Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

Background: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.

Methods: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations.

Peripheral nerve diffusion tensor imaging as a measure of disease progression in ALS.

Clinical trial design in amyotrophic lateral sclerosis (ALS) remains hampered by a lack of reliable and sensitive biomarkers of disease progression. The present study evaluated peripheral nerve diffusion tensor imaging (DTI) as a surrogate marker of axonal degeneration in ALS. Longitudinal studies were undertaken in 21 ALS patients studied at 0 and 3 months, and 19 patients at 0, 3 and 6 months, with results compared to 13 age-matched controls.

Dissociated lower limb muscle involvement in amyotrophic lateral sclerosis.

It has been suggested that corticomotoneuronal drive to ankle dorsiflexors is greater than to ankle plantar flexor muscles, despite the finding that plantar flexors are no less active than TA during walking and standing. The present study was undertaken to determine whether there was differential involvement of distal lower limb muscles in amyotrophic lateral sclerosis (ALS), to elucidate pathophysiological mechanisms of selective muscle involvement. Prospective studies were undertaken in 52 ALS patients, including clinical assessment, disease staging (revised ALS functional rating scale), Medical Research Council sum score, and a scale of upper motor neurone (UMN) dysfunction.

Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis.

Background: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein-Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells.

Objective: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course.

Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes.

Background: Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population.