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Objective Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis-specific autoantibodies (MSAs) have prognostic significance in juvenile DM. Methods Muscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow-up 4.9 years). Long-term treatment status (on or off medication over time) was modeled using generalized estimating equations. Results Muscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48-fold higher odds (95% confidence interval [95% CI] 1.12-1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10-fold higher odds (95% CI 1.01-1.21; P = 0.038). A protective effect was identified in patients with anti-Mi-2 autoantibodies, in whom the odds of remaining on treatment were 7.06-fold lower (95% CI 1.41-35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti-nuclear matrix protein 2 autoantibodies, anti-transcription intermediary factor 1γ autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61-fold higher odds (95% CI 1.16-2.22; P = 0.004), and for the total biopsy score, 1.13-fold higher odds (95% CI 1.03-1.24; P = 0.013). Conclusion Histopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease. [ABSTRACT FROM AUTHOR]

Importance: Circadian dysfunction may be associated with the symptoms and neurodegeneration in Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP), although the underlying neuroanatomical site of disruption and pathophysiological mechanisms are not fully understood., Objective: To perform a neuropathological analysis of disease-specific inclusions in the key structures of the circadian system in patients with PD, MSA, and PSP., Design, Setting, and Participants: This investigation was a brain bank case-control study assessing neuropathological inclusions in the suprachiasmatic nucleus (SCN) of the hypothalamus and pineal gland in healthy controls, PD (Lewy pathology), MSA (glial cytoplasmic inclusions), and PSP (tau inclusions). The study analyzed 12 healthy control, 28 PD, 11 MSA, and 21 PSP samples from consecutive brain donations (July 1, 2010, to June 30, 2016) to the Queen Square Brain Bank for Neurological Disorders and the Parkinson's UK Brain Bank, London, United Kingdom. Cases were excluded if neither SCN nor pineal tissue was available., Main Outcomes and Measures: Disease-specific neuropathological changes were graded using a standard semiquantitative scoring system (absent, mild, moderate, severe, or very severe) and compared between groups., Results: Because of limited tissue availability, the following total samples were examined in a semiquantitative histologic analysis: 5 SCNs and 7 pineal glands in the control group (6 male; median age at death, 83.8 years; interquartile range [IQR], 78.2-88.0 years), 13 SCNs and 17 pineal glands in the PD group (22 male; median age at death, 78.8 years; IQR, 75.5-83.8 years), 5 SCNs and 6 pineal glands in the MSA group (7 male; median age at death, 69.5 years; IQR, 61.6-77.7 years), and 5 SCNs and 19 pineal glands in the PSP group (13 male; median age at death, 74.3 years; IQR, 69.7-81.1 years). No neuropathological changes were found in either the SCN or pineal gland in healthy controls or MSA cases. Nine PD cases had Lewy pathology in the SCN, and only 2 PD cases had Lewy pathology in the pineal gland. All PSP cases showed inclusions in the SCN, but no PSP cases had pathology in the pineal gland., Conclusions and Relevance: Disease-related neuropathological changes were found in the SCN but not in the pineal gland in PD and PSP, while both structures were preserved in MSA, reflecting different pathophysiological mechanisms that may have important therapeutic implications.

Objective: The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA)., Methods: One series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA., Results: In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio [OR] = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005)., Conclusions: These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important., (© 2014 American Academy of Neurology.)