Parkinson's disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson's patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins-Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson's disease. Parkinson's disease is lacking easily accessible biomarkers. Here the authors show, that targeted blood proteomics is feasible to identify the patients and to predict the phenoconvertion in prodromal subjects up to 7 years before symptom onset.

Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson's disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-naïve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.

Background Coronavirus disease 2019 (COVID-19) is an infection which can affect the central nervous system. In this study, we sought to investigate associations between neuroimaging findings with clinical, demographic, blood and cerebrospinal fluid (CSF) parameters, pre-existing conditions and the severity of acute COVID-19. Materials and methods Retrospective multicenter data retrieval from 10 university medical centers in Germany, Switzerland and Austria between February 2020 and September 2021. We included patients with COVID-19, acute neurological symptoms and cranial imaging. We collected demographics, neurological symptoms, COVID-19 severity, results of cranial imaging, blood and CSF parameters during the hospital stay. Results 442 patients could be included. COVID-19 severity was mild in 124 (28.1%) patients (moderate n = 134/30.3%, severe n = 43/9.7%, critical n = 141/31.9%). 220 patients (49.8%) presented with respiratory symptoms, 167 (37.8%) presented with neurological symptoms first. Acute ischemic stroke (AIS) was detected in 70 (15.8%), intracranial hemorrhage (IH) in 48 (10.9%) patients. Typical risk factors were associated with AIS; extracorporeal membrane oxygenation therapy and invasive ventilation with IH. No association was found between the severity of COVID-19 or blood/CSF parameters and the occurrence of AIS or IH. Discussion AIS was the most common finding on cranial imaging. IH was more prevalent than expected but a less common finding than AIS. Patients with IH had a distinct clinical profile compared to patients with AIS. There was no association between AIS or IH and the severity of COVID-19. A considerable proportion of patients presented with neurological symptoms first. Laboratory parameters have limited value as a screening tool.

Was gibt es Neues?Diagnose/Zusatzuntersuchungen Die essenziellen Diagnosekriterien für die Diagnose des Restless Legs Syndroms (RLS) wurden 2014 durch die International Restless Legs Syndrome Study Group (IRLSSG) erarbeitet und in einer Konsensuskonferenz abgestimmt.Sie schließen, anders als in den vorherigen Diagnosekriterien, nun auch explizit den Ausschluss von Differenzialdiagnosen ein und ermöglichen somit eine bessere

Lysosomal and synaptic dysfunctions are hallmarks in multiple neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease (PD) and could be relevant from a biomarker perspective. Biomarker data on prodromal and early PD are not yet available. We performed targeted mass spectrometry measurements cross-sectionally and longitudinally over 10 years with an established biomarker panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) in prodromal subjects with isolated REM sleep behavior disorder (iRBD), drug-naïve de novo PD subjects at baseline, and sex- and age-matched healthy controls. Multiple markers of autophagy, synaptic plasticity, and secretory pathways showed reduced expression in PD and iRBD compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as the most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins correlated with clinical progression and showed predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.

Although Dementia with Lewy bodies (DLB) is the second most common form of dementia in elderly patients, it remains underdiagnosed compared with Alzheimer's (AD) and Parkinson's diseases (PD). This may be explained by overlapping clinical symptoms, e.g. Parkinsonism. While current MRI research focuses primarily on atrophy patterns of the frontal and temporal lobes, we focus on brainstem characteristics of DLB. In particular, we focused on brainstem atrophy patterns distinguishing DLB from Progressive Supranuclear Palsy (PSP) and PD based as the most common differential diagnoses. We identified patients diagnosed with DLB, PD, PSP, and a control group (CTRL) in our psychiatric and neurological archives. All patients with competing diagnoses and without a high-quality T1 MPRAGE 3D dataset were excluded. We assessed atrophy patterns in all patients (1) manually and (2) using FastSurfer’s segmentation algorithm in combination with FreeSurfer’s brainstem volumetric calculations. We compared classical measurement methods and ratios with automated volumetric approaches. One hundred two patients were enrolled and evaluated in this study. Patients with DLB (n = 37) showed on average less atrophy of the brainstem than patients with PSP (n = 21), but a significantly more pronounced atrophy than patients with PD (n = 36) and the control group (CTRL, n = 8). The mean measured sagittal diameters of the midbrain were 8.17 ± 1.06 mm (mean ± standard deviation) for PSP, 9.45 ± 0.95 mm for DLB, 10.37 ± 0.99 mm for PD and 10.74 ± 0.70 for CTRL. The mean measured areas of the midbrain were 81 ± 18 mm2 for PSP, 105 ± 17 mm2 for DLB, 130 ± 26 mm2 for PD and 135 ± 23 mm2 for CTRL. The mean segmented volumes of the midbrain were 5595 ± 680 mm3 for PSP, 6051 ± 566 mm3 for DLB, 6646 ± 802 mm3 for PD and 6882 ± 844 mm3 for CTRL. The calculated midbrain pons ratios did not show superiority over the absolute measurements of the midbrain for distinguishing PSP from DLB. Because of the relatively uniform atrophy throughout the brainstem, the ratios were not suitable for distinguishing DLB from PD. DLB patients exhibit homogenous atrophy of the brainstem and can be distinguished from patients with PSP and PD by both manual measurement methods and automated volume segmentation using absolute values or ratios.

Background: Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression. Objective: The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high-throughput sandwich immune multiplex panels in deeply phenotyped PD. Methods: Proximity Extension Assay technology on 273 markerswas applied in plasma of 109 drug-naive at baseline (BL) patients with PD (BL, 2-, 4-, and 6-year follow-up [FU]) and 96 healthy control patients (HCs; 2- and 4-year FU) from the de novoParkinson's cohort. BL plasma from 74 individuals (37 patients with PD, 37 healthy control patients) on the same platform from the Parkinson Progression Marker Initiative was used for independent validation. Correlation analysis of the identified markers and 6 years of clinical FU, including motor and cognitive progression, was evaluated. Results: At BL, 35 plasma markers were differentially expressed in PD, showing downregulation of atherosclerotic risk markers, eg, E-selectin and beta(2)-integrin. In contrast, we found a reduction of markers of the plasminogen activation system, eg, urokinase plasminogen activator. Neurospecific markers indicated increased levels of peripheral proteins of neurodegeneration and inflammation, such as fibroblast growth factor 21 and peptidase inhibitor 3. Several markers, including interleukin-6 and cystatin B, correlated with cognitive decline and progression of motor symptoms during FU. These findings were independently validated in the Parkinson ProgressionMarker Initiative. Conclusions: We identified and validated possible PD plasma biomarker candidates for state, fate, and disease progression, elucidating new molecular processes with reduced endothelial/atherosclerotic processes, increased thromboembolic risk, and neuroinflammation. Further investigations and validation in independent and larger longitudinal cohorts are needed. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disease for which readily available and non-invasive diagnostic biomarkers are scarce. Here, we present a panel of proteomic plasma biomarkers, capable of discriminating between PD and healthy controls with 100% accuracy in a machine learning model. We performed a discovery proteomics study on newly diagnosed PD patients and controls, followed by a multiplexed targeted proteomic assay applied to 99 de novo PD patients and 36 controls. The machine learning model correctly classified all patients, and multiple markers correlated with motor, non-motor symptom severity and cognitive decline. We also evaluated 18 prodromal subjects with iRBD and predicted 72 - 94% of the iRBD samples as PD. This figure matches the clinical conversion rate observed in PD, identifying a pattern already evident in iRBD and indicating pre-symptomatic molecular events. These findings may advance our understanding and supporting of future clinical trials.

Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta‐analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta‐analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α‐synuclein (aSyn) and leucine‐rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta‐analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)–positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76–2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM‐IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS‐derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over 1300 proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years. The analysis identified 73 differentially expressed proteins (DEPs) of which 14 proteins were confirmed as stable potential diagnostic markers using machine learning tools. Among the DEPs identified, eight proteins-ALCAM, contactin 1, CD36, DUS3, NEGR1, Notch1, TrkB, and BTK- significantly correlated with longitudinal clinical scores including motor and non-motor symptom scores, cognitive function and depression scales, indicating potential predictive values for progression in PD among various phenotypes. Known functions of these proteins and their possible relation to the pathophysiology or symptomatology of PD were discussed and presented with a particular emphasis on the potential biological mechanisms involved, such as cell adhesion, axonal guidance and neuroinflammation, and T-cell activation. In conclusion, with the use of advance multiplex proteomic technology, a blood-based protein signature profile was identified from serum samples of a well-characterized PD cohort capable of potentially differentiating PD from HC and predicting clinical disease progression of related motor and non-motor PD symptoms. We thereby highlight the need to validate and further investigate these markers in future prospective cohorts and assess their possible PD-related mechanisms.

BACKGROUNDThe MDS-Unified Parkinson's disease (PD) Rating Scale (MDS-UPDRS) is the most used scale in clinical trials. Little is known about the predictive potential of its single items.OBJECTIVETo systematically dissect MDS-UPDRS to predict PD progression.METHODS574 de novo PD patients and 305 healthy controls were investigated at baseline (BL) in the single-center DeNoPa (6-year follow-up) and multi-center PPMI (8-year follow-up) cohorts. We calculated cumulative link mixed models of single MDS-UPDRS items for odds ratios (OR) for class change within the scale. Models were adjusted for age, sex, time, and levodopa equivalent daily dose. Annual change and progression of the square roots of the MDS-UDPRS subscores and Total Score were estimated by linear mixed modeling.RESULTSBaseline demographics revealed more common tremor dominant subtype in DeNoPa and postural instability and gait disorders-subtype and multiethnicity in PPMI. Subscore progression estimates were higher in PPMI but showed similar slopes and progression in both cohorts. Increased ORs for faster progression were found from BL subscores I and II (activities of daily living; ADL) most marked for subscore III (rigidity of neck/lower extremities, agility of the legs, gait, hands, and global spontaneity of movements). Tremor items showed low ORs/negative values.CONCLUSIONHigher scores at baseline for ADL, freezing, and rigidity were predictors of faster deterioration in both cohorts. Precision and predictability of the MDS-UPDRS were higher in the single-center setting, indicating the need for rigorous training and/or video documentation to improve its use in multi-center cohorts, for example, clinical trials.

Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well. The gut microbiome possibly contributes to inflammatory pathways and shows specific differences in fecal samples from PD compared to healthy controls. In PD, Bacteroides abundance correlates with inflammatory markers in blood and motor impairment. Increased pro-inflammatory and decreased anti-inflammatory bacterial colonization can lead to changes in the metabolic pathways of amino acids, inducing increased membrane permeability, described as a leaky gut, enabling advanced contact between immune cells and gut microbiome and potentially a spreading of neuroinflammation through the body via the blood. Increased cytokine blood levels in PD are correlated with disease severity, motor symptoms, and clinical phenotypes.α-synuclein is a central player in PD-associated inflammation, inducing specific T-cell activity and triggering microglial activation in the central nervous system (CNS). Misfolded α-synuclein propagation possibly results in the spreading of aggregated α-synuclein from neuron to neuron leading to a sustained neuroinflammation. This is supported by age-dependent defects of protein uptake in microglia and monocytes, so-called “inflammaging”, including α-synuclein oligomers, as the key pathological protein in PD.Genetic risk markers and inherited forms of PD are also associated with inflammation, which is highly relevant for potential therapeutical targets.The documented associations of inflammatory markers and clinical phenotypes indicate a pro-inflammatory concept of specific PD pathophysiology here. An in-depth understanding of inflammatory mechanisms in PD from bottom (gut) to top (CNS) and vice versa is needed to design novel immunomodulatory approaches to delay or even stop PD. Future studies focusing on structured protocols in large patient cohorts with appropriate control groups and comparative analysis among studies will aid the discovery of novel candidate biomarkers.

Objective diagnostic biomarkers are needed to support a clinical diagnosis.

INTRODUCTION:Needle electromyography (EMG) is an essential part of electrodiagnosis (EDX) in neuromuscular disorders. As in all invasive procedures there is a risk of bleeding complications, but which is rare according to the current literature. Controlled, prospective studies that include patients under anticoagulation or antiplatelet therapy are lacking and would be difficult to conduct.CASE REPORTS:We describe two patients with no history of coagulopathy who developed an intramuscular hematoma after needle EMG. They had been under therapeutic anticoagulation but this had been discontinued, and their standard coagulation parameters had returned to normal prior to the EMG. One patient was found to have a rare genetic defect in thromboxane synthesis with associated markedly impaired platelet aggregation, while no obvious cause of the bleeding was found in the second patient. However, it could have been due to an unexpectedly strong anticoagulatory response to the oral anticoagulant apixaban.CONCLUSION:One must be aware of the increased risk of bleeding events in patients with therapeutic anticoagulation. These can occur even when the recommendations regarding discontinuation of anticoagulant drugs for the procedure have been followed. The patient must be actively questioned for ongoing use of NSAIDs, and if pain therapy is required alternatives with no antiplatelet activity should be given. A larger data pool of adverse EMG events would aid in risk assessment and decision making.

Restless legs syndrome (RLS) is a frequent neurological disorder that is twice as common in women as in men. RLS affects up to 20% of pregnant women, particularly in the third trimester. In most cases, symptoms disappear after delivery, but the risk of developing RLS after pregnancy and during future pregnancies is increased in these women. The diagnosis of RLS during pregnancy is made using the essential criteria of the International Restless Legs Study Group (IRLSSG). The differential diagnosis and exclusion of mimics such as venous stasis, legs cramps, and leg edema are important. Aggravating factors (anemia, sleep apnea, medications that aggravate RLS) should be eliminated before initiation of a specific treatment. Nonpharmacological treatments such as moderate exercise and yoga should be considered first. Pharmacological treatment including iron supplementation, levodopa/carbidopa, clonazepam, and oxycodone can be applied during the course after critical assessment of the indication.

Dieser Leserbrief ist in vollem Einklang mit denBeobachtungenundEmpfehlungenderAutoren,die leiderseit Jahrenvergeblich versuchen, die Substitution von Eisen als Therapieverfahren beim Restless-legs-Syndrom (RLS) in die deutsche Praxis umzusetzen. Diese internationalen, vor allem US-basierten Empfehlungen haben bisher in europäische oder gar deutsche Leitlinien zur RLS-Therapie keinen Eingang gefunden. Letztere werden derzeit neu überarbeitet und sind für 2021 zu erwarten. Dann können die niedergelassenen Kolleginnen und Kollegen hoffentlich trotz bisher erheblicher Widerstände, die einerseits wirtschaftlich begründet sind, andererseits auf einer Vorgabe der EMA (European Medicines Agency) beruhen, die bei jeglicher i.v. Eisengabe unabhängig vom Präparat eine Notfallversorgungsmöglichkeit fordert, eine Eiseninfusion auch ambulant umsetzen. Die Behandlung mit intravenösem dreiwertigem Eisen ist eine sichere und evidenzbasierte Therapie. Größere deutsche oder europäische Studien sind jedoch derzeit nicht verfügbar und auch nicht in Zukunft zu erwarten. Trotzdem könnte die ambulante Eisensubstitution von Ferrocarboxymaltose (500–1000mg) 1. oft stationäre Aufenthalten vermeiden, 2. die adäquate Behandlung von Patientinnen und Patienten beschleunigen sowie 3. eine Augmentation bei vielen RLS-Patienten und -Patientinnen unter dopamimetischer Therapie vermeiden, die wegen Wirkungsverlust immer höher dosiert wird, anstatt mit Eiseninfusion substituiert zu werden. Leider sind auch dazu keine Studien verfügbar, weshalb dies nur als Erfahrung der Autoren mitgeteilt werden kann.

Aim Several pathophysiological processes are involved in Parkinson’s disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort. Methods Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (baseline, 6, 12, 24, 36, and 48 months follow-up) using Elecsys® electrochemiluminescence immunoassays to quantify neurofilament light chain (NfL), soluble TREM2 receptor (sTREM2), chitinase-3-like protein 1 (YKL40), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), S100, and total α-synuclein (αSyn). Results αSyn was significantly lower in PD (mean 103 pg/ml vs. HC: 127 pg/ml, p<0.01; area under the curve [AUC]: 0.64), while all other biomarkers were not significantly different (AUC NfL: 0.49, sTREM2: 0.54, YKL40: 0.57, GFAP: 0.55, IL-6: 0.53, S100: 0.54, p>0.05) and none showed a significant difference longitudinally. We found significantly higher levels of all these markers between PD patients who developed cognitive decline during follow-up, except for αSyn and IL-6. Conclusion Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up.