model for HIV-associated neurotoxicity.
HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA and protein of the GluR-A flop subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor in cerebellar Purkinje cells. Although Purkinje cells are relatively resistant to loss, the observed disturbance of AMPA receptors may contribute to the neurotoxic process in other vulnerable brain regions and clinically to the development of dementia.
AIDS Dementia Complex↗
Assessment of neuronal density in the putamen in human immunodeficiency virus (HIV) infection. Application of stereology and spatial analysis of quadrats.
Human immunodeficiency virus causes neuronal loss in various brain regions, but it has not been reported in the putamen. However, decrease in the volume of the putamen has been observed by magnetic resonance imaging. In order to clarify this issue two complementary methods; the stereological probe, the disector, and spatial analysis of quadrats, were applied in nondemented individuals who had died of acquired immune deficiency syndrome. A 21% decrease in neuronal density was observed in the human immunodeficiency virus group, especially those cases with human immunodeficiency virus encephalitis; however the statistical significance of this finding was borderline.
Acquired Immunodeficiency Syndrome↗
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 Alzheimer's 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.
Alzheimer Disease↗
Lewy bodies and response to tacrine in Alzheimer's disease.
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Alzheimer Disease↗
Neuronal density in the superior frontal and temporal gyri does not correlate with the degree of human immunodeficiency virus-associated dementia.
Human immune deficiency virus (HIV) disease may be associated, neuropathologically, with significant neuronal loss and clinically with a severe dementia. However, the significance of neuronal loss in the development of dementia has not been established. In this study we have undertaken a stereological determination of the neuronal numerical density and neuronal volumes in post mortem tissue from the superior frontal and superior temporal gyri in 32 patients who died of acquired immune deficiency syndrome (AIDS). All were prospectively clinically characterized, with dementia identified or excluded, and antiretroviral medication documented. This study combines morphometric techniques with prospective clinical assessment of dementia. As previously demonstrated, all patients dying with AIDS showed neuronal loss, but this was not related to the presence of HIV-associated dementia.
AIDS Dementia Complex↗
Alzheimer's disease families with amyloid precursor protein mutations.
Early onset Familial Alzheimer's Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C-terminus of the beta-amyloid domain, APP 717 val-ile, APP 717 val-phe, and APP 717 val-gly, which are associated with autopsy-proven Alzheimer's disease (AD). APP 670/671 lies at the N terminus of the beta-amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val-ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive beta-amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val-gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of beta-amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.
Alzheimer Disease↗
A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia.
Over the past decade it has been realized that HIV affects the central nervous system, and various investigations have illuminated the spectrum of neuropathology in AIDS. One major advance has been the demonstration that there is substantial neuronal loss, which appears independent of the HIV-associated inflammatory lesions. Quantitative studies on neuronal populations, while fraught with methodological difficulties, are essential to the understanding of the mechanism of this neurotoxic damage. This article will review, firstly, the modern stereological procedures available for quantitative investigations; secondly, the pattern, degree and time scale of HIV-associated neuronal loss; thirdly, other morphological evidence of neuronal damage; and finally, the pathological and clinical implications of these findings.
AIDS Dementia Complex↗
Familial progressive supranuclear palsy.
A progressive extrapyramidal syndrome and dementia occurred in three members of one family. The age of onset was in the seventh decade and the affected individuals showed many of the clinical features of progressive supranuclear palsy (PSP). Necropsy of one individual revealed the neuropathological features of PSP. We propose that this family has a familial form of PSP and review the evidence in the literature that a familial form exists.
Aged↗
Neuropathological correlates of behavioural disturbance in confirmed Alzheimer's disease.
Clinico-pathological correlations were examined in 54 patients with neuropathologically verified Alzheimer's disease (AD) who were part of a prospective study. Behavioural disturbance was documented using an expanded version of the Stockton Geriatric Rating Scale (SGRS). The subscores for physical disability (P), apathy (A) and communication failure (C) (summation score PAC) were closely correlated and were high in most patients during the late stages of illness. High PAC scores correlated with an earlier onset and longer duration of illness, lower brain weight, more severe tangle pathology in the parahippocampal gyrus and the frontal and parietal neocortex, and lower neuron counts in the hippocampus and basal nucleus of Meynert. Features of the Klüver-Bucy syndrome (range behaviour and hypermetamorphosis) were significantly associated with lower counts of large neurons in the parahippocampal gyrus and parietal neocortex, but not with more severe plaque or tangle formation or with neuronal loss in the subcortical nuclei. No correction was made for multiple comparisons. These findings may signify decreased cortical inhibition in patients with relatively well preserved subcortical structures who show features suggestive of the Klüver-Bucy syndrome. High PAC scores on the SGRS could reflect more advanced and widespread cerebral pathology in the end stages of AD.
Activities of Daily Living↗
Neuronal loss in symptom-free HIV infection.
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Acquired Immunodeficiency Syndrome↗
Neurologic signs in Alzheimer's disease. Results of a prospective clinical and neuropathologic study.
Neurologic signs and their neuropathologic correlates were examined in a sample of 56 patients with autopsy-proved Alzheimer's disease (13 men, 43 women; mean age at death, 83.1 years; range, 67 to 96 years) from a prospective longitudinal study. Full-range regular rigidity with cog-wheeling was found in 20 patients and was significantly associated with lower neuron counts in the substantia nigra and with the presence of Lewy bodies in the brain stem and neocortex. Twelve patients with myoclonus had a younger age at onset, a lower age at death (mean, 78.6 years), and lower neuron counts in the serotoninergic dorsal raphe nucleus and in the noradrenergic locus coeruleus than did the patients without myoclonus. Generalized motor seizures were reported in six patients, and they had significantly lower counts of pyramidal cells in cortical layers III through IV of the parietal cortex (area 7) and slightly decreased pyramidal cell numbers in the parahippocampal gyrus (area 28). The 19 patients with a positive grasp reflex had an earlier onset of illness and a significantly inferior performance on the Mini-Mental State examination and Cambridge Cognitive Examination tests. They, and 25 patients with a positive snout reflex, had significantly lower counts of large pyramidal cells in layers III through V of the frontal cortex (area 32). These results indicate that different neurologic symptoms in Alzheimer's disease can be related to disproportionate neuronal degeneration in functionally different brain areas.
Aged↗
Clinical and neuropathological correlates of depression in Alzheimer's disease.
Depressive symptoms have been reported in patients with mild to moderate Alzheimer's 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.
Aged↗
[Organic correlates of depressive symptoms in Alzheimer's dementia. Results of a prospective study, review of the literature].
The diagnosis of Alzheimer's disease (AD) was verified at post-mortem examination in 46 patients (9 male: 37 female; mean age 83.6 +/- 6.5 years) from a prospective clinical study. Compared to 10 age-matched controls, the total AD group showed a significant neuronal loss in the locus coeruleus, dorsal raphe nucleus, substantia nigra and in the basal nucleus of Meynert. Twelve patients (1 male: 11 female) had experienced symptoms of depression. These patients had significantly lower neuronal counts in the locus coeruleus, but less severe cell loss in the basal nucleus of Meynert compared to the AD patients without depression.
Aged↗
Accuracy of clinical diagnosis of Alzheimer's disease.
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Aged↗