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Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson’s disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2’s involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

Background: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson’s disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD. Further, postmortem studies suggest involvement of neuromelanin (NM) loss and iron deposition in nigral neurodegeneration and HE+ emergence. However, the associations between HE+ and signs of nigral NM loss and iron deposition revealed by magnetic resonance imaging (MRI) have not been examined. Objective: To elucidate the magnetic resonance- (MR-) morphological representation of the HE+ by NM-weighted (NMI) and susceptibility-weighted MRI (SWI). Methods: Thirty-four PD patients and 29 healthy controls (HCs) received TCS followed by NMI and SWI. From MR images, two independent raters manually identified the SN, placed seeds in non-SN midbrain areas, and performed semi-automated SN segmentation with different thresholds based on seed mean values and standard deviations. Masks of the SN were then used to extract mean area, mean signal intensity, maximal signal area, maximum signal (for NMI), and minimum signal (for SWI). Results: There were no significant differences in NMI- and SWI-based parameters between patients and HCs, and no significant associations between HE+ extent and NMI- or SWI-based parameters. Conclusion: HE+ on TCS appears unrelated to PD pathology revealed by NMI and SWI. Thus, TCS and MRI parameters should be considered complementary, and the pathophysiological correlates of the HE+ require further study.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene–environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann–Whitney U test. Non-parametric Spearman’s correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. We found that smoking (p p p n = 237 patients with PD).

Zusammenfassung Hintergrund Das standardisierte geriatrische Assessment der oberen Extremitäten beschränkt sich häufig auf die Messung der Handkraft. Als einziges weiteres Instrument nennt die S1-Leitlinie zum geriatrischen Assessment der Stufe 2 den 20-Cents-Test (20-C-T). Neben Kraft und Feinmotorik ist jedoch das erfolgreiche Platzieren der Hand eine Voraussetzung für die Selbstversorgung. Ziel der Arbeit Zur standardisierten seitengetrennten Überprüfung des alltagsrelevanten Positionierens der Hand im Sitzen wurde der 8‑Punkte-Greifraum-Test (8P-GRT) entwickelt. Die Studie diente der Ermittlung von Gütekriterien des 8P-GRT bei geriatrischen Krankenhauspatienten. Material und Methoden Zwischen dem 31.07.2019 und dem 23.09.2019 wurden im Krankenhaus Rotes Kreuz Lübeck – Geriatriezentrum 82 stationäre Patienten mithilfe des 8P-GRT, des Shoulder Pain and Disability Index (SPADI), einem zu den Handpositionen des 8P-GRT korrespondierenden Fragebogen zu Aktivitäten der Selbstversorgung, der Handkraftmessung und dem 20-C‑T untersucht. Ergebnisse Die Interrater-Reliabilität betrug 0,99, die Retest-Reliabilität 0,95 für die rechte und 0,90 für die linke Seite. Auf die Person bezogen, trat ein Deckeneffekt (beidseits Score 8) bei 4,1 % (n = 3) auf; kein Bodeneffekt wurde beobachtet. Die interne Konsistenz (Cronbachs α) des gemäß Faktorenanalyse zweifaktoriellen Tests betrug 0,78 (rechts) bzw. 0,76 (links). Jeder der anderen Tests korrelierte enger mit dem 8P-GRT auf der rechten Seite, wobei die Korrelation mit dem oben genannten Fragebogen am höchsten war (−0,72), gefolgt vom SPADI (−0,60). Diskussion Eine standardisierte Erhebung der Handkraft, Feinmotorik und aktiven Positionierung der Hand (z. B. 8P-GRT) fügt die Hauptaspekte der Funktionsfähigkeit der oberen Extremitäten zu einem Gesamtbild zusammen.

Background Heterozygous carriers of Parkin mutations are suggested to be at risk of developing Parkinson's disease, while biallelic variants are associated with typical autosomal recessive early-onset PD. Investigating unaffected heterozygous mutation carriers holds the potential of a deeper understanding of monogenic PD and has implications for PD in general, in particular regarding the prodromal phase. Objectives To discriminate healthy Parkin mutation carriers from healthy non-mutation carriers using a multimodal approach. Methods Twenty-seven healthy heterozygous Parkin mutation carriers (13 female. age: 48 ± 13 years) and 24 healthy non-mutation carriers (14 female. age: 48 ± 15 years) from the CHRIS study (Cooperative Health Research in South Tyrol) were recalled based on their genetic profile and underwent a blinded assessment of motor and non-motor PD symptoms, transcranial sonography and sensor-based posturography and gait analyses under different conditions with increasing difficulty. For the latter, gradient-boosted trees were used to discriminate between carriers and non-carriers. The classification accuracy and the area under the curve of the receiver-operator characteristics curve were calculated. Results We observed no differences concerning motor or non-motor symptoms and substantia nigra hyperechogenicity. The best gradient-boosted trees-based model on posturography measurements (tandem feet, eyes closed, firm surface), however, showed a classification accuracy of up to 86%. The best-performing gradient-boosted trees-based model for gait analyses showed a balanced accuracy of up to 87% (dual-tasking). Conclusions Sensor-based quantification of movements allows to discriminate unaffected heterozygous mutation carriers from mutation-free controls. Thereby, it is crucial to challenge the motor system with more difficult tasks to unmask subtle motor alterations.

Patients with Parkinson’s disease (PD) carrying variants in the Glucocerebrosidase (GBA) gene (GBA-PD) suffer from orthostatic symptoms more frequently than idiopathic PD patients (IPD). Systematic measurements of the blood pressure have not yet been performed. In the present study, a prospective analysis of 33 GBA-PD and 313 IPD patients was carried out. Systolic blood pressure upon changing from the supine to the upright position dropped more strongly in GBA-PD compared to IPD patients. Diastolic blood pressure and heart rate did not differ between groups. This study provides further evidence for a pronounced involvement of the autonomic nervous system in GBA-PD.

Background The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson’s disease. Methods Thirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios. Results Subcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects. Conclusions Our study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease with both motor and non-motor manifestations. Available treatment reduces symptoms and is critical for improving quality of life. Treatment options include drugs, device-aided therapies, and non-pharmacological therapies. Complementary and alternative therapies (CATs) are also used in some countries.To examine the availability of PD treatment by country, and differences by national income as defined by the World Bank (high income countries (HICs), upper middle income countries (UMICs), lower middle income countries (LMICs) and low income countries (LICs)).This study was conducted by surveying International Parkinson and Movement Disorders Society members about availability of PD treatment. LMICs and LICs (LMICs/LICs) were analysed together.There were 352 valid responses from 76 countries (41.5% from HICs, 30.4% from UMICs, and 28.1% from LMICs/LICs). Levodopa was widely available across all income groups (99%). Availability of other PD drugs decreased with national income. Availability of device-aided therapies decreased with national income (100% availability in HICs, 92.5% among UMICs, and 57.6% among LMICs/LICs). A similar trend was observed for CATs (37.0% availability in HICs, 31.8% in UMICs, and 19.2% in LMIC/LICs). Physiotherapy was the most available non-pharmacological therapy ( 90% respondents). Occupational therapy and SALT were less available in LMIC/LICs (49.5% and 55.6% respectively) compared to HICs (80.1% and 84.9% respectively).Our survey highlights significant discrepancies in availability of PD treatments between countries and income groups. This is concerning given the symptomatic benefit patients gain from treatment. Improving equitable access to PD treatment should be prioritised.

Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson’s disease and discuss the therapeutic implications.

There is a bidirectional interaction between peripheral inflammatory processes and the brain. In the context of stress, top-down effects on the immune system have already been studied, but bottom-up effects of peripheral inflammation on neural processes are still unclear. In the present study, baseline plasma levels of the cytokine interleukin (IL)-6 were obtained as a measure of peripheral inflammatory processes and psychosocial stress was induced in 78 healthy adults during functional magnetic resonance imaging. The association of IL-6 with stress-related neural activation in the amygdala, anterior insula, and anterior cingulate cortex as regions of interest was explored. In order to account for individual differences in the stress response, salivary cortisol increase was also considered in the analyses. Stress task-related neural activity in the amygdala and anterior insula was significantly and negatively associated with IL-6 levels only in participants showing a cortisol response. These results suggest that peripheral inflammatory processes might affect the evaluation of a social stressor and highlight that individual differences in stress task responses should be considered in future studies.

Idiopathic Parkinson’s disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible.

The standardized geriatric assessment of the upper extremities is often limited to measurement of hand strength. The only other instrument mentioned in the S1 guidelines on level 2 geriatric assessment is the 20 cents test (20-C-T); however, in addition to strength and fine motor skills, successful hand placement is a prerequisite for self-care.The 8‑point reaching range test (8P-GRT) was developed for standardized separate testing of sides in a seated person concerning hand positioning relevant to daily living. The purpose of the study was to determine quality criteria of the 8P-GRT in geriatric hospital patients.Between 31 July 2019 and 23 September 2019, a total of 82 inpatients were examined at the Hospital Red Cross Lübeck Geriatrics Center using the 8P-GRT, shoulder pain and disability index (SPADI), a questionnaire on self-care activities corresponding to the hand positions of the 8P-GRT, hand strength measurement and the 20-C‑T.The interrater reliability was 0.99 and the retest reliability was 0.95 for the right side and 0.90 for the left side. On the individual level a ceiling effect (both sides score 8) occurred in 4.1% (n = 3) but no floor effect was observed. The internal consistency (Cronbach's alpha) of the two-factorial test according to factor analysis was 0.78 (right) and 0.76 (left). Each of the other tests correlated more closely with the 8P-GRT on the right side, whereby the correlation was highest with the abovenamed questionnaire (-0.72), followed by the SPADI (-0.60).A standardized survey of hand strength, fine motor skills and active positioning of the hand (e.g., 8P-GRT) synthesizes the main aspects of upper extremity functioning into an overall picture.HINTERGRUND: Das standardisierte geriatrische Assessment der oberen Extremitäten beschränkt sich häufig auf die Messung der Handkraft. Als einziges weiteres Instrument nennt die S1-Leitlinie zum geriatrischen Assessment der Stufe 2 den 20-Cents-Test (20-C-T). Neben Kraft und Feinmotorik ist jedoch das erfolgreiche Platzieren der Hand eine Voraussetzung für die Selbstversorgung.Zur standardisierten seitengetrennten Überprüfung des alltagsrelevanten Positionierens der Hand im Sitzen wurde der 8‑Punkte-Greifraum-Test (8P-GRT) entwickelt. Die Studie diente der Ermittlung von Gütekriterien des 8P-GRT bei geriatrischen Krankenhauspatienten.Zwischen dem 31.07.2019 und dem 23.09.2019 wurden im Krankenhaus Rotes Kreuz Lübeck – Geriatriezentrum 82 stationäre Patienten mithilfe des 8P-GRT, des Shoulder Pain and Disability Index (SPADI), einem zu den Handpositionen des 8P-GRT korrespondierenden Fragebogen zu Aktivitäten der Selbstversorgung, der Handkraftmessung und dem 20-C‑T untersucht.Die Interrater-Reliabilität betrug 0,99, die Retest-Reliabilität 0,95 für die rechte und 0,90 für die linke Seite. Auf die Person bezogen, trat ein Deckeneffekt (beidseits Score 8) bei 4,1 % (n = 3) auf; kein Bodeneffekt wurde beobachtet. Die interne Konsistenz (Cronbachs α) des gemäß Faktorenanalyse zweifaktoriellen Tests betrug 0,78 (rechts) bzw. 0,76 (links). Jeder der anderen Tests korrelierte enger mit dem 8P-GRT auf der rechten Seite, wobei die Korrelation mit dem oben genannten Fragebogen am höchsten war (−0,72), gefolgt vom SPADI (−0,60).Eine standardisierte Erhebung der Handkraft, Feinmotorik und aktiven Positionierung der Hand (z. B. 8P-GRT) fügt die Hauptaspekte der Funktionsfähigkeit der oberen Extremitäten zu einem Gesamtbild zusammen.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene-environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann-Whitney U test. Non-parametric Spearman's correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. We found that smoking (p 0.0001), coffee drinking (p 0.0001) and aspirin intake (p 0.0001) show an exploratory association with AAO in PD, that was further supported by multivariate regression models. The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) (n = 237 patients with PD).

BACKGROUND Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (70%) was lower in comparison to the remaining three genes (85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We have previously shown that OCTA imaging in PD patients can be challenging. Our data suggest that retinal perfusion is reduced in both plexuses in PD, which may serve as a noninvasive biomarker in the future. Yet, control of motion artifacts in OCTA measurements is critical in this motor-impaired cohort.

Aim: Validation of epigenome-wide association studies is sparse. Therefore, we evaluated the methylation markers cg06500161 ( ABCG1) and cg11024682 ( SREBF1) as classifiers for diabetes stratification. Patients & methods: DNA methylation was measured in blood (n = 167), liver (n = 99) and visceral adipose tissue (n = 99) of nondiabetic or Type 2 diabetic subjects by bisulfite pyrosequencing. Results: DNA methylation at cg11024682 in blood and liver correlated with BMI. Methylation at cg06500161 was influenced by the adjacent SNP rs9982016. Insulin-resistant and sensitive subjects could be stratified by DNA methylation status in blood or visceral adipose tissue. Conclusion: DNA methylation at both loci in blood presents a promising approach for risk group stratification and could be valuable for personalized Type 2 diabetes risk prediction in the future.

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 x 10(-11)), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 x 10(-8)) and WWOX (HR = 2.12, P = 2.37 x 10(-8)) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.A genome-wide survival study identifies variants at RIMS2 associated with progression of Parkinson's disease to dementia and highlights divergence in the genetic architecture of disease onset and progression.

To evaluate the significance of motion artifacts in optical coherence tomography angiography (OCTA) images of patients with Parkinson’s disease (PD) and healthy controls. In this prospective, cross-sectional study subjects with medicated PD (ON) and healthy, age- and gender-matched volunteers were recruited. Participants underwent specific ophthalmological examinations, including OCTA. Angiograms of the superficial retinal capillary plexus were evaluated for the type and frequency of artifacts using a validated motion artifact score (MAS). A total of 30 PD patients (60 eyes), average disease duration of 9.61 ± 5.55 years, and 30 matched, healthy controls (60 eyes) were recruited. Twenty percent of all eyes had an eye disease, unknown to the participant, with a significant impact on OCTA results. After cleansing the dataset by excluding subjects with confounding ocular comorbidities 42 eyes of 28 PD patients and 53 eyes of 29 healthy controls were further evaluated. Overall MAS and all five subtypes of motion artifacts were comparable without significant differences between groups. OCTA can be used in treated PD patients (ON) without a significant increase in motion artifacts. Nevertheless, special attention should be paid to image quality during the acquisition of OCTA data, for which an experienced OCTA operator is useful.

ObjectiveTo investigate the contribution of substantia nigra (SN) and locus coeruleus (LC) pathology to clinical signs and symptoms in Parkinson disease (PD) by applying neuromelanin-weighted imaging.MethodsForty-seven patients with PD and 53 matched controls underwent motor assessment, a neuropsychological test battery, and neuromelanin-weighted MRI. Patients with PD were enrolled after fulfilling the criteria for clinically established PD as defined by the Movement Disorders Society Clinical Diagnostic Criteria. Two independent raters identified SN and LC and calculated the contrast-to-noise ratio (CNR).ResultsThe intrarater reliability demonstrated good reliability between raters with an intraclass correlation coefficient of 0.88 (p < 0.001) and an interrater reliability of 0.80 (p < 0.001). Both SN and LC CNRs were lower in patients with PD (p ≤ 0.001) compared to controls. The CNR of SN but not of LC was strongly correlated with disease duration (p ≤ 0.001). Neuromelanin pathology of the pars compacta–containing dorsolateral SN correlated with Movement Disorders Society–sponsored version of the Unified Parkinson’s Disease Rating Scale I, II, and III but not cognitive function. In contrast, neuromelanin pathology of LC was associated with cognitive function in all tested domains but not with motor impairment or activities of daily living. No such associations were present in controls.ConclusionsNeuromelanin imaging of the SN and LC is well-suited to map neurodegeneration in PD. Neuromelanin pathology of the SN correlates with motor dysfunction whereas LC pathology is related to cognitive impairment. Neuromelanin-weighted imaging of the LC could thus serve as an imaging marker of executive and other cognitive dysfunction in PD.Classification of EvidenceThis study provides Class I evidence that neuromelanin-weighted imaging was associated with the severity of various signs and symptoms in patients with PD.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene-environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) and clinical severity in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann-Whitney U test. Non-parametric Spearman correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. Reported p-values remain descriptive because they are not corrected for multiple testing and results are exploratory. We found that smoking (r=0.08, p

Background: genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize similar to 10,000 participants. Methods: recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing. Results: initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of similar to 14% among a PD cohort from tertiary referral centers. Conclusions: the ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials., Denali Therapeutics Inc. (South San Francisco, CA) partially funded laboratory testing services.

Objectives The effect of environmental and lifestyle factors on patients with LRRK2 (leucine-rich repeat kinase 2) p.Gly2019Ser (LRRK2+ /PD+ ) compared to idiopathic PD (iPD) has yet to be thoroughly investigated. Methods In a homogeneous Tunisian Arab Berber population, we recruited 200 idiopathic PD and 199 LRRK2 p.Gly2019Ser mutation carriers, of whom 142 had PD (LRRK2+ /PD+ ) and 57 were unaffected (LRRK2+ /PD- ). Case report form (CRF) questionnaires (motor and non-motor symptoms) including the Geoparkinson Questionnaire were used to assess environmental and lifestyle factors. Results In LRRK2+ /PD+ , tobacco use was significantly associated with a later median age at onset (AAO). The median AAO was 60 years (interquartile range = 52-67.25) for tobacco users, compared to 52 years (interquartile range = 45.25-61) for non-users (P = 0.0042 at adjusted α = 0.025). Additionally, we observed an independent but additive effect of black tea consumption and tobacco use. Conclusions Our data suggest that tobacco and black tea have a protective effect on age at onset in LRRK2+ /PD+ . © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkin/PINK1 deficiency impairs mitophagy in mice, leading to the release of mitochondrial DNA (mtDNA) and triggering inflammation. Borsche et al. now demonstrate elevated serum Interleukin 6 and circulating cell-free mtDNA also in patients with Parkin/PINK1 mutations, further implicating inflammation in Parkinson’s disease., There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P

BACKGROUND The concept of prodromal Parkinson's disease (PD) involves variable combinations of nonmotor features and subtle motor abnormalities as a result of ongoing neurodegeneration in the brain stem including substantia nigra (SN) and abnormal findings upon transcranial sonography and nuclear imaging. Except for nuclear imaging, the predictive value of risk markers for the conversion to overt PD is low. OBJECTIVE The objective of this study was to determine whether PD risk markers are associated with changes in brain structure and to what extent cognitive changes are risk markers for PD. METHODS Diffusion-weighted imaging, voxel-based morphometry, and cortical thickness analysis was performed in 29 individuals with hyposmia and/or an increased SN hyperechogenicity (SN+) upon transcranial sonography and 28 controls without these 2 risk markers. Classical parkinsonian signs were an exclusion criterion. All of the participants underwent a neuropsychological test battery addressing executive functions, learning ability, and verbal fluency. RESULTS In the PD risk group, diffusion-weighted imaging mean diffusivity was increased in 4 left hemisphere clusters (posterior thalamus, inferior longitudinal fasciculus, fornix, corticospinal tract). A negative relationship of mean diffusivity and smell function was present for the posterior thalamus and the corticospinal tract. There was a significant correlation of mean diffusivity values and SN+ in all clusters. Neither voxel-based morphometry nor cortical thickness analysis revealed any group differences. No relevant group differences were observed for cognitive tests included. CONCLUSION PD-free individuals with PD risk markers show microstructural changes of the white matter, including areas relevant for motor and limbic processes. In addition, our study provides for the first time a neuroanatomical correlate for SN hyperechogenicity. © 2018 International Parkinson and Movement Disorder Society.

Objectives: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. Methods: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unrelated healthy controls. Results: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). Conclusions: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

This first comprehensive MDSGene review is devoted to the 3 autosomal recessive Parkinson's disease forms: PARK-Parkin, PARK-PINK1, and PARK-DJ1. It followed MDSGene's standardized data extraction protocol and screened a total of 3652 citations and is based on fully curated phenotypic and genotypic data on >1100 patients with recessively inherited PD because of 221 different disease-causing mutations in Parkin, PINK1, or DJ1. All these data are also available in an easily searchable online database (www.mdsgene.org), which also provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including early onset (median age at onset of ∼30 years for carriers of at least 2 mutations in any of the 3 genes) of an overall clinically typical form of PD with excellent treatment response, dystonia and dyskinesia being relatively common and cognitive decline relatively uncommon. However, when comparing actual data with common expert knowledge in previously published reviews, we detected several discrepancies. We conclude that systematic reporting of phenotypes is a pressing need in light of increasingly available molecular genetic testing and the emergence of first gene-specific therapies entering clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Objective:To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples).Methods:Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks.Results:A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E–6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E–4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3.Conclusions:We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.

Background Mild parkinsonian signs (MPS) are frequent in the elderly population and associated with the presence of risk markers for Parkinson's disease (PD). Both MPS and non-motor signs may be present in prodromal PD and may significantly impair quality of life (QoL). Objective To disentangle the contribution of motor impairment and extra-motor manifestations to QoL in subjects with MPS (n=63), manifest PD (n=69), disorders with motor symptoms due to non-neurodegenerative diseases (n=213) and healthy controls (n=258). Methods Subjects with MPS, healthy controls, disease controls (patients with motor impairment due to, eg, arthrosis and spondylosis), and PD patients (total n=603) were selected from a large epidemiological longitudinal study, the EPIPARK cohort. Motor function was determined using the UPDRSIII protocol, and information on depressive symptoms, anxiety, sleep, and QoL was assessed via rating scales and data were analyzed. Results Depressive symptoms, anxiety, and sleep problems were equally frequent in the MPS group and controls. Health-related QoL was slightly reduced in the MPS group. Motor impairment and its extent was comparable between the MPS group and disease controls (UPDRSIII 5-6 points). Higher motor dysfunction was associated with lower QoL. Depressive symptoms, but not anxiety and daytime sleepiness, was significant predictors of general QoL, independent of motor function. Conclusions Quality of life is slightly decreased in an elderly population with MPS. QoL is associated with severity of motor impairment but also with non-motor aspects, ie, depressive symptoms. Follow-up studies in large cohorts are warranted to determine the natural course of MPS and its impact on QoL.