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  • Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson's disease: record linkage studies.

    24 October 2018

    OBJECTIVE: To determine the risk of cancer before and after the diagnosis of motor neuron disease (MND), multiple sclerosis (MS) and Parkinson's disease (PD). METHODS: Analysis of statistical database of linked statistical abstracts of hospital and mortality data in an area in southern England. RESULTS: Only people with PD showed a significant difference in the overall incidence of cancer compared with controls (rate ratio (RR) 0.76, 95% CIs 0.70 to 0.82 before PD; RR 0.61, 0.53 to 0.70, after PD). RRs were close to 1 for cancer in patients after MND (0.98, 0.75 to 1.26) and after MS (0.96, 0.83 to 1.09). There were high rate ratios for malignant brain cancer (7.4, 2.4 to 17.5) and Hodgkin's lymphoma (5.3, 1.1 to 15.6) in patients diagnosed with MND after cancer. In people with MS, malignant brain cancer also showed an increased RR both before hospital admission with a diagnosis of MS (3.2, 1.1 to 7.6) and after (2.4, 1.2 to 4.5). In people with PD, several specific cancers showed significantly and substantially reduced RRs for cancer, notably smoking related cancers, including lung cancer (0.5, 0.4 to 0.7, before PD; 0.5, 0.4 to 0.8, after PD) but also cancers that are not strongly smoking related, including colon cancer (0.7, 0.6 to 0.9, before PD; 0.5, 0.4 to 0.8, after PD). CONCLUSIONS: People with MND, or MS, do not have an altered risk of cancer overall. There may sometimes be misdiagnosis between MND or MS and brain tumours. PD carries a reduced risk of cancer overall, of some smoking related cancers and of some cancers that are not smoking related.

  • Functional vitamin B12 deficiency.

    24 October 2018

    We describe a case of functional vitamin B12 deficiency where the repeated measurement of a serum B12 level within the normal range led to delay in the diagnosis of subacute combined degeneration of the spinal cord, and possibly permanent neurological damage as a result. Failure of intracellular transport of B12 by transcobalamin-2 can lead to functional B12 deficiency but with apparently normal serum levels, and is suggested by raised levels of either serum methylmalonic acid or homocysteine, associated with low levels of transcobalamin-2. Such patients may respond to repeated high-dose injections of B12.

  • Neuronal loss associated with cognitive performance in amyotrophic lateral sclerosis: an (11C)-flumazenil PET study.

    24 October 2018

    Amyotrophic lateral sclerosis (ALS) is a multi-system disorder. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS. Detailed neuropsychological assessments reveal deficits of word retrieval including impairments on tests of verbal fluency and confrontation naming. The PET GABA(A) receptor ligand [11C]-flumazenil is a marker of neuronal dysfunction in ALS. This study used [11C]-flumazenil PET to identify correlations between cortical regions and impairments in word retrieval. Twelve patients with ALS underwent [11C]-flumazenil PET and neuropsychological assessment, including tests of written letter fluency and confrontation naming. Poorer performance on verbal fluency correlated with decreased [11C]-flumazenil binding in a region including the right inferior frontal gyrus, superior temporal gyrus, and anterior insula. Poorer performance on a test of confrontation naming correlated with decreased binding in the left middle frontal gyrus (extending to Broca's area) and left cuneus. This study indicates that [11C]-flumazenil PET can be used to help localize cortical regions associated with cognitive deficits in ALS.

  • Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS.

    24 October 2018

    Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

  • Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis.

    24 October 2018

    BACKGROUND: The basis of heterogeneity in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS) is poorly understood. OBJECTIVES: To use diffusion tensor imaging as a measure of axonal pathologic features in vivo in ALS and to compare a homogeneous form of familial ALS (homozygous D90A SOD1 [superoxide dismutase 1]) with sporadic ALS. DESIGN: Cross-sectional diffusion tensor imaging study. SETTING: Tertiary referral neurology clinic. PATIENTS: Twenty patients with sporadic ALS, 6 patients with homozygous D90A SOD1 ALS, and 21 healthy control subjects. MAIN OUTCOME MEASURE: Fractional anisotropy in cerebral white matter. RESULTS: Patients with homozygous D90A SOD1 ALS showed less extensive pathologic white matter in motor and extramotor pathways compared with patients with sporadic ALS, despite similar disease severity assessed clinically using a standard functional rating scale. Fractional anisotropy correlated with clinical measures of severity and upper motor neuron involvement. CONCLUSION: In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS.

  • Biomarkers in amyotrophic lateral sclerosis.

    24 October 2018

    Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency--riluzole--has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.