The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings.

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 ~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 ~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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of pre-admission oral anticoagulation on ischaemic stroke volume, lesion pattern, and frequency of intracranial arterial occlusion in patients with atrial fibrillation.

Aims: Therapeutic oral anticoagulation on hospital admission reduces morbidity and mortality after acute ischaemic stroke in patients with atrial fibrillation (AF). The underlying mechanism is not fully understood. In order to assess the impact of INR-level on admission on stroke volume, lesion pattern and the frequency of intracranial arterial occlusion, we analysed serial MRI measurements in AF patients suffering acute ischaemic stroke. Methods and results: This subgroup analysis of the prospective '1000Plus' study included patients with acute ischaemic stroke and known AF or a first episode of AF in hospital. All patients underwent serial brain magnetic resonance imaging. Stroke patients were categorized as follows: Group1, phenprocoumon intake, international normalized ratio (INR) ≥1.7 on admission, no thrombolysis; Group2, INR < 1.7 on admission, thrombolysis; and Group3, INR < 1.7, no thrombolysis. In 98 AF patients {77 ± 9 years, 60% male; median National Institute of Health Stroke Scale [NIHSS] score on admission 5 (interquartile range [IQR] 2-8)} with known AF before admission, territorial infarction was less often found in Group 1 (n = 20) compared with Group 2 + 3 (20% vs. 47%, P = 0.022). Arterial occlusion rate on admission differed among groups (30%, 75%, and 35%, respectively, P = 0.004) but not between Group 1 vs. Group 2 + 3 (30% vs. 45%, P = 0.31). Median FLAIR volume on Days 5-7 was lower in Group1 compared with Group 2 (n = 20) [3.2 cm3 (IQR 1.1-11.3) vs. 18.6 cm3 (IQR 8.2-49.4); P = 0.009] but not compared with Group 2 + 3 [7.8 cm3 (IQR 1.6-25.9); P = 0.23]. An INR ≥ 1.7 on admission was not associated with smaller stroke volume in multivariable regression analysis. Adding 57 patients with a first AF episode during the in-hospital stay, similar results were observed in 155 AF patients. Conclusion: In this AF cohort, an INR ≥ 1.7 at stroke onset affects lesion pattern but does not affect significantly lower stroke volume and the frequency of arterial occlusion on admission.

Case report of a young stroke patient showing interim normalization of the MRI diffusion-weighted imaging lesion.

BACKGROUND: In acute ischemic stroke, diffusion weighted imaging (DWI) shows hyperintensities and is considered to indicate irreversibly damaged tissue. We present the case of a young stroke patient with unusual variability in the development of signal intensities within the same vessel territory. CASE PRESENTATION: A 35-year-old patient presented with symptoms of global aphasia and hypesthesia of the left hand. MRI demonstrated a scattered lesion in the MCA territory. After rtPA therapy the patient received further MRI examination, three times on day 1, and once on day 2, 3, 5 and 43. The posterior part of the lesion showed the usual pattern with increasing DWI hyperintensity and decreased ADC, as well as delayed FLAIR positivity. However, the anterior part of the lesion, which was clearly visible in the first examination completely normalized on the first day and only reappeared on day 2. This was accompanied by a normalization of the ADC as well as an even further delayed FLAIR positivity. CONCLUSION: We showed that interim normalization of DWI and ADC in the acute phase can not only be found in rodent models of stroke, but also in humans. We propose that DWI lesion development might be more variable during the first 24 h after stroke than previously assumed.

Complete early reversal of diffusion-weighted imaging hyperintensities after ischemic stroke is mainly limited to small embolic lesions.

BACKGROUND AND PURPOSE: Case reports have demonstrated complete early reversal of hyperintensities on diffusion-weighted imaging (DWI) after clinically diagnosed stroke. We aimed to investigate systematically the rate and characteristics of reversible diffusion hyperintensities (RDHs) in the first week after stroke. METHODS: Patients with clinical diagnosis of an acute cerebrovascular event and evidence of ischemia on DWI were included. MRI scans were performed on admission, on the following day, and 4 to 7 days after onset of symptoms with DWI and fluid-attenuated inversion recovery. Baseline and follow-up DWIs were coregistered and examined for individual RDHs. Characteristics of patients and of hyperintensities associated with early reversal were identified. RESULTS: We included 153 patients with a median National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-8). In 3 patients (2%), MR images normalized completely. Thirty-seven patients (24%) displayed individual RDHs. Of 611 initial DWI hyperintensities, 97 (16%) reversed. Thirteen percent of the RDHs had corresponding abnormalities on fluid-attenuated inversion recovery images at the third measurement. Median size of the RDHs was 0.029 mL (interquartile range, 0.013-0.055). RDHs were associated with a multiple infarct pattern (odds ratio, 22.1; 95% confidence interval, 4.5-109.7) and symptomatic carotid stenosis (odds ratio, 5.5; 95% confidence interval, 1.4-21.5). Fifty-nine percent of the patients with RDHs had new additional lesions on follow-up DWI. RDHs were not associated with functional improvement on the National Institutes of Health Stroke Scale score. CONCLUSIONS: In this population of mainly minor to moderate stroke patients, complete normalization of MR images was rare. Complete reversal of individual DWI hyperintensities was limited to very small lesions and mostly occurred in embolic stroke patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533.

Early new diffusion-weighted imaging lesions appear more often in stroke patients with a multiple territory lesion pattern.

BACKGROUND AND PURPOSE: New diffusion-weighted imaging (DWI) lesions are common in patients with acute ischemic stroke. They are associated with an initial nonsingle lesion pattern. Previous studies have not analyzed this association in detail. We differentiated nonsingle lesions in 1 vascular supply territory only (scattered lesion pattern) from nonsingle lesions in ≥2 vascular supply territory (multiple territory lesion -pattern). METHODS: Patients with an acute ischemic stroke underwent 3 MRI (3T) examinations: on admission, on the following day, and 4 to 7 days after symptom onset. First, DWI lesions were delineated manually by raters blinded to clinical details. Second, DWI images were coregistered and analyzed visually for new hyperintensities. The initial lesion pattern was categorized as single, scattered, or multiple territory. RESULTS: Of 340 patients enrolled, 43% had a single lesion pattern, 40% had a scattered lesion pattern, and 17% had a multiple territory lesion pattern. In multivariable analysis, the categorical variable lesion pattern was independently associated with new DWI lesions (odds ratio multiple territory lesion pattern, 3.64 [95% confidence interval, 1.75-7.58]; odds ratio scattered lesion pattern, 1.96 [95% confidence interval, 1.09-3.56]). Patients with multiple territory lesion pattern had significantly more often diabetes mellitus, and their new lesions were more often located remotely from the initial area of hypoperfusion compared with patients with scattered lesion pattern. CONCLUSION: Lesion pattern on initial image is an independent risk factor for new DWI lesions. The risk for new DWI lesions is highest in patients with multiple territory lesion pattern.

Theory of mind deficits in Parkinson's disease are not modulated by dopaminergic medication.

Introduction: Patients with Parkinson's disease (PD) exhibit deficits in social cognition, particularly with respect to Theory of Mind (ToM) capacities. It is unclear whether they are associated with PD-related dopamine deficiency and modulated by levodopa replacement therapy. Methods: A total of 15 persons with PD and 13 healthy controls (HC) participated in the study. They performed different neuropsychological tasks, including the Faux Pas Recognition Test (FPRT), assessing different dimensions of cognitive ToM (e.g., detection, inappropriateness, intentions), and the Reading the Mind in the Eyes Test (RMET) as an index of affective ToM. Persons with PD were tested twice, once under their regular treatment and another time after at least 18 h of levodopa withdrawal (MED-ON and MED-OFF, respectively). On either occasion, serum drug levels and motor symptom severity [Unified Parkinson's Disease Rating Scale (UPDRS)] were measured. Results: MED-ON and MED-OFF conditions in patients with PD were confirmed by higher serum drug levels in the former than in the latter state and a corresponding amelioration of the motor deficit. In so doing, no performance difference in any ToM-related task was identified as a function of the levodopa therapy. Generally, patients performed worse than controls in both affective and cognitive ToM tests. Conclusion: Patients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions.

GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.

Glucosylceramidase beta 1 (GBA1) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson's disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1-regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1-regulated pathway by repositioning treatment strategies for Gaucher's disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1-regulated pathways in PD patients.

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner.

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

Depressive symptoms in Parkinson's disease are insufficiently but more often treated than in other chronic conditions.

Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment of depressive symptoms both in PD and DC should be improved.

Incidence of new diffusion-weighted imaging lesions outside the area of initial hypoperfusion within 1 week after acute ischemic stroke.

BACKGROUND AND PURPOSE: New diffusion-weighted imaging (DWI) lesions are common in patients with acute ischemic stroke. The pathophysiology of these new lesions is unclear. We differentiated new DWI lesions outside the area of initial hypoperfusion from those confined to the area of initial hypoperfusion. METHODS: Patients with acute stroke underwent 3 MRI examinations: on admission, on the next day, and 4 to 7 days after symptom onset. Patients were included if a perfusion deficit was present on the initial scan. Lesions on DWI images were delineated manually. Coregistered DWI images were analyzed visually for new hyperintensities. In reference to the perfusion maps (mean transit time), patients were classified as having "outside lesions" if new DWI lesions were outside or both outside and inside the area of the initial perfusion deficit or "inside lesions" if new DWI lesions were completely inside. RESULTS: We enrolled 164 patients. Thirty-eight patients (23%) had outside lesions and 34 patients (21%) had inside lesions. In multivariable regression analysis, new outside lesions were significantly associated with symptomatic carotid stenosis, multiple index lesions pattern, and high low-density lipoprotein levels. New inside lesions were significantly associated with (spontaneous or thrombolytic) vessel recanalization, multiple index lesions pattern, and low low-density lipoprotein levels. CONCLUSIONS: Outside and inside lesions represent different pathophysiological entities. More specifically patients with outside lesions may have an increased risk for subsequent cerebrovascular events.

Pronounced Orthostatic Hypotension in GBA-Related Parkinson's Disease.

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.

Validity and Prognostic Value of a Polygenic Risk Score for Parkinson's Disease.

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.

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.

Early Recurrent Ischemic Lesions in Patients With Cryptogenic Stroke and Patent Foramen Ovale: An Observational Study.

Background: Randomized controlled trials indicate that patent foramen ovale (PFO) closure reduces risk of stroke recurrence in patients with cryptogenic stroke and PFO. However, the optimal time point for PFO closure is unknown and depends on the risk of stroke recurrence. Objective: We aimed to investigate risk of early new ischemic lesions on cerebral magnetic resonance imaging (MRI) in cryptogenic stroke patients with and without PFO. Methods: Cryptogenic stroke patients underwent serial MRI examinations within 1 week after symptom onset to detect early new ischemic lesions. Diffusion-weighted imaging (DWI) lesions were delineated, co-registered, and analyzed visually for new hyperintensities by raters blinded to clinical details. A PFO was classified as stroke-related in patients with PFO and a Risk of Paradoxical Embolism (RoPE) score >5 points. Results: Out of 80 cryptogenic stroke patients, risk of early recurrent DWI lesions was not significantly different in cryptogenic stroke patients with and without PFO. Similar results were observed in patients ≤60 years of age. Patients with a stroke-related PFO even had a significantly lower risk of early recurrent ischemic lesions compared to all other patients with cryptogenic stroke (unadjusted odds ratio 0.23 [95% confidence interval 0.06-0.87], P = 0.030). Conclusion: Our data argue against a high risk of early stroke recurrence in patients with cryptogenic stroke and PFO.

Early New Ischemic Lesions Located Outside the Initially Affected Vascular Territory Appear More Often in Stroke Patients with Elevated Glycated Hemoglobin (HbA1c).

BACKGROUND: Early new ischemic lesions are common in patients with an acute ischemic stroke. These new ischemic lesions may represent the natural course of the initial stroke or de novo events. OBJECTIVE: We hypothesized that early new ischemic lesions located outside the initially affected vascular territory would point at de novo events. Therefore, we differentiated new ischemic lesions located outside the initially affected vascular territory from those occurring only inside the initially affected vascular territory to identify risk factors that are associated with de novo events. METHODS: Stroke patients underwent three magnetic resonance imaging examinations (at 3-T): on admission, on the next day and 4-7 days after symptom onset (clinicaltrials.gov: NCT00715533). Diffusion-weighted imaging (DWI) lesions were delineated, coregistered, and then analyzed for new hyperintensities on follow-up examinations by raters blinded to clinical details. Patients were classified as having "new distant lesions" if new DWI lesions appeared outside or both outside and inside the initially affected vascular territory or "new local lesions" if they were only inside. RESULTS: 115 patients with early new DWI lesions constitute the study population. Sixteen patients (14%) had new distant lesions and 99 patients (86%) had new local lesions. In comparison between patients with new distant and new local lesions, patients with new distant lesions had significantly more often elevated glycated hemoglobin (HbA1c ≥ 6.5%; p = 0.022). CONCLUSION: Our data indicate that patients with elevated HbA1c have an increased risk for new, de novo ischemic lesions in the acute phase after an ischemic stroke.

Decreased medial prefrontal cortex activation during self-referential processing in bipolar mania.

BACKGROUND: Patients with bipolar disorder in mania exhibit symptoms pointing towards altered self-referential processing, such as decreased self-focus, flight of ideas and high distractibility. In depression, the opposite pattern of symptoms has been connected to increased activation of medial prefrontal cortex (mPFC) during self-referential processing. In this study, we hypothesized that (1) patients with mania will exhibit decreased activation in the mPFC during self-referential processing and (2) will be more alexithymic and that levels of alexithymia will correlate negatively with mPFC activation. METHODS: The neural response to standardized pictures was compared in 14 patients with bipolar I disorder in mania to 14 healthy controls using blood oxygen level dependent contrast magnetic resonance imaging. Participants were asked to indicate with button press during the scanning session for each picture whether the pictures personally related to them or not. Toronto alexithymia scale (TAS) scores were recorded from all participants. RESULTS: In the group analysis, patients with mania exhibited decreased activation in a predefined region of interest in the mPFC during self-referential processing compared to healthy controls. Patients with mania showed significantly higher levels of alexithymia, attributable to difficulties in identifying and describing emotions. Activation in the mPFC correlated negatively with levels of alexithymia. LIMITATIONS: Results presented here should be replicated in a larger group, potentially including unmedicated patients. CONCLUSIONS: The finding of decreased mPFC activation during self-referential processing in mania may reflect decreased self-focus and high distractibility. Support for this view comes from the negative correlation between higher alexithymia scores and decreased mPFC activation. These findings represent an opposite clinical and neuroimaging pattern to findings in depression.