Charcot-Marie-Tooth disease type 1A is most commonly caused by a duplication of a 1.5 Mb region of chromosome 17 which includes the peripheral myelin protein 22 gene (PMP22). Over-expression of this gene leads to a hypomyelinating/demyelinating neuropathy and to severely reduced nerve conduction velocity. Previous mouse and rat models have had relatively high levels of expression of the mouse or human PMP22 gene leading to severe demyelination. Here we describe five lines of transgenic mice carrying increasing copies of the human PMP22 gene (one to seven) and expressing increasing levels of the transgene. From histological and electrophysiological observations there appears to be a threshold below which expression of PMP22 has virtually no effect; below a ratio of human/mouse mRNA expression of approximately 0.8, little effect is observed. Between a ratio of 0.8 and 1.5, histological and nerve conduction velocity abnormalities are observed, but there are no behavioural signs of neuropathy. An expression ratio >1.5 leads to a severe neuropathy. A second observation concerns the histology of the different lines; the level of expression does not affect the type of demyelination, but influences the severity of involvement.
Important questions remain unanswered about the sequence of events leading to progressive and ultimately irreversible tissue damage in MS. This study was designed to investigate the pathological characteristics of, and function of, the blood-brain barrier within longstanding MS lesions using quantitative and Gd-DTPA enhanced MRI techniques. The ultrastructural appearances of postmortem lesions from a single, separate case of MS have been correlated with the MRI findings. Both MRI and ultrastructural analysis revealed considerable heterogeneity in the chronic lesions: some are 'closed' with no detectable extracellular water, but most are 'open' and show expansion of the extracellular space to as much as 87% of tissue area. This variable expansion probably results from differing degrees of axonal loss. Evidence of blood-brain barrier damage was found in only 17% of lesions, was less severe than that seen in acute lesions, and may result from repeated previous inflammatory insults. The findings imply progressive axonal loss in lesions as they age. It is possible that this loss is related to clinical progression of the disease.
There is a dearth of longitudinal studies on psychometric and psychiatric change in multiple sclerosis (MS) particularly on the evolution of these abnormalities early in the disease process. A 41 year follow up study documenting magnetic resonance imaging (MRI), psychometric, and psychiatric abnormalities was undertaken in a group of 48 patients with clinically isolated lesions-for example, optic neuritis-which are frequently the harbinger of MS. At follow up about half the subjects had developed clinically definite MS, with memory deficits becoming apparent. Deficits in attention documented at initial assessment were present but unchanged in those subjects who still had a clinically isolated lesion status. However, after MS was categorised into a relapsing-remitting or chronic progressive course, patients with a chronic progressive course were found to have significantly deteriorated with regard to auditory attention tasks. T1 relaxation times in apparently normal white matter correlated with certain indices of cognitive impairment. In developing a model to explain the pathogenesis of intellectual and emotional change in MS, the interaction of organic, psychological, and social factors needs to be emphasised. (7 Neurol Neurosurg Psychiatry 1992;55:869-876 tions were controlled for,'6 the preliminary evidence after a 1 to 2 year follow up period showed little cognitive deterioration. The only available longer follow up study also suggested that cognitive deterioration had occurred in less than a quarter of patients with multiple sclerosis four years after initial assessment and that there was considerable individual variation. 7An analogous position exists with respect to psychiatric disturbance in MS. The high prevalence of affective symptomatology is now well established.'8 Though there is firm evidence linking the presence of euphoria to cerebral involvement'9 it is unclear to what extent depressive features can be similarly explained.20 The developent and evolution of early psychiatric symptoms and the interplay of organic and social factors in their pathogenesis have yet to be studied.The study over time of patients with clinically isolated lesions (CIL-namely, optic neuritis and the brain stem and spinal cord syndromes-which are frequently the harbinger of MS,2' provides an unique opportunity to monitor cognitive and psychiatric changes early in the disease. Cognitive abnormalities are already discernible in some of these studies at presentation,22 23 and a follow up of such cases would allow the early natural history to be observed. In addition, the initial paucity of psychiatric symptomatology in subjects with CIL24 offers the opportunity to unravel the various aetiological factors that contribute to greater psychiatric morbidity in those who subsequently develop MS.In an earlier study, we reported that patients with CIL had significantly greater deficits in auditory and visual attention when compared with a physically disabled control group without brain involvement, matched for age, sex, and pr...
A case control study technique was employed to test for an association between non-traumatic cervical artery dissection and several possible risk factors. A significant positive association was shown with migraine, independent of type and treatment regimen. No such relationship was found with smoking history, hypertension or past oral contraceptive use. There was, however a significant and independent association with current oral contraceptive use.
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