IRCCS San Raffaele Scientific Institute
Laboratory of Human Genetics of Neurological Disorders

Author Of 2 Presentations

Prognostic Factors Poster Presentation

P0431 - Assessment of clinical, genetic and immune repertoire data to predict disease activity and progression in RRMS (ID 1330)

Speakers
Presentation Number
P0431
Presentation Topic
Prognostic Factors

Abstract

Background

Multiple Sclerosis (MS) has a highly heterogeneous clinical course and, given the broad spectrum of approved therapies, there is a strong need to identify parameters that can guide treatment choice

Objectives

The present study investigates clinical, genetic and immunological parameters associated with MS severity in order to combine them into a predictive model.

Methods

An “Extended” cohort of ~1,000 patients who started a first-line drug, with available clinical and genetic data, and a “Core” dataset of ~200 patients with clinical, genetic and immune repertoire information obtained before first-line treatment start were enrolled. The following outcomes were considered at the 4-year follow-up: NEDA-3 criterion, time to first relapse (TFR), EDSS and MS Severity Score (MSSS). A regression analysis was performed on both cohorts and results were meta-analyzed.

Results

A younger age at onset (AAO) and a shorter disease duration strongly correlate with higher inflammatory activity; a higher baseline EDSS and AAO are the best prognostic markers of disability increase. The genetic study identified some interesting signals with suggestive association: rs6925307 is associated with NEDA status (OR 0.55, p:1.53e-06) and has an eQTL effect on CLVS2 gene, required for normal morphology of endosomes and lysosomes in neurons. Rs9264731, an intronic variant in the HLA-C gene, is associated with TFR (HR 1.49, p:4.11e-06). T-cell receptor (TCR) sequencing is ongoing and immune repertoire data are already available for 123 patients: overall more than 16.000.000 sequences have been obtained, of which 81.5% are productive, corresponding on average to ~77.000 unique clonotypes per patient.

Conclusions

We confirmed the association of clinical parameters with disease severity and we identified some interesting genetic markers whose association need to be replicated. TCR data are being generated and will be integrated in a predictive model of disease activity.

Collapse
Rehabilitation and Comprehensive Care Poster Presentation

P1091 - Effect of BDNF Val66Met polymorphism on motor recovery after rehabilitation in progressive MS (ID 1676)

Speakers
Presentation Number
P1091
Presentation Topic
Rehabilitation and Comprehensive Care

Abstract

Background

It is known that a single-nucleotide polymorphism mapping to the Brain-Derived Neurotrophic Factor (BDNF) gene and resulting in the valine to methionine change (Val66Met or V66M), impacts memory, cognition and motor learning. Previous studies have shown that V66M polymorphism may exert a protective effect on grey matter atrophy in multiple sclerosis (MS) patients; however, its influence on motor recovery after rehabilitation is not known.

Objectives

To explore the possible influence of BDNF V66M polymorphism on motor recovery after rehabilitation in progressive MS subjects and to investigate the effect of two SNPs (rs2289656 and rs1212171) in NTRK2 gene, which encodes for BDNF receptor.

Methods

We retrospectively included in the study patients with primary progressive (PP) and secondary progressive (SP) MS, who were admitted to the Neurorehabilitation Unit and who had already available genetic data. The results of tests for gait (Six-minutes Walking Test, 6MWT; 10-Meters Test, 10MT) and hand dexterity (Nine-Hole Peg Test, 9HPT) were collected at baseline and after a 4-week inpatient rehabilitation program. We used ANCOVA models to explore the effects of the selected SNPs on the change of such clinical outcomes after rehabilitation, expressed as ratio values.

Results

100 patients (79 SP, 21 PP) with available clinical and genetic data were included in the study. Female:Male ratio was 1.27, mean age was 51±10 years and median EDSS score was 6.0 (range: 5.5-6.5). Sixty-eight patients were carriers of the more common genotype (GG), while the remaining were heterozygote (n=28) or homozygote (n=4) carriers of the V66M polymorphism (Met-carriers). Among 89 subjects with available data on 6MWT, Met-carriers showed greater improvement after rehabilitation if compared to GG patients (p=0.024; mean variation=0.16 [CI: 0.02-0.29]). SNPs in NTRK2 did not show any association with 6MWT change after rehabilitation neither alone, nor in interaction with V66M. As regards data on 10MT (n=42) and 9HPT (n=45), no associations were found for V66M or SNPs in NTRK2.

Conclusions

In the present pilot study, progressive MS patients carrying V66M polymorphism seem to have a greater improvement in walking performance at 6MWT after rehabilitation. These data need to be confirmed in larger and independent datasets, in order to better explore the effect of this polymorphism in MS patients undergoing intense rehabilitation program.

Collapse