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N Leigh

Publications and source records attributed to N Leigh.

At least 19 recordsLinked to original sources
PubMed2002

Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia.

Two types of ubiquitinated inclusions have been described in motor neurone disease (MND). (1) Skein or globular ubiquitinated inclusions in the motor neurones (more frequently in the lower motor neurones). This is a characteristic feature of all motor neurone disease categories. (2) Dot-shape or crescentric ubiquitinated inclusions in the upper layers of cortex and dentate gyrus described in cases of motor neurone disease with dementia (DMND). We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls. SN and spinal cord sections were stained with ubiquitin (alpha-synuclein, tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN was quantified by using a computer-based image analysis system. Four out of six DMND cases showed rounded ubiquitin positive inclusions with irregular frayed edges, associated with neuronal loss, reactive astrocytosis and a large number of activated microglia cells. These inclusions are negative with antibodies to (alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB dementia and MND showed occasional neuronal loss and no inclusions. The ubiquitin-only inclusions in SN of DMND cases are similar (but not identical) to the ubiquitinated inclusions described previously in the spinal cord of MND cases and are distinct from Lewy bodies (LBs). The degeneration of SN is most likely a primary neurodegenerative process of motor neurone disease type frequently involving the DMND cases. MND disease is a spectrum and multisystem disorder with DMND located at the extreme end of a spectrum affecting the CNS more widely than just the motor system.

Aged↗
PubMed2001

Progress in the pathogenesis of amyotrophic lateral sclerosis.

This decade has seen the discovery of one cause for amyotrophic lateral sclerosis (ALS)--mutations in the copper/zinc superoxide dismutase (SOD1) gene. Mutant SOD1 has provided an invaluable tool for transgenic and cellular experiments designed to elicit the biochemical pathways that are disturbed in ALS. We highlight recent advances in ALS research, including diagnostic issues, new loci for ALS genes, and progress in understanding the toxicity of mutant SOD1. The evidence for persistant viral infection, glutamate-mediated excitotoxicity, oxidative stress, altered neurofilament and peripherin expression, disrupted axonal transport, neurotrophin deficiency, and mitochondrial dysfunction are critically reviewed. As yet, no consensus has been achieved on the pathways that lead to selective neuronal death, and the underlying causes are still unknown in the vast majority of patients. Further clues about genetic susceptibility and environmental triggers are urgently needed so that more effective treatments for ALS can be developed, with the ultimate goal being prevention.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis.

We have studied the distribution of cyclin dependent kinase-5 (cdk-5) within spinal cord in sporadic and two superoxide dismutase type 1 (SOD1) familial cases of amyotrophic lateral sclerosis (ALS). Although most neurofilament accumulations in ALS motor neurones did not appear to contain high levels of cdk-5, intense cdk-5 immunoreactivity was observed in perikarya of degenerating neurones in many ALS cases. Here, cdk-5 co-localised with lipofuscin. Co-localisation of cdk-5 with lipofuscin was also observed in some aged non-affected controls although this labelling was less intense than the ALS cases. The biogenesis of lipofuscin is believed to be linked to oxidative stress and oxidative stress and free radical damage have been suggested to be part of the pathogenic process of ALS, possibly involving apoptotic mechanisms. cdk-5 has recently been associated with apoptosis. These observations suggest a role for cdk-5 in the pathogenesis of ALS.

Adult↗
PubMed1994

Serum carnosinase activities in central nervous system disorders.

Serum carnosinase activity was assayed in five groups of patients with neurological disorders. Enzyme activities in patients with idiopathic epilepsy (mean +/- S.E.M., 148 +/- 11 nmol/ml per min) and motor neurone disease (155 +/- 15 nmol/ml per min) were similar to the control group (161 +/- 7 nmol/ml per min). Reduced serum carnosinase activity was observed in patients with Parkinson's disease (109 +/- 11 nmol/ml per min, P < 0.005), multiple sclerosis (82.5 +/- 10.0 nmol/ml per min, P < 0.005) and patients following a cerebrovascular accident (74.6 +/- 5.4 nmol/ml per min, P < 0.001) compared with the control group. Carnosinase activity, 5-10% of that found in serum, was detected in CSF samples. The cause of reduced serum carnosinase activities in central nervous system disorders is unclear, although anoxic damage to carnosinase-producing cells or disruption of the blood-brain barrier may be responsible.

Adult↗
PubMed1993

The relationship between muscle fibre atrophy factor, plasma carnosinase activities and muscle RNA and protein composition in chronic alcoholic myopathy.

The relationship between chronic ethanol consumption and muscle biopsy morphometry (i.e. atrophy factor), plasma analytes, including carnosinase activities and tissue composition was investigated. In approximately half of chronic alcohol misusers there was Type II-fibre atrophy, which was correlated with reductions in muscle protein and serum carnosinase activities. The protein composition was also correlated with RNA composition. These results directly implicate defects in protein and RNA turnover as characteristics of chronic alcoholic myopathy and re-affirms the routine diagnostic use of fibre-type morphometry to identify these patients.

Adult↗
PubMed1992

Criteria for diagnosis of familial amyotrophic lateral sclerosis. European FALS Collaborative Group.

Clinical criteria for the diagnosis of motor neuron disease, agreed at the inaugural meeting of the European Familial Amyotrophic Lateral Sclerosis Collaborative Group, are described. The criteria are derived from those developed for the study of sporadic amyotrophic lateral sclerosis, and allow the inclusion of certain recognized clinical sub-types of familial amyotrophic lateral sclerosis. They will require testing for consistency and sensitivity.

Amyotrophic Lateral Sclerosis↗
PubMed1988

MRI appearances of the CNS manifestations of Mycoplasma pneumoniae: a report of two cases.

Two patients are reported with Mycoplasma pneumoniae-related cervical myelitis. Magnetic resonance imaging in each case demonstrated clinically silent lesions suggesting more extensive neurological involvement. This supports the concept of widespread immunologically mediated disease occurring as a remote effect of initial M. pneumoniae respiratory infection. Differences from the MRI appearances of a patient with mycoplasma-related Guillian-Barré syndrome imply that more than one antigenic determinant is involved.

Adolescent↗
PubMed1986

Urea-induced stimulus-sensitive myoclonus in the rat.

Uremia in humans can cause spontaneous and stimulus-sensitive myoclonus that responds to clonazepam. Uremic myoclonus in humans resembles the reticular reflex form of postanoxic action myoclonus. Previous investigations have established that urea infusions in the cat can produce spontaneous and stimulus-sensitive myoclonus. This has been shown, electrophysiologically, to arise in the brainstem medullary reticular formation, and it does not require forebrain structures. Our own studies in the rat have shown that urea infusions also produce spontaneous and stimulus-sensitive myoclonus. Electrophysiologically, this resembles human reticular reflex myoclonus. It can be reduced by clonazepam. The myoclonus produced by urea infusions in the rat progresses very rapidly into uncontrollable tonic-clonic convulsions. Although the urea model in the rat mimics some forms of human myoclonus that arise in the brainstem, it is not suitable as a routine animal model for pharmacological investigations.

Animals↗
PubMed1981

Hypophysectomy does not prevent development of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment.

Hruska et al. (1980) reported that hypophysectomy prevented the onset of dopamine receptor supersensitivity. We have repeated this investigation administering haloperidol (0.75 mg/day) or sulpiride (2 X 15 mg/day) or saline for 17 days, followed by a 3 day drug washout period, to sham-operated or hypophysectomised rats. Haloperidol or sulpiride pretreatment caused an enhancement of apomorphine-induced stereotyped behaviour and increased the number of specific striatal [3H]spiperone binding sites (Bmax) in both hypophysectomised and sham-operated animals compared to their respective saline controls. We conclude that hypophysectomy does not prevent the onset of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment in the rat.

Animals↗
PubMed1979

Dopamine-mediated circling behaviour does not involve the nigro-tectal pathway.

Extensive unilateral or bilateral electrolytic ablation of the rat superior colliculus failed to reduce apomorphine- or amphetamine-induced rotation in animals with a unilateral 6-hydroxydopamine lesion of one nigro-striatal dopaminergic pathway. These findings suggest that a nigro-tectal pathway does not play a crucial role in mediating the circling response caused by striatal dopamine receptor stimulation. However, electrolytic lesions of the dorsal tegmental decussation reduced apomorphine- but not amphetamine-induced rotation in such animals, perhaps by sectioning some commissural pathway between the two nigro-striatal systems.

Animals↗
PubMed1979

Turning behaviour induced by injection of muscimol or picrotoxin into the substantia nigra demonstrates dual GABA components.

Injection of the GABA agonist muscimol into rat caudal substantia nigra caused contralateral turning, whereas injection into the rostral substantia nigra caused ipsilateral turning. The GABA antagonist picrotoxin had the opposite effect. These findings support the hypothesis that GABA has dual actions in the substantia nigra. Ipsilateral turning induced by injection of muscimol into rostral nigra was abolished by haloperidol pretreatment, indicating the involvement of dopaminergic mechanisms. Haloperidol pre-treatment did not prevent turning induced by muscimol injected into the caudal nigra, supporting the existence of a non-dopaminergic nigral output system.

Animals↗