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Archive for March, 2017

Prognostic factors in C9orf72 ALS: the battle of genders?

28 Mar, 17 | by Dr Jose Manuel Matamala, JNNP web editor.

 

The C9orf72 hexanucleotide repeat expansion has been defined as the main genetic factor in amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (FTD) continuum. Clinically, the C9orf72-related ALS cases have several distinct features including an earlier age of onset, reduced survival, higher prevalence of bulbar onset and dementia, contributing to the broad clinical variability in this group of patients.

In the current issue of JNNP, Rooney and colleagues contribute to the understanding of the prognostic factors associated with the C9orf72 mutation. The authors investigated the prognostic impact of C9orf72 in European ALS patients and its interactions with demographic features such as age, gender, and site of onset. In summary, C9orf72 status and demographic/clinical data from 4925 ALS patients were analyzed using flexible parametric survival models that included the already known prognostic factors (age, diagnostic delay, and site of onset), gender and C9orf72 status. The meta-analysis of C9orf72 status estimated a survival hazard ratio (HR) of 1.36 (1.18 – 1.57). Models analysis demonstrated that males with spinal onset diseases were driving the reduced survival seen in patients with this mutation.

 

Spinal-onset disease in male patients drives the poor survival in a large population of C9orf72 ALS patients

 

This study is the largest combined analysis of the prognostic features of C9orf72 ALS. Regarding gender effect on survival, it is well known that the incidence and prevalence of ALS is higher in males (male: female ratio 3:2), with a greater likelihood of earlier disease onset and spinal onset. Moreover, it has been reported that male transgenic SOD1 mice have reduced survival in comparison with female littermates, suggesting differential motor neurone vulnerability determined by gender. Even though the exact mechanics of this difference is not well understood, a recent study suggests that mitochondrial dysfunction is expressed earlier in male compared to female mice, probably attributable to oestrogen levels. Without any doubt, the definition of prognostic factors associated with the C9orf72 mutation is not trivial given the advances in molecular biology and genetics, as well as their impact on the development of future targeted therapeutic strategies. This information is highly relevant for the design of future clinical trials, particularly in the C9orf72 ALS population.

 

Read more at http://jnnp.bmj.com/content/jnnp/88/4/281.1.full

 

 

 

 

 

 

Immunomodulatory therapy modulates progression in advanced multiple sclerosis

5 Mar, 17 | by Dr Jose Manuel Matamala, JNNP web editor.

 

In the current issue of JNNP, Lizak and colleagues have published an interesting epidemiological study based on global multiple sclerosis (MS) database (MSBase), to evaluate prognostic factors in moderately advanced and advanced MS, specifically the impact of highly active immunomodulatory therapy. Using prospectively collected data from over 4000 patients with MS, the cohort was divided into three epochs between EDSS steps 3-6, 4-6 and 6-6.5 respectively. A multivariate survival model was used to examine the role of immunomodulatory therapy and clinical/demographic variables on progression to the outcome EDSS step 6/6.5. In summary, the disability trajectories showed large variability. The probability to reach the outcome was not associated with baseline variables, suggesting that previous disease activity before progress into advanced stages does not have a significant impact on later disease progression. However, higher relapsed rate was associated with disability. Additionally, highly active immunomodulatory therapy was associated with lower risk of reaching the outcome disability step. The authors conclude that disease progression in moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time with active immunomodulatory therapy are associated with decreased risk of accumulating further disability.

 

Highly active immunomodulatory therapy may delay disability in moderately advanced and advanced multiple sclerosis

 

In the last decade, we have seen significant advances in our understanding of MS, together with a rapid rate of progress in developing new effective disease modifying drugs. All these advances have reduced the levels of disability in comparison to patients who developed the condition decades ago. Although active immunomodulatory therapy has been proven to prevent relapses and reduce first disability progression, their effect in accumulative disability remains undefined. Moreover, the hypothesis of two possible MS pathophysiological phases, the first one dominated by an autoimmune inflammatory process and the second one driven by neurodegenerative mechanisms, which may be independent of each other, have suggested that the immunomodulatory therapy is not effective in advanced MS stages. However, the results of the study propose that highly active immunomodulatory therapy may delay disability in advanced MS, bringing hope to MS patients in this disease stage. Therefore, further randomized controlled trials are needed to evaluate the efficacy of these treatments during advanced disease stages. In the meantime, MS management needs to focus on optimizing clinical vigilance of progression and consider drug therapy modification in patients with incomplete responses.

 

Read more at http://jnnp.bmj.com/content/jnnp/88/3/196.full

 

 

 

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