Showing papers by "Samuel K. Ludwin published in 2010"

Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices.

Abstract: Remyelination, which occurs subsequent to demyelination, contributes to functional recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated into myelinating cells. Therapeutics that impact remyelination in the CNS could be critical determinants of long-term functional outcome in multiple sclerosis (MS). Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier. Previous studies using isolated dissociated cultures indicate that neural cells express S1P receptors and respond to receptor engagement. Our objective was to assess the effects of fingolimod on myelin-related processes within a multicellular environment that maintains physiological cell-cell interactions, using organotypic cerebellar slice cultures. Fingolimod treatment had no impact on myelin under basal conditions. Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes, while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein. The number of phagocytosing microglia was not increased by fingolimod. Using S1P receptor specific agonists and antagonists, we determined that fingolimod-induced effects on remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas enhanced microgliosis was mediated through S1P1 and S1P5. Taken together, these data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain.

Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids: novel imaging findings

Abstract: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a paediatric autosomal dominant dysmyelinating disease.1 Rare adult onset cases manifest with personality change, cognitive decline and gait impairment.1–3 Diagnosis is often made following brain biopsy with the presence of giant neuroaxonal swellings known as spheroids.4 Characteristic brain MRI abnormalities of HDLS include decreased T1-weighted signal intensity of the frontoparietal white matter and corpus callosum.2 T2-weighted images reveal patchy increased signal intensity in the subcortical white matter with corticospinal tract involvement.1–4 To our knowledge, this is the first report of an abnormal apparent diffusion coefficient (ADC) map in HDLS. A previously healthy 46-year-old man presented following a 1 year history of slurred speech and word finding difficulty that progressed until …