Kliniko-genetische Stratifizierung der Parkinson-Krankheit in der Luxemburger Parkinson-Studie

Die Parkinson-Krankheit (PK) ist die zweithäufigste neurodegenerative Störung. Die Variabilität des klinischen Erscheinungsbildes verblüfft jedoch seit Jahrzehnten sowohl Kliniker als auch Forscher. In dieser Arbeit haben wir uns bemüht, die Schlüsselelemente zu entschlüsseln, die das klinische Profil und den Schweregrad von Morbus Parkinson bestimmen. Unter Verwendung eines einzigartigen, tiefgreifend phänotypisierten und genotypisierten Datensatzes aus der monozentrischen Beobachtungsstudie in Luxemburg haben wir eine Analyse von über 1000 Personen nach dem Ausschluss von PK-assoziierten Mutationen ausschließt durchgeführt. Auf der Grundlage unserer Ergebnisse bieten wir eine neue Perspektive darauf, inwieweit der beobachtete PK-Phänotyp, der auf dem Alter bei Krankheitsbeginn (AKB) basiert, durch einen parallelen Alterungsprozess bestimmt wird und nicht durch eine andere Dynamik der Neurodegeneration. Überraschenderweise zeigten unsere Daten, dass die meisten nicht-motorischen Symptome eher auf den Alterungsprozess als auf den neurodegenerativen Prozess bei PK zurückzuführen sind. Wir vermuten, dass die physiologische Alterung für die meisten der nicht-motorischen Symptome verantwortlich ist, die in früheren Studien mit AKB in Verbindung gebracht wurden. Darüber hinaus untersuchten wir einen möglichen Beitrag mehrerer häufiger genetischer Varianten mit geringer Effektgröße, die in den polygenen Risikoscore (PRS) einfließen. Wir untersuchten eine mögliche Störwirkung des PRS auf die AKB bei PK und fragten anschließend, ob der PRS einen Einfluss auf den Schweregrad des Phänotyps haben könnte. Wir fanden eine signifikante negative Korrelation zwischen PRS und AKB, jedoch hatte der polygene Risikoscore keine signifikante Auswirkung auf den Schweregrad des PD-Phänotyps. Darüber hinaus folgten wir dem Konzept der Stratifizierung von PK auf Body-First- und Brain-First-Modell, was darauf hindeutet, dass die REM-Schlaf-Verhaltensstörung (verkürzt RBD aus englischem REM-Sleep behaviour disorder) Teil des Body-First-Modell mit spezifischem Phänotyp ist. Basiert auf unsere Modelle konnten wir feststellen, dass PK mit einer komorbiden wahrscheinlichen Schlafstörung (wRBD) signifikant mit einem nicht-motorisch dominanten klinischen Phänotyp assoziiert ist, der eine höhere Belastung durch autonome Funktionsstörungen und Depressionen aufweist, was dem Konzept des Body-First-Modells entspricht. Darüber hinaus untersuchten wir eine mögliche genetische Assoziation des APOE4-Trägerstatus mit wRBD sowie die Auswirkungen von APOE4 auf das gesamte klinische Profil bei PK, ohne dass in beiden Fällen signifikante Ergebnisse erzielt wurden. Schließlich untersuchten wir die potenziellen Auswirkungen des Geschlechts bei Morbus Parkinson und stellten fest, dass das männliche Geschlecht nur einen signifikanten positiven Effekt auf das ,Freezing of Gait‘ sowie einen negativen Effekt auf das Riechvermögen hat. Diese Arbeit ist ein Beitrag zu den aktuellen Erkenntnissen über die Stratifizierungsstrategie, die einen Einblick in das komplexe Zusammenspiel zwischen (i) Alter, Alterung und PRS auf der einen Seite und (ii) Geschlecht, wRBD und APOE4 auf der anderen Seite ermöglicht, die alle die phänotypische Variabilität von Parkinson bestimmen können. Die Einbeziehung dieser Stratifikatoren in künftige klinische Studien wird eine Schlüsselrolle bei der Festlegung krankheitsmodifizierender Maßnahmen bei PK spielen

Converging peripheral blood micro-RNA profiles in idiopathic Parkinson’s disease and progressive supranuclear palsy

peer reviewedR-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejko3. Good health and well-bein

Multilingual Validation of the First French Version of Munich Dysphagia Test-Parkinson's Disease (MDT-PD) in the Luxembourg Parkinson's Study

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect early oropharyngeal symptoms and aspiration risk in patients with idiopathic Parkinson's disease (iPD). In order to make this tool accessible for prevention in the French speaking populations worldwide, we performed the first French translation and provide a linguistic and psychometric validation in the unique multilingual environment of the Luxembourg Parkinson's Study

Multifactorial assessment of Parkinson’s disease course and outcomes using trajectory modeling in a multiethnic, multisite cohort – extension of the LONG-PD study

BackgroundThe severity, progression, and outcomes of motor and non-motor symptoms in Parkinson’s disease (PD) are quite variable. Following PD cohorts holds promise for identifying predictors of disease severity and progression.MethodsPD patients (N = 871) were enrolled at five sites. Enrollment occurred within 5 years of initial motor symptom onset. Disease progression was assessed annually for 2-to-10 years after onset. Group-based trajectory modeling was used to identify groups differing in disease progression. Models were developed for UPDRS-III scores, UPDRS-III tremor and bradykinesia-rigidity subscores, Hoehn & Yahr (H&Y) stage, Mini-Mental Status Exam (MMSE) scores, and UPDRS-III, H&Y and MMSE scores considered together. Predictors of trajectory-group membership were modeled simultaneously with the trajectories. Kaplan–Meier survival analysis evaluated survival free of PD outcomes.ResultsThe best fitting models identified three groups. One showed a relatively benign, slowly progressing trajectory (Group 1), a second showed a moderate, intermediately progressing trajectory (Group 2), and a third showed a more severe, rapidly progressing trajectory (Group 3). Stable trajectory-group membership occurred relatively early in the disease course, 5 years after initial motor symptom. Predictors of intermediate and more severe trajectory-group membership varied across the single variable models and the multivariable model jointly considering UPDRS-III, H&Y and MMSE scores. In the multivariable model, membership in Group 2 (28.4% of patients), relative to Group 1 (50.5%), was associated with male sex, younger age-at-onset, fewer education-years, pesticide exposure, absence of reported head injury, and akinetic/rigid subtype at initial presentation. Membership in Group 3 (21.3%), relative to Group 1, was associated with older age-at-onset, fewer education-years, pesticide exposure, and the absence of a tremor-predominant subtype at initial presentation. Persistent freezing, persistent falls, and cognitive impairment occurred earliest and more frequently in Group 3, later and less frequently in Group 2, and latest and least frequently in Group 1. Furthermore, autonomic complications, dysphagia, and psychosis occurred more frequently in Groups 2 and 3 than in Group 1.ConclusionModeling disease course using multiple objective assessments over an extended follow-up duration identified groups that more accurately reflect differences in PD course, prognosis, and outcomes than assessing single parameters over shorter intervals

Gut microbiome is not associated with mild cognitive impairment in Parkinson's disease

Gut microbiome differences between people with Parkinson's disease (PD) and control subjects without Parkinsonism are widely reported, but potential alterations related to PD with mild cognitive impairment (MCI) have yet to be comprehensively explored. We compared gut microbial features of PD with MCI (n = 58) to cognitively unimpaired PD (n = 60) and control subjects (n = 90) with normal cognition. Our results did not support a specific microbiome signature related to MCI in PD

Towards the development and verification of a 3D-based advanced optimized farm machinery trajectory algorithm

Efforts related to minimizing the environmental burden caused by agricultural activities and increasing economic efficiency are key contemporary drivers in the precision agriculture domain. Controlled Traffic Farming (CTF) techniques are being applied against soil compaction creation, using the on-line optimization of trajectory planning for soil-sensitive field operations. The research presented in this paper aims at a proof-of-concept solution with respect to optimizing farm machinery trajectories in order to minimize the environmental burden and increase economic efficiency. As such, it further advances existing CTF solutions by including (1) efficient plot divisions in 3D, (2) the optimization of entry and exit points of both plot and plot segments, (3) the employment of more machines in parallel and (4) obstacles in a farm machinery trajectory. The developed algorithm is expressed in terms of unified modeling language (UML) activity diagrams as well as pseudo-code. Results were visualized in 2D and 3D to demonstrate terrain impact. Verifications were conducted at a fully operational commercial farm (Rostenice, the Czech Republic) against second-by-second sensor measurements of real farm machinery trajectories

Mild cognitive impairment is not associated with gut microbiota alterations in Parkinson’s disease

Abstract Gut microbiome differences between people with Parkinson’s disease (PD) and control subjects without parkinsonism are widely reported, but potential alterations related to PD with mild cognitive impairment (MCI) have yet to be comprehensively explored. We compared gut microbial features of PD with MCI (n=58) to cognitively unimpaired PD (n=60) and control subjects (n=90) without MCI. Our results did not support a specific microbiome signature related to MCI in PD.R-AGR-3870 - IAS - MCI-BIOME (01/01/2020 - 31/12/2023) - WILMES Paul3. Good health and well-beingv

Body-First Subtype of Parkinson's Disease with Probable REM-Sleep Behavior Disorder Is Associated with Non-Motor Dominant Phenotype

Background: The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction. Objective: To identify distinctive clinical subtypes of idiopathic Parkinson’s disease (iPD) in line with the formerly proposed concept of body-first vs. brain-first subtypes in PD, we analyzed the presence of probable RBD (pRBD), sex, and the APOE ɛ4 carrier status as potential sub-group stratifiers. Methods: A total of 400 iPD patients were included in the cross-sectional analysis from the baseline dataset with a completed RBD Screening Questionnaire (RBDSQ) for classifying as pRBD by using the cut-off RBDSQ≥6. Multiple regression models were applied to explore (i) the effect of pRBD on clinical outcomes adjusted for disease duration and age, (ii) the effect of sex on pRBD, and (iii) the association of APOE ɛ4 and pRBD. Results: iPD-pRBD was significantly associated with autonomic dysfunction (SCOPA-AUT), level of depressive symptoms (BDI-I), MDS-UPDRS I, hallucinations, and constipation, whereas significantly negatively associated with quality of life (PDQ-39) and sleep (PDSS). No significant association between sex and pRBD or APOE ɛ4 and pRBD in iPD was found nor did we determine a significant effect of APOE ɛ4 on the PD phenotype. Conclusion: We identified an RBD-specific PD endophenotype, characterized by predominant autonomic dysfunction, hallucinations, and depression, corroborating the concept of a distinctive body-first subtype of PD. We did not observe a significant association between APOE ɛ4 and pRBD suggesting both factors having an independent effect on cognitive decline in iPD

Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect

Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study.

peer reviewedHeterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.R-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejko3. Good health and well-bein