Population-based observational study of claudication in older men: The health in men study

Objectives: To assess the prevalence of and risk factors for claudication and its association with subsequent cardiovascular events. Design, setting and participants: Observational cohort study of 12 203 Western Australian men aged 65 years and over, recruited from 1996 to 1999, and followed up from 2001 to 2004. Main outcome measures: Prevalence of claudication and incidence of peripheral arterial disease (PAD); risk factors for claudication and its association with subsequent cardiovascular events. Results: The prevalence of claudication was 5.3% (638 of 11 970 men). At follow-up, after exclusion of 148 men with claudication at baseline and 76 with missing data at follow-up, the crude average annual incidence of new PAD (claudication or procedure for PAD) was 0.85% (95% CI, 0.72%–0.96%). The risk factors for prevalent claudication and incident PAD were similar, with age, smoking, hypertension, diabetes and history of cardiovascular disease dominating. Of the men with claudication at baseline, nearly half (47.5%; 303 of 638) were not taking aspirin. At follow-up, 42.5% (82 of 193) of the men with incident PAD were not taking aspirin. Claudication at baseline was associated with twice the risk of cardiovascular death (hazard ratio, 2.00; 95% CI, 1.52–2.64). There was a J-shaped relationship between aortic diameter, and both prevalent claudication and subsequent cardiovascular events. Conclusions: Among older men, claudication is prevalent and is associated with factors that can still be modified in older age, including smoking, exercise and diet. Relatively few men with claudication or at risk of PAD use aspirin. Claudication is a significant predictor of cardiovascular outcome.Rahul Lakshmanan, Zoë Hyde, Konrad Jamrozik, Graeme J Hankey and Paul E Norma

Analysis of mutations in AARS2 in a series of CSF1R-negative patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Importance: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder.Objective: To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations.Design, Settings, and Participants: In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016.Main Outcomes and Measures: Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity.Results: Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP.Conclusions and Relevance: This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.</p