The objective of this study was to characterize the diagnostic timelines and their predictors in people with amyotrophic lateral sclerosis (ALS). Patients were identified through ALS billing codes. Time from presenting symptom to first doctor visit, first doctor visit to suspected ALS diagnosis, suspected to confirmed ALS diagnosis, and presenting symptom to confirmed ALS diagnosis (total diagnostic time) were collected. Regression models were used to analyze the predictors of diagnostic delay. Three hundred and four ALS patients were included in the analysis. Median total diagnostic time was 11.5 months. Diagnostic timelines were longer in patients with age > 60 years (p < 0.001), sporadic ALS (p = 0.043), and limb onset (p = 0.010). The presence of fasciculations, slurred speech, and lower extremity weakness when symptoms were first noted were independent predictors of shorter time to ALS diagnosis (p = 0.04, p = 0.02, and p = 0.04, respectively). About half of the patients (52%) received an alternative diagnosis and each patient saw an average of three different physicians before ALS diagnosis was confirmed. In conclusion, diagnostic timelines in ALS are long, and patients see many physicians and receive multiple alternative diagnoses before the diagnosis of ALS is confirmed. Older age, sporadic disease, and limb onset can delay ALS diagnosis.

The development of neural circuits relies on axon projections establishing diverse, yet well-defined, connections between areas of the nervous system. Each projection is formed by growth cones (GCs), subcellular specializations at the tips of growing axons, encompassing sets of molecules that control projection-specific growth, guidance, and target selection1. To investigate the set of molecules within native GCs forming specific connections, we developed GC Sorting and Subcellular RNA-Proteome Mapping, an approach that identifies and quantifies local transcriptomes and proteomes from labeled GCs of single projections in vivo. Using this approach on the developing callosal projection of the mouse cerebral cortex, we mapped molecular enrichments in trans-hemispheric GCs relative to their parent cell bodies, producing paired subcellular proteomes and transcriptomes from single neuron subtypes directly from the brain. These data provide generalizable proof-of-principle for this approach, and reveal novel GC molecular specializations, including accumulations of the growth-regulating kinase mTOR2, together withmRNAs containing mTOR-dependent motifs3,4. These findings illuminate therelationships of RNA and protein subcellular distributions in developing projectionneurons, and provide a new systems-level approach for discovery of subtype- and stage-specific molecular substrates of circuit wiring, miswiring, and potential for regeneration.