Altogether, these findings suggest that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7‐CP‐IP; Project No: 261357; 2010–2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large‐scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy‐related diseases. To complement the population‐based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Apart from the well-defined factors in neuronal cells 1 , only few reports consider that variability of sporadic ALS progression can depend on the less-defined contributions from glia 2,3 and blood vessels 4 .In this study we use an expression weighted cell-type enrichment method to infer cell activity in spinal cord samples from sporadic ALS patients and mouse models of this disease. Here we report that sporadic ALS patients present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded the microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in sporadic ALS patients. Moreover, in plasma of 574 ALS patients from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently-discovered perivascular fibroblast can predict ALS patient survival and provide a novel conceptual framework to re-evaluate definitions of ALS etiology.

Key Points Question Can metabolic brain changes be detected in presymptomatic individuals who are carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) using time-of-flight fluorine 18–labeled fluorodeoxyglucose positron emission tomographic imaging and magnetic resonance imaging, and what is the association between the mutation and clinical and fluid biomarkers of amyotrophic lateral sclerosis and frontotemporal dementia? Findings In a case-control study including 17 preSxC9 participants and 25 healthy controls, fluorine 18–labeled fluorodeoxyglucose positron emission tomographic imaging noted significant clusters of relative hypometabolism in frontotemporal regions, the insular cortices, basal ganglia, and thalami in the preSxC9 participants. Use of this strategy allowed detection of changes at an individual level. Meaning Glucose metabolic changes appear to occur early in the sequence of events leading to manifest amyotrophic lateral sclerosis and frontotemporal dementia. Fluorine 18–labeled fluorodeoxyglucose positron emission tomographic imaging may provide a sensitive biomarker of a presymptomatic phase of disease.