Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Implementation and the effects of a Parkinson Network Therapy (PaNTher) on activities of daily living and health-related quality of life in Parkinson's disease patients: study protocol of an mixed-method observational cohort study in outpatient care.

INTRODUCTION: Parkinson's disease (PD) represents the fastest growing neurodegenerative disease with an increasing prevalence worldwide. It is characterised by complex motor and non-motor symptoms that lead to considerable disability. Specialised physiotherapy has been shown to benefit patients with PD. The Parkinson Netzwerk Therapie (PaNTher) was created to improve access to specialised physiotherapy tailored to care priorities of PD patients. This study aims to evaluate the effectiveness, acceptability and needs of the PaNTher network by neurologists and physiotherapists involved in the network in outpatient care. METHODS AND ANALYSIS: This is a mixed-method, prospective, pragmatic non-randomised cohort study of parallel groups, with data collection taking place in Bavaria, Germany, between 2020 and 2024. Patients with PD insured by the Allgemeine Ortskrankenkasse Bayern (AOK Bayern) living in Bavaria will be recruited for study participation by network partners. Patients in the intervention group must reside in Munich or the surrounding area to ensure provision of specialised physiotherapy in close proximity to their place of residence. Controls receive care as usual. Six and 12 months after baseline, all patients receive a follow-up questionnaire. Mixed-effect regression models will be used to examine changes in impairment of activities of daily living and quality of life of patients with PD enrolled in the programme over time compared with usual care. Qualitative interviews will investigate the implementation processes and acceptability of the PaNTher network among neurologists and physiotherapists. The study is expected to show that the PaNTher network with an integrative care approach will improve the quality and effectiveness of the management and treatment of patients with PD. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee at the medical faculty of the Ludwig-Maximilians-University Munich (20-318). Results will be published in scientific, peer-reviewed journals and presented at national and international conferences.

Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal.

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer's disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies. 72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson's syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20-40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored. Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected. Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Activities of Daily Living Are Improved by Inpatient Multimodal Complex Treatment for PD-a Real-World Cohort Study.

Background: The multimodal complex treatment for Parkinson's disease (MCT) provides inpatient care by a multi-disciplinary team for people with Parkinson's disease (PwP) in Germany. Objectives: We conducted a 5-year real-world mono-center cohort study to describe the effectiveness of MCT in the full cohort and various subgroups and outcome predictors. Methods: We collected an anonymized dataset between Jan 2015 and Dec 2019, involving N = 1773. The self-reported MDS-UPDRS part II was used as primary outcome, and clinical routine data for explanatory variables. PwP were categorized as responders or non-responders according to a response of at least 3 points 4 weeks after discharge. Results: N = 591 complete data records were available for statistical analyses. The full group improved by -2.4 points on the MDS-UPDRS II (P = <0.0001). 47.7% (n = 282) and 52.3% (n = 309) were coded as responders and non-responders, respectively. A clinically meaningful response was positively associated to age (χ2 = 11.07, P = 0.018), as well as baseline-severity of the MDS-UPDRS II (χ2 = 6.05, P = 0.048) and negatively associated to the presence of psychiatric disorder (χ2 = 3.9, P = 0.048) and cognitive dysfunction (χ2 = 7.29, P = 0.007). Logistic regression showed that baseline severity of the MDS-UPDRS II predicted therapy success. PwP with moderate baseline-severity had an about 2fold chance (OR 2.08; 95% CI 1.20-3.61; P = 0.009) and with severe an about 6fold chance (OR 5.92; 95% CI 2.76-12.68; P < 0.0001) to benefit clinically meaningful. Discussion: In a naturalistic setting of a specialized Parkinson's center, MCT improved ADL disability of PwP at least 4 weeks after discharge. Moderately and severely impaired patients were more likely to achieve clinically meaningful responses.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders.

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.

Neurodevelopmental disorder with dystonia due to SOX6 mutations.

BACKGROUND: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date, <25 cases have been reported in the literature. METHODS AND FINDINGS: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 C>T. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain. CONCLUSION: SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism.

Effects of Low-Intensity Vestibular Noise Stimulation on Postural Instability in Patients with Parkinson's Disease.

BACKGROUND: Postural instability is a major disabling factor in patients with advanced Parkinson's disease (PD) and often resistant to treatment. Previous studies indicated that imbalance in PD may be reduced by low-intensity noisy galvanic vestibular stimulation (nGVS). OBJECTIVE: To investigate the potential mode of action of this therapeutic effect. In particular, we examined whether nGVS-induced reductions of body sway in PD are compatible with stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can paradoxically enhance sensory information transfer. METHODS: Effects of nGVS of varying intensities (0-0.7 mA) on body sway were examined in 15 patients with PD standing with eye closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal reductions of sway 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: nGVS-induced reductions of body sway compatible with SR were found in 10 patients (67%) with optimal improvements of 23±13%. In 7 patients (47%), nGVS-induced sway reductions exceeded the minimally important clinical difference (optimal improvement: 30±10%), indicative of strong SR. This beneficial effect was more likely in patients with advanced PD (R = 0.45; p = 0.045). CONCLUSIONS: At least half of the assessed patients showed robust improvements in postural balance compatible with SR when treated with low-intensity nGVS. In particular, patients with more advanced disease stages and imbalance may benefit from the non-invasive and well-tolerated treatment with nGVS.

18F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18F-labeled tau PET tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine (18F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18F-PI-2620 PET. The gain of sensitivity by adding 18F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

The Role of Ultrasound for the Personalized Botulinum Toxin Treatment of Cervical Dystonia.

The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique.

Voice Analysis to Differentiate the Dopaminergic Response in People With Parkinson's Disease.

Humans' voice offers the widest variety of motor phenomena of any human activity. However, its clinical evaluation in people with movement disorders such as Parkinson's disease (PD) lags behind current knowledge on advanced analytical automatic speech processing methodology. Here, we use deep learning-based speech processing to differentially analyze voice recordings in 14 people with PD before and after dopaminergic medication using personalized Convolutional Recurrent Neural Networks (p-CRNN) and Phone Attribute Codebooks (PAC). p-CRNN yields an accuracy of 82.35% in the binary classification of ON and OFF motor states at a sensitivity/specificity of 0.86/0.78. The PAC-based approach's accuracy was slightly lower with 73.08% at a sensitivity/specificity of 0.69/0.77, but this method offers easier interpretation and understanding of the computational biomarkers. Both p-CRNN and PAC provide a differentiated view and novel insights into the distinctive components of the speech of persons with PD. Both methods detect voice qualities that are amenable to dopaminergic treatment, including active phonetic and prosodic features. Our findings may pave the way for quantitative measurements of speech in persons with PD.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

High-Resolution Motor State Detection in Parkinson's Disease Using Convolutional Neural Networks.

Patients with advanced Parkinson's disease regularly experience unstable motor states. Objective and reliable monitoring of these fluctuations is an unmet need. We used deep learning to classify motion data from a single wrist-worn IMU sensor recording in unscripted environments. For validation purposes, patients were accompanied by a movement disorder expert, and their motor state was passively evaluated every minute. We acquired a dataset of 8,661 minutes of IMU data from 30 patients, with annotations about the motor state (OFF,ON, DYSKINETIC) based on MDS-UPDRS global bradykinesia item and the AIMS upper limb dyskinesia item. Using a 1-minute window size as an input for a convolutional neural network trained on data from a subset of patients, we achieved a three-class balanced accuracy of 0.654 on data from previously unseen subjects. This corresponds to detecting the OFF, ON, or DYSKINETIC motor state at a sensitivity/specificity of 0.64/0.89, 0.67/0.67 and 0.64/0.89, respectively. On average, the model outputs were highly correlated with the annotation on a per subject scale (r = 0.83/0.84; p < 0.0001), and sustained so for the highly resolved time windows of 1 minute (r = 0.64/0.70; p < 0.0001). Thus, we demonstrate the feasibility of long-term motor-state detection in a free-living setting with deep learning using motion data from a single IMU.

Interrelation between Sarcopenia and the Number of Motor Neurons in Patients with Parkinsonian Syndromes.

INTRODUCTION: Pathogenesis in a subgroup of sarcopenic patients seems to be based on a reduced number of motor neurons. This study aimed at investigating the overlap between sarcopenia and neurodegeneration, as reflected by a low number of motor neurons in patients with Parkinsonian syndromes (PS). METHODS: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size (MUSIX) of motor units (MUs) in patients with idiopathic Parkinson disease (iPD, n = 53), patients with atypical Parkinsonian syndrome (aPS, n = 21), and a control group (n = 30). Mean age of participants was 70.3 years and 54.1% were female. Skeletal muscle mass by bioelectrical impedance analysis, hand-grip strength and gait speed were measured. Based on these assessments, sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People. RESULTS: Sarcopenia criteria were met by 10 patients with PS (13.5%). The study group had significantly lower MUNIX values than the control group (109 [SD ±39.1] vs. 129 [SD ±45.1]; p = 0.020) even after adjustment for age and sex. Three of the 5 sarcopenic iPD patients (75%) had pathological low MUNIX values (<80). DISCUSSION/CONCLUSION: Sarcopenia is a frequent comorbidity in PS. The pathologically low MUNIX values found in 75% of our sarcopenic iPD patients provides further support for the existence of a neurodegenerative overlap syndrome with a reduced number of MUs potentially leading to sarcopenia. This finding warrants further evaluation.

The Minimal Clinically Relevant Change of the FOG Score.

BACKGROUND: Freezing of gait is a highly disabling symptom in persons with Parkinson's disease (PwP). Despite its episodic character, freezing can be reliably evaluated using the FOG score. The description of the minimal clinically relevant change is a requirement for a meaningful interpretation of its results. OBJECTIVE: To determine the minimal clinically relevant change of the FOG score. METHODS: We evaluated video recordings of a standardized freezing-evoking gait parkour, i.e., the FOG score just before and 30 minutes after the intake of a regular levodopa dose in a randomized blinded fashion. The minimal clinically relevant response was considered a value of one or more on a 7-step Likert-type response scale [-3; +3] that served as the anchor. The minimal clinically relevant change was determined by ROC analysis. RESULTS: 37 PwP (Hoehn & Yahr stages 2.5-4, 27 male, 10 female) were aged 68.2 years on average (range 45-80). Mean disease duration was 12.9 years (2-29 years). Minimum FOG score was 0 and Maximum FOG score was 29. Mean FOG scores before medication were 10.6, and 11.1 after medication intake, with changes ranging from -14.7 to +16.7. The minimal clinically relevant change (MCRC) for improvement based on expert clinician rating was three scale points with a sensitivity of 0.67 and a specificity of 0.96. CONCLUSIONS: The FOG score is recognized as a useful clinical instrument for the evaluation of freezing in the clinical setting. Knowledge of the MCRC should help to define responses to interventions that are discernible and meaningful to the expert physician and to the patient.

A Multi-Layer Gaussian Process for Motor Symptom Estimation in People With Parkinson's Disease.

The assessment of Parkinson's disease (PD) poses a significant challenge, as it is influenced by various factors that lead to a complex and fluctuating symptom manifestation. Thus, a frequent and objective PD assessment is highly valuable for effective health management of people with Parkinson's disease (PwP). Here, we propose a method for monitoring PwP by stochastically modeling the relationships between wrist movements during unscripted daily activities and corresponding annotations about clinical displays of movement abnormalities. We approach the estimation of PD motor signs by independently modeling and hierarchically stacking Gaussian process models for three classes of commonly observed movement abnormalities in PwP including tremor, (non-tremulous) bradykinesia, and (non-tremulous) dyskinesia. We use clinically adopted severity measures as annotations for training the models, thus allowing our multi-layer Gaussian process prediction models to estimate not only their presence but also their severities. The experimental validation of our approach demonstrates strong agreement of the model predictions with these PD annotations. Our results show that the proposed method produces promising results in objective monitoring of movement abnormalities of PD in the presence of arbitrary and unknown voluntary motions, and makes an important step toward continuous monitoring of PD in the home environment.

Gait festination in parkinsonism: introduction of two phenotypes.

Gait festination is one of the most characteristic gait disturbances in patients with Parkinson's disease or atypical parkinsonism. Although festination is common and disabling, it has received little attention in the literature, and different definitions exist. Here, we argue that there are actually two phenotypes of festination. The first phenotype entails a primary locomotion disturbance, due to the so-called sequence effect: a progressive shortening of step length, accompanied by a compensatory increase in cadence. This phenotype strongly relates to freezing of gait with alternating trembling of the leg. The second phenotype results from a postural control problem (forward leaning of the trunk) combined with a balance control deficit (inappropriately small balance-correcting steps). In this viewpoint, we elaborate on the possible pathophysiological substrate of these two phenotypes of festination and discuss their management in daily clinical practice.

Body height loss characterizes camptocormia in Parkinson's disease.

Axial deformities such as camptocormia or Pisa syndrome in people with Parkinson's disease (PwP) are poorly understood. The scarcity of information may result from the shortage of reliable and responsive evaluation instruments. We evaluated the body height loss (BHL) as a new measure for PwP with axial deformities. 50 PwP with axial deformity defined by an UPDRS item 28 value of at least 2 were included in this mono-center study. We measured body height while lying supine and after 1 min of standing, providing a percentage value of BHL, and compared this measure to other clinical variables. BHL depended on the Hoehn and Yahr clinical stage and correlated with clinical scales for function and mobility, but not with timely measures of the axial disorder such as age at diagnosis or duration of disease. ANOVA showed that only lumbar flexion explained the variability of BHL (F = 21.0, p < 0.0001), but not kyphosis (F = 0.4, p = 0.74) or lateroflexion (F = 0.6, p = 0.6). Re-test reliability of BHL was good with к = 0.76 (p < 0.0001). BHL resulted from the lumbar spine and the hip joint and not from the thoracic spine or lateroflexion. This observation conforms to the concept of upper-type and lower-type camptocormia with only the latter leading to a BHL. The assessment of the BHL is shown to be a well defined, easy to perform, and reliable measure for the clinical evaluation of lower-type camptocormia.