Systematic review-based guideline "Parkinson's disease" of the German Society of Neurology: diagnostic use of transcranial sonography.

BACKGROUND AND OBJECTIVE: Transcranial brain parenchyma sonography (TCS) has been recommended as a tool for the early and differential diagnosis of Parkinson's disease (PD) in German and European clinical guidelines. Still, the brain structures to be examined for the diagnostic questions and the requirements for being a qualified investigator were not specified in detail. These issues have now been addressed in the 2023 update of the clinical guideline on PD by the German Society of Neurology (DGN). METHODS: The recommendations were based on a systematic literature review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three diagnostic questions were defined: (1) What is the accuracy of TCS in the differential diagnosis of PD versus atypical and secondary Parkinsonian syndromes? (2) What is the accuracy of TCS in the differential diagnosis of PD versus essential tremor? (3) What is the accuracy of TCS in the diagnosis of PD in persons with typical early symptoms, compared with the diagnosis established by clinical follow-up? The brain structures to be assessed and the level of recommendation were formulated for these questions. The training requirements for being regarded as qualified TCS investigator were stipulated by the responsible medical societies (German Society of Ultrasound in Medicine, DEGUM; German Society for Clinical Neurophysiology and Functional Imaging, DGKN). Finally, the recommendations for these diagnostic questions reached strong consensus (each ≥ 97%) of the guideline committee. Here, the details of review and recommendations are presented. CONCLUSION: The updated guideline clarifies the diagnostic uses and limitations of TCS in PD.

Precision Balance Assessment in Parkinson's Disease: Utilizing Vision-Based 3D Pose Tracking for Pull Test Analysis.

Postural instability is a common complication in advanced Parkinson's disease (PD) associated with recurrent falls and fall-related injuries. The test of retropulsion, consisting of a rapid balance perturbation by a pull in the backward direction, is regarded as the gold standard for evaluating postural instability in PD and is a key component of the neurological examination and clinical rating in PD (e.g., MDS-UPDRS). However, significant variability in test execution and interpretation contributes to a low intra- and inter-rater test reliability. Here, we explore the potential for objective, vision-based assessment of the pull test (vPull) using 3D pose tracking applied to single-sensor RGB-Depth recordings of clinical assessments. The initial results in a cohort of healthy individuals (n = 15) demonstrate overall excellent agreement of vPull-derived metrics with the gold standard marker-based motion capture. Subsequently, in a cohort of PD patients and controls (n = 15 each), we assessed the inter-rater reliability of vPull and analyzed PD-related impairments in postural response (including pull-to-step latency, number of steps, retropulsion angle). These quantitative metrics effectively distinguish healthy performance from and within varying degrees of postural impairment in PD. vPull shows promise for straightforward clinical implementation with the potential to enhance the sensitivity and specificity of postural instability assessment and fall risk prediction in PD.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

The why and how of the SynNerGe criteria of Parkinson´s disease.

In pursuit of early therapeutic interventions for Parkinson's disease, the proposed SynNeurGe classification system integrates α-synuclein pathology (S), neurodegeneration evidence (N), and pathogenic gene variants (G). This approach aims to address the disease's complexity and biological diversity. It suggests categorizing patients based on the presence or absence of α-synuclein pathology in tissues or cerebrospinal fluid, neurodegeneration indicators from specific imaging techniques, and identification of pathogenic gene variants associated with Parkinson's disease. The proposed system emphasizes the future need for precision medicine and aims to facilitate both basic and clinical research toward disease-modifying therapies. However, the authors stress that initial implementation should be confined to research settings, considering ethical implications and current limitations. Prospective validation of these criteria is deemed necessary to ensure their efficacy and ethical application in clinical practice.

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnosis and treatment of Parkinson´s disease (guideline of the German Society for Neurology).

INTRODUCTION: The aim of this German national guideline is to optimize the clinical care of patients with Parkinson's disease (PD) in terms of diagnostics, drug and surgical treatment and care. This guidance was prepared for the German Society of Neurology (DGN) in collaboration with the Austrian Society of Neurology (ÖGN) and the Swiss Neurological Society (SNG) for German-speaking countries. The guidelines for the diagnosis and treatment of PD have been revised by a national expert group and the guideline commission of the DGN at S2k level. The main objective of these guidelines is to optimize the clinical care of PD patients regarding diagnosis, including early detection, technical diagnostic examinations, and pharmacological as well as invasive treatment options. RECOMMENDATIONS: The updated PD diagnosis and treatment guidelines are emphasizing optimized clinical care. Key revisions include preferring the name "Parkinson's disease" over previous terms and adopting International Parkinson and Movement Disorder Society (MDS) diagnostic criteria. Recommendations cover genetic and imaging diagnostics, initial pharmacotherapy considering efficacy and patient factors, and tailored pharmacological combinations for complications. Guidelines extend to managing cognitive, affective, psychotic, and autonomic symptoms, along with non-oral therapies like pump therapy and deep brain stimulation. Special situations like akinetic crisis, driving ability, and care concepts are addressed, ensuring comprehensive management for PD patients at various stages and conditions. CONCLUSIONS: This guidance reflects the state of the art at the beginning of 2024.

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials.

BACKGROUND: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. OBJECTIVE: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. METHODS: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. RESULTS: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. CONCLUSIONS: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

PURPOSE: [18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. METHODS: In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. RESULTS: AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. CONCLUSION: Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

Low-intensity vestibular noise stimulation improves postural symptoms in progressive supranuclear palsy.

BACKGROUND: Postural imbalance and falls are an early disabling symptom in patients with progressive supranuclear palsy (PSP) of multifactorial origin that may involve abnormal vestibulospinal reflexes. Low-intensity noisy galvanic vestibular stimulation (nGVS) is a non-invasive treatment to normalize deficient vestibular function and attenuate imbalance in Parkinson's disease. The presumed therapeutic mode of nGVS is stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can enhance sensory information processing. OBJECTIVE: To examine potential treatment effects of nGVS on postural instability in 16 patients with PSP with a clinically probable and [18F]PI-2620 tau-PET-positive PSP. METHODS: Effects of nGVS of varying intensity (0-0.7 mA) on body sway were examined, while patients were standing with eyes closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal sway reductions at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR. RESULTS: We found nGVS-induced reductions of body sway compatible with SR in 9 patients (56%) with optimal improvements of 31 ± 10%. In eight patients (50%), nGVS-induced sway reductions exceeded the minimal clinically important difference (improvement: 34 ± 5%), indicative of strong SR. CONCLUSION: nGVS yielded clinically relevant reductions in body sway compatible with the exhibition of SR in vestibular sensorimotor pathways in at least half of the assessed patients. Non-invasive vestibular noise stimulation may be thus a well-tolerated treatment strategy to ameliorate postural symptoms in PSP.

Combined treatment with allogeneic Epstein-Barr- and human polyomavirus 1 specific T-cells in progressive multifocal leukoencephalopathy and EBV infection: a case report.

Opportunistic viral infections in individuals with severe immunodeficiency can lead to fatal conditions such as progressive multifocal leukoencephalopathy (PML), for which treatment options are limited. These infections pose significant risks, especially when co-infections with other viruses occur. We describe a combined therapy approach using directly isolated allogeneic Human Polyomavirus 1 (also known as BKV) and Epstein-Barr virus (EBV) specific cytotoxic T-cells for the treatment of PML in conjunction with identified EBV in the cerebrospinal fluid (CSF) of a male patient infected with human immunodeficiency virus (HIV). A 53-year-old HIV-positive male, recently diagnosed with PML, presented with rapidly worsening symptoms, including ataxia, tetraparesis, dysarthria, and dysphagia, leading to respiratory failure. The patient developed PML even after commencing highly active antiretroviral therapy (HAART) 3 months prior. Brain magnetic resonance imaging (MRI) revealed multifocal demyelination lesions involving the posterior fossa and right thalamus suggestive of PML. In addition to the detection of human polyomavirus 2 (also known as JCV), analysis of CSF showed positive results for EBV deoxyribonucleic acid (DNA). His neurological condition markedly deteriorated over the following 2 months. Based on MRI, there was no evidence of Immune Reconstitution Inflammatory Syndrome contributing to this decline. The patient did not have endogenous virus-specific T-cells. We initiated an allogeneic, partially human leukocyte antigen-matched transfer of EBV and utilizing the cross-reactivity between BKV and JCV-BKV specific T-cells. This intervention led to notable neurological improvement and partial resolution of the MRI lesions within 6 weeks. Our case of a patient with acquired immune deficiency syndrome demonstrates that PML and concurrent EBV co-infection can still occur despite undergoing HAART treatment. This innovative experimental therapy, involving a combination of virus-specific T-cells, was demonstrated to be an effective treatment option in this patient.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

Clinical practice of continuous rhythm monitoring after embolic stroke of undetermined source.

AIMS: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes annually. Undetected atrial fibrillation (AF) is one important potential underlying cause. For AF, oral anticoagulation has evolved as the most preferable means of secondary stroke prevention. To detect unrecognized paroxysmal AF, long-term ECG monitoring is required, and implantable cardiac monitors (ICM) appear most suitable. Yet, ICMs are particularly costly, implantation is invasive, and remote monitoring places a personnel burden on health care providers. Here, we use data from a large cohort of ESUS patients to systematically analyze the effort of ICM remote monitoring for AF diagnosis and the strain on health care providers. METHODS AND RESULTS: From a prospective, single-center, observational ESUS registry, we analyzed all ICM-equipped patients post-ESUS (n = 172) between January 1st, 2018, and December 31st, 2019. Through January 2nd, 2023, 48 patients (27.9%) were diagnosed with AF by ICM remote monitoring. During follow-up, a total of 29,180 remote monitoring episodes were transmitted, of which 17,742 were alarms for AF. A systematic estimation of workload revealed that on average, 20.3 trained physician workhours are required to diagnose one patient with AF. CONCLUSION: ICM remote monitoring is useful to diagnose AF in cohort of post-ESUS patients. However, the number of ICM alarms is high, even in a cohort at known high risk of AF and in whom AF detection is therapeutically consequential. Improved automated event classification, clear recommendations for ICM interrogation after AF diagnosis, and a careful patient selection for ICM monitoring are warranted.

Towards a biological diagnosis of PD.

Since the original description by James Parkinson, Parkinson's disease (PD) has intrigued us for over 200 years. PD is a progressive condition that is incurable so far, and affects millions of people worldwide. Over the years, our knowledge has expanded tremendously, and a range of criteria have been put forward and used to try to define PD. However, owing to the complexity of the problem, it is still not consensual how to diagnose and classify a disease that manifests with diverse features, and that responds differently to existing therapies and to those under development. We are now living a time when 'biological' information is becoming abundant, precise, and accessible enabling us to attempt to incorporate different sources of information to classify different forms of PD. These refinements are essential for basic science, as they will enable us to develop improved models for studying PD, and to implement new findings into clinical practice, as this will be the path towards effective personalized medicine.