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A Al-Chalabi

Publications and source records attributed to A Al-Chalabi.

At least 19 recordsLinked to original sources
PubMed2006

A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia.

OBJECTIVE: To perform genetic linkage analysis in a family affected with ALS and frontotemporal dementia (FTD). METHODS: The authors performed a genome-wide linkage analysis of a four-generation, 50-member Scandinavian family in which five individuals were diagnosed with ALS and nine with FTD. Linkage calculations assuming autosomal dominant inheritance of a single neurodegenerative disease manifesting as either ALS or FTD with age-dependent penetrance were performed. Further analyses for ALS alone and FTD alone were performed. A parametric logarithm of odds (lod) score of 2.0 or greater was required for further study of a potential locus and crossover (haplotype) analysis. RESULTS: A new ALS-FTD locus was identified between markers D9s1870 and D9s1791 on human chromosome 9p21.3-p13.3. A maximum multipoint lod score of 3.00 was obtained between markers D9s1121 and D9s2154. Crossover analysis indicates this region covers approximately 21.8 cM, or 14Mb. CONCLUSIONS: A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

Aged↗
PubMed2005

Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET.

Five to ten percent of amyotrophic lateral sclerosis (ALS) cases are associated with mutations of the superoxide dismutase-1 (SOD1) gene, and the 'D90A' mutation is associated with a unique phenotype and markedly slower disease progression (mean survival time 14 years). Relative sparing of inhibitory cortical neuronal circuits might be one mechanism contributing to the slower progression in patients homozygous for the D90A mutation (homD90A). The GABA(A) receptor PET ligand [11C]flumazenil has demonstrated motor and extra-motor cortical changes in sporadic ALS. In this study, we used [11C]flumazenil PET to explore differences in the pattern of cortical involvement between sporadic and genetically homogeneous ALS groups. Twenty-four sporadic ALS (sALS) and 10 homD90A patients underwent [11C]flumazenil PET of the brain. In addition, two subjects homozygous for the D90A mutation, but without symptoms or signs ('pre-symptomatic', psD90A), also underwent imaging. Results for each group were compared with those for 24 healthy controls of similar age. Decreases in the binding of [11C]flumazenil in the sALS group were found within premotor regions, motor cortex and posterior motor association areas. In the homD90A group of ALS patients, however, decreases were concentrated in the left fronto-temporal junction and anterior cingulate gyrus. In the two psD90A subjects, a small focus of reduced [11C]flumazenil binding at the left fronto-temporal junction was seen, similar to the pattern seen in the clinically affected patients. Within the sALS group, there was no statistically significant association between decreases in cortical [11C]flumazenil binding and revised ALS functional rating scale (ALSFRS-R score), whereas the upper motor neuron (UMN) score correlated with widespread and marked cortical decreases over the dominant hemisphere. In the homD90A group, there was a stronger statistical association between reduced cortical [11C]flumazenil binding and the ALSFRS-R, rather than the UMN, score, and also with disease duration. This study provides evidence for differences in the distribution of reduced cortical [11C]flumazenil binding in homD90A compared with sALS patients. We hypothesize that this might reflect differences in cortical neuronal vulnerability.

Adult↗
PubMed2005

Detection of serum reverse transcriptase activity in patients with ALS and unaffected blood relatives.

BACKGROUND: Retroviral involvement in the etiology of sporadic ALS has been suspected for several years since the recognition that both murine and human retroviruses can cause motor neuron disease-like syndromes. In a pilot study, an increased prevalence of a retroviral marker (reverse transcriptase [RT] activity) was demonstrated in the serum of British patients with ALS. The current investigation was designed to confirm and extend these findings in a geographically distinct patient cohort under blinded testing conditions. METHODS: A highly sensitive product-enhanced RT assay was employed to test coded sera obtained from 30 American patients with sporadic ALS and from 14 of their blood relatives, 16 of their spouses, and 28 nonrelated, nonspousal control subjects. RESULTS: Serum RT activity was detected in a higher proportion of ALS patients (47%) than in non-blood-related controls (18%; p = 0.008). The prevalence of RT activity in the serum of spousal controls (13%) was similar to that in other non-blood-related controls. Unexpectedly, the prevalence of serum RT activity in blood relatives of ALS patients (43%) approached that in the ALS patients themselves. CONCLUSIONS: These results confirm that patients with ALS have a significantly higher prevalence of serum reverse transcriptase (RT) activity than that seen in unrelated control subjects. The finding of a similarly increased prevalence in blood relatives of ALS patients raises the possibility that the observed RT activity might be due to an inherited endogenous retrovirus.

Adult↗
PubMed2005

[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Adult↗
PubMed2005

Mills' and other isolated upper motor neurone syndromes: in vivo study with 11C-(R)-PK11195 PET.

(11)C-(R)-PK11195 positron emission tomography (PET) was used to explore and delineate in vivo the cortical lesion in three clinically isolated upper motor neurone syndromes of similar presentation, with reference to the syndrome of progressive spastic hemiparesis first described by Mills. Three patients with isolated UMN syndromes underwent (11)C-(R)-PK11195 PET of the brain. One patient fulfilled criteria for PLS. Two others had clinical features similar to the cases described by Mills; one of these had a high cervical cord inflammatory lesion previously noted on magnetic resonance imaging. The patient with PLS showed focal increase in the binding of (11)C-(R)-PK11195, indicating microglial activation, in the motor cortex contralateral to the predominantly affected limbs. Of the other two patients, one demonstrated marked increases in binding in the superior frontal region (supplementary motor region) contralateral to the affected limbs. In contrast, no focal areas of increased binding were seen in the cerebral cortex of the third patient, who had a high cervical cord lesion and was presumed to have extra-cerebral inflammatory disease. (11)C-(R)-PK11195 PET demonstrates in vivo that active pathology may be detectable many years after the onset of symptoms, and that it can occur in disparate sites with clinically similar presentations. We conclude that Mills' syndrome is a purely clinical description that should be reserved for patients with a progressive spastic hemiparesis for which no other explanation can be found.

Adult↗
PubMed2005

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS.

BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Adult↗
PubMed2004

No association of the SOD1 locus and disease susceptibility or phenotype in sporadic ALS.

Mutations in the copper zinc superoxide dismutase gene (SOD1) are found in 20% of familial and 3% of sporadic ALS patients. SOD1 protein aggregation can be detected in motor neurons of mutation-negative sporadic cases but a pathogenic role for wild-type SOD1 in ALS has not been demonstrated. In this study of 233 ALS cases and 248 controls the authors found no significant association between four individual single nucleotide polymorphisms and a deletion spanning the SOD1 locus (or their combined haplotypes), and disease susceptibility, or phenotype.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990-2002.

Motor neuron disease is a clinically heterogeneous disease with significant differences in survival. The authors have characterised a subset of long term survivors seen in a tertiary clinic over a 12 year period in terms of clinical variables and demographics, comparing them with short term survivors and the remaining population. Thirty of 769 patients survived more than 10 years, corresponding to 4% of the total population. Significantly younger onset of disease symptoms and a predominance of pure upper motor neuron signs at presentation characterised the long term survivors, but factors traditionally regarded as being associated with poor prognosis were also well represented. For a few people with motor neuron disease there remains the hope, whatever the initial presentation, that their subsequent survival will be longer than expected.

Adult↗
PubMed2002

Prognostic modelling of therapeutic interventions in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease with a widely varying prognosis. The majority of patients survive about 3 years, but a significant number survive for 10 years or more, leading to problems in clinical trial design. OBJECTIVE: To demonstrate that simple clinical variables can be used to construct a robust predictive model for survival, and to assess the effect of a known treatment within this model. METHODS: We carried out a retrospective multivariate modelling of a database of 841 patients with ALS seen over a 10-year period in a specialist motor neuron disorders clinic. The use of riluzole was tested as a prognostic factor within the model. RESULTS: A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r(2) = 0.78). Prognostic variables included site of onset, age of onset, time from symptom onset to diagnosis, and El Escorial category at presentation. Riluzole therapy was an independently significant prognostic factor (relative risk of death 0.48, P < 0.0001, model chi(2) 297, P < 0.0001). CONCLUSIONS: Clinical databases can be used to generate multivariate prognostic models in ALS. Such models could be used to predict survival, to improve criteria for matching of patients in future clinical trials, and to test the impact of interventions.

Age of Onset↗
PubMed2000

Detection of reverse transcriptase activity in the serum of patients with motor neurone disease.

The recognition that both human and murine retroviruses can cause motor neurone disease-like syndromes has raised the possibility that a retrovirus may be involved in the aetiology of motor neurone disease. This possibility was explored by looking for evidence of reverse transcriptase in the serum of motor neurone disease patients. Sera from 56 patients with motor neurone disease and 58 controls were tested by the product-enhanced reverse transcriptase assay, a technique that is approximately a million fold more sensitive than conventional reverse transcriptase assays and capable of detecting very low numbers of retroviral particles. Cell-free reverse transcriptase activity was detected in the serum of 33 of the 56 motor neurone disease patients (59%) but in only 3 of the controls (P < 0.00001). The reverse transcriptase activity was detectable in the presence of a large excess of an effective inhibitor of human cellular DNA polymerases and was therefore tentatively considered to be compatible with a retroviral origin. The reverse transcriptase activity, however, was not found to be due to the presence of known human exogenous retroviruses including HIV-1, HIV-2, HTLV-I, HTLV-II, HRV-5 or human foamy virus, as assessed by PCR-based assays. Further investigations will be required to determine the source of the reverse transcriptase activity observed in these motor neurone disease patient sera.

Adult↗
PubMed2000

Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil.

We used the benzodiazepine GABA(A) marker [(11)C] flumazenil to study cerebral dysfunction in amyotrophic lateral sclerosis (ALS) with PET. Seventeen non-demented patients with clinically definite or probable ALS were scanned and statistical parametric maps were derived to localize changes in regional flumazenil volumes of distribution (FMZVD), which correlate closely with receptor density (B(max)), and the results were compared with those of 17 controls. The ALS group showed statistically significant decreases in relative FMZVD in the prefrontal cortex (areas 9 and 10 bilaterally), parietal cortex (area 7 bilaterally), visual association cortex (area 18 bilaterally) and left motor/premotor cortex (including area 4) (P < 0.001). Relative reductions in FMZVD were also seen in the left ventrolateral and dorsolateral prefrontal cortex (areas 45, 46 and 47), Broca's area and the right temporal (area 21) and right visual association cortex (area 19). These observations suggest that cerebral dysfunction in ALS involves motor/premotor and extramotor areas, particularly the prefrontal regions.

Adult↗
PubMed2000

Recent advances in amyotrophic lateral sclerosis.

The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degeneration resulting in paralysis and death, usually within 3 years of onset. Pathological and animal studies implicate neurofilament involvement in ALS, but whether this is primary or secondary is not clear. The heavy neurofilament subunit (NFH) tail is composed of a repeating amino acid motif, usually X-lysine-serine-proline-Y-lysine (XKSPYK), where X is a single amino acid and Y is one to three amino acids. There are two common polymorphic variants of 44 or 45 repeats. The tail probably regulates axonal calibre, with interfilament spacing determined by phosphorylation of the KSP motifs. A previous study suggested an association between sporadic cases of ALS and NFH tail deletions, but two subsequent studies have found none. We have analysed samples from two different populations (UK 207, Scandinavia 323) with age-matched controls for each group (UK 219, Scandinavia 228) and have found four novel NFH tail deletions, each involving a whole motif. These were found in three patients with sporadic ALS and a family with autosomal dominant ALS, although another was also found in two young controls. In all cases motif deletions were only associated with disease when paired with the long NFH allele. The deletions all occurred within a small region of the NFH tail. This has allowed us to propose a structural organization of the tail as well as allowing observed deletions both from this study and previous reports to be organized into logical groups. These results strongly suggest that NFH motif deletions can be a primary event in ALS but that they are not common.

Adult↗
PubMed1998

Mutations in all five exons of SOD-1 may cause ALS.

Eight of 38 patients (21%) with familial and 5 of 175 patients (3%) with sporadic amyotrophic lateral sclerosis (ALS) had missense mutations in the SOD-1 gene. Two novel mutations were identified. One in exon 4 substituting leucine with phenylalanine (L84F) in a familial patient and the second in exon 3 at substituting glycine with serine (G72S) in an "apparently" sporadic patient. Over 60 point mutations have now been described in all five exons of SOD-1, involving 43 of the 153 residues. Hypotheses about the toxic role of mutant SOD-1 in the pathogenesis of ALS must account for this molecular diversity.

Adult↗
PubMed1998

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.

Amino Acid Substitution↗
PubMed1997

Lack of evidence for HTLV tax-rex DNA in motor neurone disease.

It has recently been claimed (Ferrante et al., 1995. HTLV tax-rex DNA and antibodies in idiopathic amyotrophic lateral sclerosis. J. Neurol. Sci. 129 (Suppl.) 140-144) that human T-lymphotropic virus (HTLV) tax-rex sequences are detectable in the peripheral blood mononuclear cells (PBMCs) of 40% of patients with motor neurone disease (MND). In an attempt to confirm this we employed a highly sensitive 'nested' polymerase chain reaction (PCR) assay, capable of detecting single molecules of HTLV proviral DNA, to look for tax-rex sequences in the PBMCs of 43 patients with MND. We were unable to detect the presence of HTLV tax-rex in any of 43 MND patients tested, using three different PCR primer sets under both high and low stringency conditions. Using the same DNA samples we were able to detect the presence of the single-copy pyruvate dehydrogenase gene, thus demonstrating that the extracted DNA was indeed amplifiable by PCR. To further exclude the possibility that the extracted DNA samples contained unrecognised inhibitory factors we conducted spiking experiments with trace amounts (approximately 10 copies) of HTLV proviral DNA. Spiked samples yielded PCR products of the expected size. We are therefore unable to confirm the presence of HTLV tax-rex sequences in this disease.

Adult↗