The first quarter of the twenty-first century has transformed Parkinson’s disease (PD) from a predominantly motor, dopamine-deficiency syndrome into a heterogeneous multisystem disorder defined across clinical, genetic and molecular dimensions. This overview follows the trajectory of these advances from the historical foundations established prior 2000 to present concepts of prodromal disease, progression, biological classification and precision medicine. Epidemiological work has established PD as the fastest-growing major neurological disorder, while systematic characterization of non-motor symptoms has shifted diagnosis and attention beyond the nigrostriatal system in PD research. Imaging has progressed from exclusionary structural magnetic resonance imaging (MRI) to quantitative susceptibility, diffusion and molecular approaches, although no single imaging biomarker yet provides a stand-alone diagnosis of PD. The discovery of α-synuclein gene mutations and its presence as protein in Lewy bodies and neurites connected genetics, protein aggregation and selective neuronal vulnerability. Seed amplification assays (SAA) now enable robust detection of pathological α-synuclein in cerebrospinal fluid and have catalysed biologically anchored staging proposals. At the same time, negative phase 2 antibody against α-synuclein trials illustrate the challenges of target engagement, disease heterogeneity and intervention timing. Genetics and cell biology have placed lysosomal proteostasis, in particular glucocerebrosidase 1 (GBA1) dependent pathways, at the center of disease-modification strategies. Dopaminergic therapy remains extraordinarily effective symptomatically, with continuous delivery systems extending its utility for intermediate and late stages of the disease, whereas cell replacement has re-entered clinical development through standardized pluripotent-stem-cell-derived midbrain dopaminergic progenitors. The next phase of PD research will depend less on a single unifying mechanism than on integrating molecular state, the pattern of neuronal injury, clinical phenotype and individual trajectory to select the right intervention at the right biological stage.
Musician's dystonia is a devastating task-specific movement disorder that robs performers of voluntary motor control during playing and, in progressive cases, extends to daily life, severely impacting mental health and career continuity. While research on musician's dystonia is extensive, studies specifically targeting professionally trained pianists are limited, and its etiology and optimal treatment remain unclear. This study investigated the characteristics and risk factors of focal dystonia among pianists who have received specialized piano training. An anonymous questionnaire was distributed to 2,863 individuals, including members of a professional musicians’ association in Japan (Japan Federation of Musicians), as well as students, piano teachers, and performers at music universities. Individuals reporting involuntary finger or wrist movements occurring exclusively during piano performance were operationally classified as suspected dystonia, a self-reported category that does not constitute a clinical diagnosis, and underwent secondary screening. Comparative statistical analysis was performed between the suspected dystonia group and a non-dystonia group. Among 241 valid respondents, 28 (11.6
Germany has a longstanding tradition of excellence in neuroscience and Parkinson’s research, supported by outstanding academic institutions, specialized clinical centers, and a strong scientific community. Building on this strong foundation, the country now has the opportunity to transform its clinical research landscape into a more integrated ecosystem for Parkinson syndromes. Despite major advances in molecular understanding, biomarker development, and therapeutic innovation, important structural, regulatory, financial, and organizational barriers continue to limit the full translational potential of German Parkinson research. Participants in an expert workshop identified identify recurring challenges, including fragmented trial infrastructures, slow and bureaucratic regulatory procedures, insufficient funding for investigator-initiated clinical research, limited integration of patient organizations, and suboptimal patient recruitment pathways. This workshop-derived perspective outlines a strategic framework to elevate Germany from a country with excellent individual centers to a globally competitive and integrated hub for innovative Parkinson clinical research. Key recommendations include transforming the German Parkinson Study Group into a nationally coordinated, service-oriented trial network; establishing centralized digital and regulatory infrastructures; diversifying public and philanthropic funding; implementing platform and observational trial structures; strengthening incentives for participating centers; and enhancing patient engagement through national registries, decentralized trial approaches, real-world data based evidence surveillance, and systematic integration of patient organizations. The authors argue that Germany must move beyond isolated university-based structures toward a nationally coordinated and highly efficient research ecosystem capable of rapidly delivering disease-modifying and precision medicine trials. Such a transformation could strengthen Germany’s international position in neurodegenerative disease research and accelerate therapeutic innovation for patients with Parkinson syndromes.
Pathogenic variants in the colony-stimulating factor 1 receptor (CSF1R) gene cause CSF1R-related disorder (CSF1R-RD), which encompasses a broad phenotypic spectrum including a classical adult-onset leukoencephalopathy phenotype. Within this spectrum, considerable phenotypic heterogeneity has been increasingly recognized. The pathogenic missense variant c.2539G>A has been reported in a small number of patients with CSF1R-associated leukoencephalopathy; however, its associated clinical spectrum remains incompletely characterized. To characterize the clinical spectrum associated with the CSF1R c.2539G>A pathogenic variant in a Japanese family with CSF1R-RD. Clinical evaluations and genetic analyses, including whole-exome sequencing and Sanger sequencing, were performed in available family members. We detected the same heterozygous CSF1R c.2539G>A pathogenic variant in four members from a Japanese family. Two affected individuals presented with parkinsonism, cognitive decline, and white matter abnormalities typical of CSF1R-RD, whereas the other affected individual exhibited a phenotype consistent with typical Parkinson’s disease (PD), without apparent cognitive impairment or radiological white matter abnormalities. The fourth individual initially had no overt neurological symptoms despite white matter changes on MRI and subsequently developed spastic gait with pyramidal signs, indicating intrafamilial phenotypic variability. These findings broaden the phenotypic spectrum associated with the CSF1R c.2539G>A pathogenic variant and highlight marked intrafamilial phenotypic heterogeneity, including a PD-like phenotype without typical cognitive or white matter abnormalities.
Cerebellar ataxias are a diverse group of hereditary and acquired disorders that impair balance, gait, posture and ocular movements. With limited treatment options, particularly in hereditary forms, neuromodulation has emerged as a promising therapeutic approach particularly the transcranial direct current stimulation (tDCS). This scoping review aims to discuss the role of tDCS as a potential therapy in reducing ataxia symptoms in both hereditary and acquired forms. A total of 787 studies were found after searching Pubmed, EMBASE, and Cochrane. After removing 273 duplicates, 514 studies remained for title and abstract screening. Of these, 387 studies were excluded, leaving 127 studies for full-text assessment. Following retrieval of full text, 26 was assessed for eligibility. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive literature search was performed using PubMed, EMBASE, and Cochrane databases. Two independent reviewers screened studies through title/abstract and full-text review, with disagreements resolved by discussion or adjudication by two additional reviewers when necessary. We included 18 studies for the final analysis. Most studies reviewed showed that tDCS is a potential option for the treatment of ataxia, however, differences among participants, neuromodulation techniques, or trial protocols may have led to differences in the clinical outcomes. Our review highlights that the vast majority of the randomized controlled studies of tDCS in neurodegenerative ataxias have demonstrated clinical beneficial effect. There are preliminary observations that tDCS in combination therapy with rehabilitation or exercise may provide greater or more functional improvements. Future multicenter studies with long term follow up of individual disease groups, supported by clinical, imaging and biological marker measurements will help address the current limitations.
