To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1636-z) contains supplementary material, which is available to authorized users.

We identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 × 10−9, odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. An increase in the number of fusiform swellings of Purkinje cell axons in LINGO1 knockout models highlights the potential role of LINGO1 in essential tremor pathophysiology.

We performed a randomized double-blind study within-group comparison in 11 patients to study the effect of subcutaneous injections of botulinum A toxin in focal hyperhidrosis of the palms. A total dose of 120 mU (mouse units) of botulinum A toxin (Dysport) was injected into six different sites on one palm, whereas the other was injected with sterile saline. Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets. Three weeks after treatment, the mean reduction of sweat production in the botulinum A toxin-treated palms was 26% (P < 0.001), after 8 weeks 26% (P = 0.002) and after 13 weeks 31% (P < 0.001). Subjective assessment of sweat production by the patients using a visual analogue scale showed a 38% improvement in the botulinum A toxin-treated palms at 3 weeks (P = 0.002), 40% at 8 weeks (P = 0.002) and 38% at 13 weeks (P = 0.002). Neither the objective measurement nor the subjective rating showed a statistically significant reduction of sweating in the placebo-treated palms. Three patients reported reversible minor weakness of powerful handgrip after injection at the toxin-treated site, lasting between 2 and 5 weeks.

We performed a randomized double-blind study within-group comparison in 11 patients to study the effect of subcutaneous injections of botulinum A toxin in focal hyperhidrosis of the palms. A total dose of 120 mU (mouse units) of botulinum A toxin (Dysport) was injected into six different sites on one palm, whereas the other was injected with sterile saline. Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets. Three weeks after treatment, the mean reduction of sweat production in the botulinum A toxin-treated palms was 26% (P < 0.001), after 8 weeks 26% (P = 0.002) and after 13 weeks 31% (P < 0.001). Subjective assessment of sweat production by the patients using a visual analogue scale showed a 38% improvement in the botulinum A toxin-treated palms at 3 weeks (P = 0.002), 40% at 8 weeks (P = 0.002) and 38% at 13 weeks (P = 0.002). Neither the objective measurement nor the subjective rating showed a statistically significant reduction of sweating in the placebo-treated palms. Three patients reported reversible minor weakness of powerful handgrip after injection at the toxin-treated site, lasting between 2 and 5 weeks.