The possibility of gene interactions in Alzheimer's disease (AD) has been suggested by the finding of an association of the AA genotype of the alpha-1 antichymotrypsin (AACT) gene and the apolipoprotein E (apoE) epsilon 4/4 genotype in AD. We tested this possibility by genotyping a large series of clinically and neuropathologically confirmed cases of AD and a series of cases with dementia with Lewy bodies (DLB) with a matched control group for the AACT locus and apoE. ApoE genotyping showed the established finding of an increased frequency of the apoE epsilon 4 allele in AD and in DLB. The AD and DLB groups differed between each other with a higher epsilon 2 allele frequency and a reduced incidence of the epsilon 4/4 genotype in DLB. Differences in the apoE frequencies may account for some of the differences between the two diseases. No association was found for the AACT A allele in AD or DLB in the groups as a whole or when stratified with respect to apoE, with the exception of a trend showing an increased incidence of the apoE epsilon 4/4 AACT AA genotype combination in AD patients (chi 2 = 3.18, p = 0.07), although in DLB this was not apparent (chi 2 = 0.0, p = 1.0). The AACT A allele is not a major risk factor for late-onset AD or DLB.
Using the monoclonal antibody ME 20.4, p75 nerve growth factor (NGF) receptor immunoreactivity has been studied in the hippocampus and adjacent cortex in a series of 57 cases ranging in age from 24 weeks gestation to 95 years of age. The activity of the neurotransmitter-synthesizing enzyme choline acetyltransferase (ChAT), the activity of which is regulated by NGF, has also been determined in parallel experiments. p75 NGF receptor immunoreactivity was detected in the fetal neocortex as nerve terminal staining, potentially derived from basal forebrain neurons which were positive for NGF receptor, and was also localized in nerve cells of the cerebral cortex. Cortical reactivity for NGF receptor increased with age up to the 4th decade thereafter remaining constant. NGF receptor reactivity localized to neocortical neuronal cell bodies was not present in the postnatal or adult brain. Hippocampal reactivity for the NGF receptor was not present before birth appearing first in the postnatal period and thereafter showing an identical development pattern to the neocortex. ChAT activity in the entorhinal cortex and hippocampus partially paralleled NGF receptor development being present in the neocortex in the fetus but not in the fetal hippocampal formation and increasing postnatally to reach maximum levels in the 4th decade. Whilst entorhinal cortex ChAT values remain relatively constant with ageing, hippocampal ChAT declined with age after the 4th decade. The results may have implications for the aetiology of age-related cholinergic deficits in the hippocampus.
A retrospective survey of 100 patients dying from carcinoma of the lung showed that neurological presentation and central nervous system metastases are more frequently present when the primary carcinoma is situated in the peripheral lung tissue (including lung apex). The high incidence of cases presenting neurologically and the high incidence of single secondary deposits involving the central nervous system from peripheral or apical growths suggest a difference in the mode of spread or other properties of such growths compared with the more common central carcinoma.
Alzheimer's disease (AD) and vascular dementia (VaD) are two of the common dementias in the elderly. Imaging studies have demonstrated white matter changes of vascular etiology to occur in both disorders. While there have increased efforts to differentiate white matter pathology by quantitative magentic resonance imaging in these disorders there is no clear consensus. We assessed white matter lesions in brains of the first 100 demented patients who came to autopsy from our prospectively evaluated series. We examined the extent of axonal pathology by conventional methods including LFB for myelin, and amyloid‐β precursor protein (AβPP) immunocytochemistry with antibodies to 22C11. AβPP has recently been used to examine axonal injury in head trauma. Our results indicated AβPP reactive accumulation along white matter tracts in the temporal cortex encompassing the hippocampal formation to be common. The highest reactivity was evident in tissue from VaD subjects compared with that from AD or dementia with Lewy bodies (DLB). Compared with conventional myelin stains, AβPP immunocytochemistry was more sensitive to visualize subtle changes. We suggest AβPP immunocytochemistry is a useful index to assess ischaemic white matter lesions to differentiate dementias. Acknowledgements: Supported by the MRC (UK), Alzheimer's Research Trust (UK) and Alzheimer's Association (USA).
Nerve growth factor (NGF) receptor-like immunoreactivity has been demonstrated in the normal human adult spinal cord using the monoclonal antibody ME20.4. Intense immunoreactivity was associated with fibres and terminals in the substantia gelatinosa. In lamina IX the neuropil demonstrated punctate staining, the motor neurons themselves being negative. At thoracic levels occasional neurons of the intermediolateral column cell group were NGF receptor positive. Fine axonal and punctate terminal reactivity was observed in the gracile fasciculus, corresponding to axons in transverse section. Similar, though slightly less dense immunoreactivity was observed in the cuneate fasciculus. The demonstration of NGF receptor immunoreactivity may provide a useful marker of sensory innervation in the human spinal cord.
Hyperoxia and mechanical ventilation cause acute lung injury which may be mitigated by prophylactic intratracheal (IT) administration of recombinant human CuZn superoxide dismutase (rhSOD). However, little is known about the localization, activity, and metabolism of rhSOD after IT administration by instillation or nebulization. Twenty-six newborn piglets were intubated, mechanically ventilated, and given either saline or fluorescently labeled rhSOD (5 mg/kg IT) by instillation or nebulization. Animals were killed 1, 6, or 12 h later. Intact rhSOD (% total fluorescence still associated with macromolecules) and total SOD activity in lung tissue were then determined. Results indicate that, after 1 and 6 h of administration, the majority of rhSOD present in the lung was still associated with the fluorescent label. By 12 h, most of the rhSOD was no longer fluorescently labeled. At 1 h, lung SOD activity increased by 100% compared with untreated control values, with activity remaining elevated at 6 and 12 h. Laser confocal microscopy of lung tissue showed that at 1 h, labeled rhSOD was found throughout the lung, inside a variety of cell types of airways, respiratory bronchioles, and alveoli. Deposition was more homogeneous after nebulization. Negative controls had minimal background fluorescence. These data indicate that after IT administration, rhSOD is rapidly incorporated into cells in the lung and significantly increases lung SOD activity. These observations have important implications for the clinical use of rhSOD in human trials.
Two alternative hypotheses – that there is either a unitary or a multiple neuropathological basis for dementia in diseases associated with Lewy bodies – are considered in relation to Parkinson's disease (PD) and Lewy body dementia (LBD including senile dementia of Lewy body type, SDLT). Densities of limbic (cingulate) cortical Lewy bodies, neocortical Lewy bodies, neocortical plaques, neocortical tangles, Braak staging, and Apo E frequency have been quantified in PD (demented and nondemented), SDLT, and Alzheimer's disease (AD with presenile and senile onset). Of these parameters the mean density of cingulate Lewy bodies is significantly greater in SDLT compared with all PD cases. There is no obvious correlation between Lewy body density and cognitive impairment assessed using a simple test of mental ability, and other measures of mental function in LBD may need to be considered. Since there is no absolute density of limbic Lewy bodies that clearly differentiates SDLT or demented PD cases from all nondemented PD cases, neuropathological criteria may need to incorporate severity of Alzheimer-type pathology as an additional optional factor. Mean neocortical plaque density is significantly lower in SDLT compared with AD cases but it is also significantly higher than in demented and nondemented PD cases, and higher than densities in normals. Even so, neocortical plaque density does not itself differentiate all SDLT cases from the normal. It is likely that the biological basis for dementia or psychoses in LBD, a cardinal feature of which is fluctuating symptomatology, is in part a functional or neurochemical abnormality.
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