Faculty Bibliography

Finding biomarkers of human neurological diseases is one of the most pressing goals of modern medicine. Most neurological disorders are recognized too late because of the lack of biomarkers that can identify early pathological processes in the living brain. Late diagnosis leads to late therapy and poor prognosis. Therefore, during the past decade, a major endeavor of clinical investigations in neurology has been the search for diagnostic and prognostic biomarkers of brain disease. Recently, a new field of metabolomics has emerged, aiming to investigate metabolites within the cell/tissue/ organism as possible biomarkers. Similarly to other "omics" fields, metabolomics offers substantial information about the status of the organism at a given time point. However, metabolomics also provides functional insight into the biochemical status of a tissue, which results from the environmental effects on its genome background. Recently, we have adopted metabolomics techniques to develop an approach that combines both in vitro analysis of cellular samples and in vivo analysis of the mammalian brain. Using proton magnetic resonance spectroscopy, we have discovered a metabolic biomarker of neural stem/progenitor cells (NPCs) that allows the analysis of these cells in the live human brain. We have developed signal-processing algorithms that can detect metabolites present at very low concentration in the live human brain and can indicate possible pathways impaired in specific diseases. Herein, we present our strategy for both cellular and systems metabolomics, based on an integrative processing of the spectroscopy data that uses analytical tools from both metabolomic and spectroscopy fields. As an example of biomarker discovery using our approach, we present new data and discuss our previous findings on the NPC biomarker. Our studies link systems and cellular neuroscience through the functions of specific metabolites. Therefore, they provide a functional insight into the brain, which might eventually lead to discoveries of clinically useful biomarkers of the disease.

We sought to identify clinical characteristics and socio-demographic variables associated with longitudinal patterns of fatigue in multiple sclerosis (MS) patients. A questionnaire including the Fatigue Severity Scale (FSS) was mailed to a community sample of 502 MS patients three times 1 year apart. Three patterns of fatigue were defined: persistent fatigue (PF) (mean FSS score > or = 5 at all time-points), sporadic fatigue (SF) (mean FSS score > or = 5 at one or two time-points) and no fatigue (mean FSS score < 5 at all time-points). Among the 267 (53%) patients who responded at all time-points, 101 [38%, 95% confidence intervals (CI) 32-44] had persistent, 98 (37%, 95% CI 31-43) sporadic and 68 (25%, 95% CI 20-31) no fatigue. Persistent and sporadic fatigue were more common in patients with, increased neurological impairment (P < 0.001), primary progressive MS (P = 0.01), insomnia (P < 0.001), heat sensitivity (P < 0.001), sudden-onset fatigue (P < 0.001) or mood disturbance (P < 0.001) compared with patients without fatigue. Multivariable analysis showed that depression (PF P = 0.02, SF P < 0.001), heat sensitivity (PF P = 0.04, SF P = 0.02) and physical impairment (PF P = 0.004, SF P = 0.01) were associated with both sporadic and persistent fatigue. About 75% of the patients had persistent or sporadic fatigue over a 2 years observation period. Multivariable analyses confirmed a significant association between levels of depression, physical impairment and persistent fatigue.

BACKGROUND: The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. METHODS: 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. FINDINGS: MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7.4 [SD 4.2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11.2 [4.5] years; p<0.0001) or monofocal (12.0 [3.8] years; p=0.0005) presentations. Permanent physical disability (EDSS>or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. INTERPRETATION: Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.