UNASSIGNED: Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson\'s disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD.
UNASSIGNED: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies.
UNASSIGNED: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy.
UNASSIGNED: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity.
UNASSIGNED: P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.

Parkinson\'s disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers (\"good\" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.

In recent years, a precision medicine approach, which customizes medical treatments based on patients\' individual profiles and incorporates variability in genes, the environment, and lifestyle, has transformed medical care in numerous medical fields, most notably oncology. Applying a similar approach to Parkinson\'s disease (PD) may promote the development of disease-modifying agents that could help slow progression or possibly even avert disease development in a subset of at-risk individuals. The urgent need for such trials partially stems from the negative results of clinical trials where interventions treat all PD patients as a single homogenous group. Here, we review the current obstacles towards the development of precision interventions in PD. We also review and discuss the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD.

In recent years, numerous clinical trials for disease modification in Parkinson\'s disease (PD) have failed, possibly because of a \"one-size-fits all\" approach. Alternatively, a precision medicine approach, which customises treatments based on patients\' individual genotype, may help reach disease modification. Here, we review clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD. In summary, six ongoing studies which explicitely recruit GBA-PD patients, and two studies which recruit LRRK2-PD patients, were identified. Available data on mechanisms of action, study design, and challenges of therapeutic trials are discussed.

The worldwide spread of Parkinson\'s disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease.
We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls. Moreover, to detect sui generis language disturbances, we ran analysis of covariance tests using executive functions as covariate.
The two clinical groups showed impairments in all measures, most of which survived covariation with executive functions. However, the key finding concerned asymptomatic mutation carriers. While these subjects showed intact executive, semantic, and action-verb production skills, they evinced deficits in a syntactic test with minimal working memory load.
We propose that this sui generis disturbance may constitute a prodromal sign anticipating eventual development of PD. Moreover, our results suggest that mutations on specific genes (PARK2 and LRRK2) compromising basal ganglia functioning may be subtly related to language-processing mechanisms. (JINS, 2017, 23, 150-158).