Biomedical subjects

G C DeLuca

Publications and source records attributed to G C DeLuca.

6 recordsLinked to original sources

PubMed2006

The contribution of demyelination to axonal loss in multiple sclerosis.

The traditional notion that multiple sclerosis is a primary demyelinating disease has led to a plaque-centred view of both aetiology and the pathogenesis of disease progression. The presence of axonal loss has received increasing recognition. However, the relative roles of demyelination and axonal loss have not been fully clarified in multiple sclerosis nor have their possible interrelationships been elucidated. Post-mortem material from the cerebrum, brainstem and spinal cord of 55 multiple sclerosis patients (29 males) with an age range of 25-83 years (mean = 57.5 years) and length of disease history ranging from 2 to 43 years (mean = 17.1 years) was stained for myelin. Plaque load was calculated by summing the relative proportion of plaque area compared with total white matter area of the corticospinal and sensory tracts at each level. This was related to estimates of axonal density and of total axon number in these tracts in the spinal cord. Our results indicate that plaque load did not correlate with brain weight. Unexpectedly, after adjusting for sex, age and duration of disease, correlations between total plaque load and axonal loss in both the corticospinal tract and sensory tracts were weak or absent at each level investigated. Since there was little correlation between plaque load and axonal loss, the possibility that demyelination is not the primary determinant of spinal cord axonal loss warrants consideration.

Adult↗

PubMed2004

Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions.

Imaging studies in multiple sclerosis have shown that spinal cord atrophy correlates with clinical disability. The pathological substrate of atrophy has not as yet been investigated adequately. In order to determine the cause of spinal cord atrophy in multiple sclerosis, five different sections of the spinal cord were examined histopathologically in 33 controls and 55 multiple sclerosis cases. In the multiple sclerosis cases in each section the total lesion load and the cross-sectional area of the cord were measured. Multiple regression models were estimated, controlling for sex, age, duration of the disease and location of the cord sections. The multiple sclerosis cords were found to be significantly smaller than the controls. The duration of the disease played the most important role in determining cord atrophy. The degree of atrophy varied in different parts of the cord. Individual lesions played a minor role in local atrophy. Our findings suggest that axonal degeneration, possibly caused by the cumulative number of lesions in the brain and cord, or an alternative atrophic process, is responsible for spinal cord atrophy in multiple sclerosis, rather than tissue loss within individual lesions.

Adult↗

PubMed2004

Evidence of axonal damage in human acute demyelinating diseases.

UNLABELLED: Substantial axon damage, detected by immunostaining for beta amyloid precursor protein (betaAPP) has been demonstrated in acute demyelinating lesions in multiple sclerosis. AIMS: The present study aimed to determine if this was also the case in the other human acute demyelinating diseases, acute hemorrhagic leucoencephalitis (AHLE), acute disseminated encephalomyelitis (ADEM) and central pontine myelinolysis (CPM). METHODS: BetaAPP immunostaining was used as a marker of axonal damage in autopsy material from these conditions. RESULTS: Axonal damage was detected in all these conditions. Its extent varied within and between them. Axonal damage was largely confined to tissue adjacent to veins and venules in AHLE and ADEM but was unrelated to proximity to these vessels in CPM. CONCLUSION: Substantial axon damage occurs in fatal cases of AHLE, ADEM and CPM.

Acute Disease↗

PubMed2004

Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts.

Clinical, imaging, and pathological studies in multiple sclerosis have generally emphasized the relative preservation of axons in comparison with myelin. Recent evidence, however, demonstrates that axonal loss is also significant, affects long tracts such as the corticospinal and sensory tracts and relates closely to functional disability. Accordingly, the distribution and extent of this axonal loss is the focus of the current investigation. Post-mortem material of 55 multiple sclerosis patients and 32 matched controls was used to examine quantitatively the population of axons in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to the upper cervical spinal cord. Myelin- and axon-stained sections have been prepared to estimate the notional area and axon density, respectively of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction of the area and axon density at all levels investigated in multiple sclerosis cases when compared with controls. In contrast, the sensory tracts in multiple sclerosis cases showed a significant reduction in area and axon density only in the upper regions of the spinal cord. As has been found with MRI plaque load and T2 burden, correlations of axonal loss with duration of disease were not strong. Of the fibres lost in multiple sclerosis, we have found that small fibres (<3 microm2) seem to be particularly affected, with large fibres remaining relatively preserved in both the corticospinal and sensory tracts. In multiple sclerosis, axonal loss is widespread, and its extent is tract specific and size selective.

Adult↗

PubMed2004

TCR beta polymorphisms and multiple sclerosis.

A total of 267 families with two or more siblings with multiple sclerosis (MS) were genotyped with 14 restriction fragment length polymorphisms at the TCR beta locus. A nonparametric linkage analysis of the data showed no evidence for linkage to this locus (mlod=0.11). No significant allelic or haplotype transmissions were observed in the total sample of 565 patients. After stratification for the presence of HLA DRB1*15, an association was observed between the BV25S1*1-BV26S1*1-BV2S1*1 haplotype and MS (P=0.00089). This was not significant upon correction for multiple comparisons. It was also not significant when the haplotype frequency in affected individuals was compared to a normal control sample (P=0.77). Furthermore, the associated haplotype was followed-up in an independent sample of 97 nuclear families with a single DRB1*15-positive child with MS. The BV25S1*1-BV26S1*1-BV2S1*1 haplotype did not show significant evidence for transmission distortion but the same trend was seen (P=0.21). There were no significant associations observed in the DRB1*15-negative patients and no detectable difference was seen in the DRB1*15-positive BV25S1*1-BV26S1*1-BV2S1*1 association when comparing different subgroups based on clinical course of MS. These results show no evidence for linkage and fail to establish an association between MS susceptibility and the TCR beta locus.

Female↗

PubMed2002

Evidence for a role for apoptosis in central pontine myelinolysis.

We have performed an immunocytochemical study of autopsy material from five cases of central pontine myelinolysis (CPM) and five age and sex-matched control subjects with the aim of exploring the possible involvement of apoptotic mechanisms in oligodendrocytes in this condition. We searched for immunoreactivity of glial cells for the apoptotic-related markers death receptor (DR) 3, Bax and Bak, the anti-apoptotic marker Bcl-2 and the cell cycle marker Ki-67. The latter marker was studied because it is known that entry of cells into the cell division cycle can trigger apoptosis if it does not result in mitosis. In CPM there was marked up-regulation of expression of the myelination-related enzyme carbonic anhydrase isoenzyme II and also markedly increased expression of Ki-67 in nuclei of glial cells of all types but particularly those of cells morphologically resembling oligodendrocytes. Despite this, there was no clear increase in density of such cells in CPM. The pro-apoptotic markers Bax, Bak and DR3 were all modestly increased in glial cell cytoplasm in CPM, while there was no change in expression of Bcl-2, which was only sparsely detected in glial cells both in controls and cases of CPM. The ratio of pro- to anti-apoptotic factors would appear from this evidence to have altered in favour of apoptosis in glial cells, most of which had the appearance of oligodendrocytes and many of which expressed Ki-67. We interpret this preliminary study as favouring apoptosis as a mechanism of oligodendrocytic death in CPM. Further study of this mechanism in CPM may lead to identification of factors that could reduce or prevent this rare but serious and often fatal disease.

Aged↗