Sarm1 knockout modifies biomarkers of neurodegeneration and spinal cord circuitry but not disease progression in the mSOD1G93A mouse model of ALS.

The mechanisms underlying the loss of motor neuron axon integrity in amyotrophic lateral sclerosis (ALS) are unclear. SARM1 has been identified as a genetic risk variant in sporadic ALS, and the SARM1 protein is a key mediator of axon degeneration. To investigate the role of SARM1 in ALS-associated axon degeneration, we knocked out Sarm1 (Sarm1KO) in mSOD1G93ATg (mSOD1) mice. Animals were monitored for ALS disease onset and severity, with motor function assessed at pre-symptomatic and late-stage disease and lumbar spinal cord and sciatic nerve harvested for immunohistochemistry at endpoint (20 weeks). Serum was collected monthly to assess protein concentrations of biomarkers linked to axon degeneration (neurofilament light (NFL) and tau), and astrogliosis (glial fibrillary acidic protein (GFAP)), using single molecule array (Simoa®) technology. Overall, loss of Sarm1 in mSOD1 mice did not slow or delay symptom onset, failed to improve functional declines, and failed to protect motor neurons. Serum NFL levels in mSOD1 mice increased between 8 -12 and 16-20 weeks of age, with the later increase significantly reduced by loss of SARM1. Similarly, loss of SARM1 significantly reduced an increase in serum GFAP between 16 and 20 weeks of age in mSOD1 mice, indicating protection of both global axon degeneration and astrogliosis. In the spinal cord, Sarm1 deletion protected against loss of excitatory VGluT2-positive puncta and attenuated astrogliosis in mSOD1 mice. In the sciatic nerve, absence of SARM1 in mSOD1 mice restored the average area of phosphorylated neurofilament reactivity towards WT levels. Together these data suggest that Sarm1KO in mSOD1 mice is not sufficient to ameliorate functional decline or motor neuron loss but does alter serum biomarker levels and provide protection to axons and glutamatergic synapses. This indicates that treatments targeting SARM1 could warrant further investigation in ALS, potentially as part of a combination therapy.

Association between socioeconomic status and incident atrial fibrillation.

BACKGROUND: Low socioeconomic status is associated with cardiovascular diseases, and an association with atrial fibrillation (AF) could guide screening. AIM: To investigate if indices of advantage/disadvantage (IAD), index of education/occupation (IEO) and index of economic resources were associated with incident AF, independent of risk factors and cardiac function. METHODS: We studied community-based participants aged ≥65 years with AF risk factors (n = 379, age 70 ± 4 years, 45% men). The CHARGE-AF score (a well validated AF risk score) was used to assess 5-year risk of developing AF. Participants also had baseline echocardiograms. IAD, IEO and index of economic resources were obtained from the 2011 Socio-Economic Indexes for Areas score, in which higher decile ranks indicate more advantaged areas. Patients were followed up for incident AF (median 21 (range 5-31) months), with AF diagnosed by clinical review, including 12-lead electrocardiogram (ECG), as well as single-lead portable ECG monitoring used to record 60 s ECG tracings five times/day for 1 week. Cox proportional hazards models were used to assess the association between socioeconomic status and incident AF. RESULTS: Subjects with AF (n = 50, 13%) were more likely to be male (64 vs 42%, P = 0.003) and had higher CHARGE-AF score (median 7.1% (5.2-12.8%) vs 5.3% (3.3-8.6%), P < 0.001). Areas with lower socioeconomic status (IAD and IEO) had a higher risk of incident AF independent of LV function and CHARGE-AF score (hazard ratio for IAD 1.16, 95% confidence interval 1.05-1.29, P = 0.005 and hazard ratio for IEO 1.18, 95% confidence interval 1.07-1.30, P = 0.001). CONCLUSION: Regional socioeconomic status is associated with risk of incident AF, independent of LV function and clinical risk. This association might permit better regional targeting of prevention.