[How the implementation of a school for people with Parkinson's disease can succeed-Results of a consensus study and a formative evaluation]. / Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann ­ Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation.

BACKGROUND: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson's disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson's disease with skills to manage the disease better and to participate in shared decision making. MATERIAL AND METHODS: To prepare the implementation of a concept for patient education for people with Parkinson's disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. RESULTS: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6-8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. DISCUSSION: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Continuous deep brain stimulation of the nucleus accumbens reduces food intake but does not affect body weight in mice fed a high-fat diet.

Obesity is an enormous health problem, and many patients do not respond to any of the available therapies. Deep brain stimulation (DBS) is currently investigated as a potential treatment for morbid obesity. In this study, we tested the hypothesis that high-frequency DBS targeting the nucleus accumbens (NAc) shell region reduces food intake and weight gain in mice fed a high-fat diet. We implanted male C57BL/6J mice with bilateral electrodes and a head-mounted microstimulator enabling continuous stimulation for up to 5 weeks. In successfully operated animals (n = 9 per group, high-frequency vs. sham stimulation), we investigated immediate and long-term stimulation effects on metabolic and behavioral phenotypes. Here we show that stimulation acutely induced a transient reduction in energy expenditure and locomotor activity but did not significantly affect spontaneous food intake, social interaction, anxiety or exploratory behaviors. In contrast, continuous stimulation over 5 weeks led to a decrease in food intake and thigmotaxis (the tendency to stay near walls in an open lit arena). However, chronic stimulation did not substantially change weight gain in mice fed a high-fat diet. Our results do not support the use of continuous high-frequency NAc shell DBS as a treatment for obesity. However, DBS can alter obesity-related parameters with differing short and long-term effects. Therefore, future research should employ time and context-sensitive experimental designs to assess the potential of DBS for clinical translation in this area.

Brainstem atrophy in dementia with Lewy bodies compared with progressive supranuclear palsy and Parkinson's disease on MRI.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

New Insights into Potential Biomarkers in Patients with Mild Cognitive Impairment Occurring in the Prodromal Stage of Dementia with Lewy Bodies.

BACKGROUND: Prodromal dementia with Lewy bodies (DLB) can emerge with the onset of mild cognitive impairment (MCI). Standard biomarkers can help identify such patients to improve therapy and treatment strategies. Our review aims to describe the latest evidence on promising biomarkers in prodromal DLB with MCI onset (MCI-LB). METHODS: We selected articles on different biomarkers in MCI-LB from PubMed and conducted a narrative review. RESULTS: We identified potentially promising clinical biomarkers, e.g., (1) assessing autonomic symptoms specifically, (2) describing the cognitive profile in several subdomains including executive and visual functions, and (3) measuring the speed of speech. In addition, we describe the measurement of seeding amplification assays of alpha-synuclein in cerebrospinal fluid as a relevant biomarker for MCI-LB. Electroencephalographic markers, as in calculating the theta/beta ratio or intermittent delta activity, or analyzing peak frequency in electroencephalography-methods also potentially useful once they have been validated in large patient cohorts. The 18F fluorodesoxyglucose positron emission tomography (FDG-PET) technique is also discussed to investigate metabolic signatures, as well as a specific magnetic resonance imaging (MRI) technique such as for the volumetric region of interest analysis. CONCLUSIONS: These biomarker results suggest that MCI-LB is a promising field for the use of biomarkers other than established ones to diagnose early prodromal DLB. Further large-scale studies are needed to better evaluate and subsequently use these promising biomarkers in prodromal DLB.

Ectosomes and exosomes modulate neuronal spontaneous activity.

Extracellular vesicles (EVs) are important mediators in intercellular communication. However, understanding the biological origin and functional effects of EVs subtypes has been challenging due to the moderate differences in their physical properties and absence of reliable markers. Here, we characterize the proteomes of ectosomes and exosomes using an improved differential ultracentrifugation protocol and quantitative proteomics. Our analyses revealed singular proteomic profiles for ectosomes and exosomes that enabled us to establish specific protein markers that can be used for their biochemical distinction. Cytoskeleton and glycolytic proteins are distinctively present in ectosomes, while endosomal sorting complexes proteins and tetraspanins are enriched in exosomes. Furthermore, annexin-A2 was identified as a specific marker for ectosomes derived from cell media and human cerebrospinal fluid. Expression of EGFP as a cytosolic reporter leads to its incorporation in EVs and enables their imaging with higher resolution. Assessment of neuronal network activity using multi-electrode array recordings demonstrated that spontaneous neuronal activity can be modulated by EVs. Ectosomes and exosomes internalization in neuronal cells disrupted their regular synchronized bursting activity, resulting in overall lower and more disorganized spiking activity. Our findings suggest that EVs cargoes reflect core intracellular processes, and their functional properties might regulate basic biological and pathological processes. SIGNIFICANCE: This article presents novel approaches for studying the origin, composition, and biological effects in neuronal activity of ectosomes and exosomes. Our findings suggest that EVs cargoes reflect core intracellular processes, and their functional properties might regulate basic biological and pathological processes. Ultimately, our study also forms the foundation for future biomarker studies and for the understanding of the molecular basis of different diseases.

Prospective CERAD Neuropsychological Assessment in Patients With Multiple System Atrophy.

The objective of the study was to characterize the pattern of cognitive dysfunction in patients with multiple system atrophy (MSA) applying a standardized neuropsychological assessment. A total of 20 patients with the diagnosis of probable or possible MSA were enrolled for neuropsychological assessment applying the CERAD plus battery. All patients were tested at baseline and 14/20 patients received additional follow-up assessments (median follow-up of 24 months). Additionally, relationship between cortical thickness values/subcortical gray matter volumes and CERAD subitems was evaluated at baseline in a subgroup of 13/20 patients. Trail Making Test (TMT) was the most sensitive CERAD item at baseline with abnormal performance (z-score < -1.28) in one or both pathological TMT items (TMT-A, TMT-B) in 60% of patients with MSA. Additionally, there was a significant inverse correlation between the volume of the left and the right accumbens area and the TMT A item after adjusting for age (left side: p = 0.0009; right side p = 0.003). Comparing both subtypes, patients with MSA-C had significant lower values in phonemic verbal fluency (p = 0.04) and a trend for lower values in semantic verbal fluency (p = 0.06) compared to MSA-P. Additionally, patients with MSA-C showed significantly worse performance in the TMT-B task (p = 0.04) and a trend for worse performance in the TMT-A task (p = 0.06). Concerning longitudinal follow-up, a significant worsening in the TMT-B (p = 0.03) can be reported in MSA. In conclusion, frontal-executive dysfunction presents the hallmark of cognitive impairment in MSA.

The relevance of synuclein autoantibodies as a biomarker for Parkinson's disease.

Several studies have investigated if the levels of α-synuclein autoantibodies (α-syn AAb) differ in serum of Parkinson's disease (PD) patients and healthy subjects. Reproducible differences in their levels could serve as a biomarker for PD. The results of previous studies however remain inconclusive. With the largest sample size examined so far, we aimed to validate serum α-syn AAb levels as a biomarker for PD and investigated the presence of AAbs against other synucleins. We performed ELISA and immunoblots to determine synuclein AAb levels in the serum of 295 subjects comprising 157 PD patients from two independent cohorts, 46 healthy subjects, and 92 patients with other neurodegenerative disorders. Although serum α- and ß-syn AAb levels were significantly reduced in patients with PD and other neurodegenerative disorders as compared to controls, the AAb levels displayed high inter-and intra-cohort variability. Furthermore, α-syn AAb levels showed no correlation to clinical parameters like age, disease duration, disease severity, and gender, that might also be directed against beta- and gamma-syn. In conclusion, serum synuclein AAb levels do allow the separation of PD from healthy subjects but not from other neurodegenerative disorders. Thus, synuclein AAbs cannot be regarded as a reliable biomarker for PD.

Determining an efficient deep brain stimulation target in essential tremor - Cohort study and review of the literature.

INTRODUCTION: Deep brain stimulation (DBS) is a highly efficacious treatment for essential tremor (ET). Still, the optimal anatomical target in the (sub)thalamic area is a matter of debate. The aim of this study was to determine the optimal target of DBS for ET regarding beneficial clinical outcome and impact on activities of daily living as well as stimulation-induced side effects and compare it with previously published coordinates. METHODS: In 30 ET patients undergoing bilateral DBS, severity of tremor was assessed by blinded video ratings before and at 1-year follow-up with DBS ON and OFF. Tremor scores and reported side effects and volumes of tissue activated were used to create a probabilistic map of DBS efficiency and side effects. RESULTS: DBS was effective both in tremor suppression as well as in improving patient reported outcomes, which were positively correlated. The "sweet spot" for tremor suppression was located inferior of the VIM in the subthalamic area, close to the superior margin of the zona incerta. The Euclidean distance of active contacts to this spot as well as to 10 of 13 spots from the literature review was predictive of individual outcome. A cluster associated with the occurrence of ataxia was located in direct vicinity of the "sweet spot". CONCLUSION: Our findings suggest the highest clinical efficacy of DBS in the posterior subthalamic area, lining up with previously published targets likely representing the dentato-rubro-thalamic tract. Side effects may not necessarily indicate lead misplacement, but should encourage clinicians to employ novel DBS programing options.

Levodopa-Induced Dyskinesia Are Mediated by Cortical Gamma Oscillations in Experimental Parkinsonism.

BACKGROUND: Levodopa is the most efficacious drug in the symptomatic therapy of motor symptoms in Parkinson's disease (PD); however, long-term treatment is often complicated by troublesome levodopa-induced dyskinesia (LID). Recent evidence suggests that LID might be related to increased cortical gamma oscillations. OBJECTIVE: The objective of this study was to test the hypothesis that cortical high-gamma network activity relates to LID in the 6-hydroxydopamine model and to identify new biomarkers for adaptive deep brain stimulation (DBS) therapy in PD. METHODS: We recorded and analyzed primary motor cortex (M1) electrocorticogram data and motor behavior in freely moving 6-OHDA lesioned rats before and during a daily treatment with levodopa for 3 weeks. The results were correlated with the abnormal involuntary movement score (AIMS) and used for generalized linear modeling (GLM). RESULTS: Levodopa reverted motor impairment, suppressed beta activity, and, with repeated administration, led to a progressive enhancement of LID. Concurrently, we observed a highly significant stepwise amplitude increase in finely tuned gamma (FTG) activity and gamma centroid frequency. Whereas AIMS and FTG reached their maximum after the 4th injection and remained on a stable plateau thereafter, the centroid frequency of the FTG power continued to increase thereafter. Among the analyzed gamma activity parameters, the fraction of longest gamma bursts showed the strongest correlation with AIMS. Using a GLM, it was possible to accurately predict AIMS from cortical recordings. CONCLUSIONS: FTG activity is tightly linked to LID and should be studied as a biomarker for adaptive DBS. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subthalamic beta oscillations correlate with dopaminergic degeneration in experimental parkinsonism.

Excessive beta activity has been shown in local field potential recordings from the cortico-basal ganglia loop of Parkinson's disease patients and in its various animal models. Recent evidence suggests that enhanced beta oscillations may play a central role in the pathophysiology of the disorder and that beta activity may be directly linked to the motor impairment. However, the temporal evolution of exaggerated beta oscillations during the ongoing dopaminergic neurodegeneration and its relation to the motor impairment and histological changes are still unknown. We investigated motor behavioral, in-vivo electrophysiological (subthalamic nucleus, motor cortex) and histological changes (striatum, substantia nigra compacta) 2, 5, 10 and 20-30 days after a 6-hydroxydopamine injection into the medial forebrain bundle in Wistar rats. We found strong correlations between subthalamic beta power and motor impairment. No correlation was found for beta power in the primary motor cortex. Only subthalamic but not cortical beta power was strongly correlated with the histological markers of the dopaminergic neurodegeneration. Significantly increased subthalamic beta oscillations could be detected before this increase was found in primary motor cortex. At the latest observation time point, a significantly higher percentage of long beta bursts was found. Our study is the first to show a strong relation between subthalamic beta power and the dopaminergic neurodegeneration. Thus, we provide additional evidence for an important pathophysiological role of subthalamic beta oscillations and prolonged beta bursts in Parkinson's disease.

The spectrum of involuntary vocalizations in humans: A video atlas.

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Pulse duration settings in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. METHODS: A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients' efficacy and side effect thresholds. RESULTS: The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). INTERPRETATION: Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

High-fat diet-induced obesity and insulin resistance are characterized by differential beta oscillatory signaling of the limbic cortico-basal ganglia loop.

The concept of brain circuit disorders has been proposed for a variety of neuropsychiatric diseases, characterized by pathological disturbances of neuronal networks including changes in oscillatory signaling of re-entrant cortico-subcortical loops in the basal ganglia system. Parts of this circuitry play a pivotal role in energy homeostasis. We therefore investigated whether high-fat diet (HFD) induced obesity is associated with changes in oscillatory signaling in the limbic cortico-basal ganglia loop. We performed multi-site in-vivo electrophysiological recordings of local field potentials within this network under urethane anesthesia in adult rats after 4 weeks of HFD feeding compared to age-matched controls. Recordings were performed at baseline and during systemic glucose challenge. Our analysis demonstrates increased oscillatory beta power in the nucleus accumbens (NAC) associated with decreased beta coherence between cortex and NAC in animals fed a HFD. Spontaneous beta oscillatory power strongly correlated with endocrine markers of obesity. The glucose challenge increased beta oscillations in control animals but not in animals receiving the HFD. Furthermore direct intracerebroventricular insulin injection increased beta oscillations in the NAC. The present study provides evidence for aberrant oscillatory signaling in the limbic cortico-basal ganglia loop that might contribute to the dysfunctional information processing in obesity.

Differential effects of levodopa and apomorphine on neuronal population oscillations in the cortico-basal ganglia loop circuit in vivo in experimental parkinsonism.

The current pharmacotherapy of Parkinson's disease (PD) is primarily based on two classes of drugs: dopamine precursors, namely levodopa, and dopamine receptor agonists, such as apomorphine. Although both types of agents exert their beneficial clinical effects on motor and non-motor symptoms in PD via dopamine receptors, clinical efficiency and side effects differ substantially between levodopa and apomorphine. Levodopa can provide a greater symptomatic relief than dopamine receptor agonists. However, because long-term levodopa use is associated with early debilitating motor fluctuations, dopamine receptor agonists are often recommended in younger patients. The pharmacodynamic basis of these profound differences is incompletely understood. It has been hypothesized that levodopa and dopamine receptor agonists may have diverging effects on beta and gamma oscillations that have been shown to be of importance for the pathophysiology of PD. Here, we used electrophysiological recordings in anesthetized dopamine-intact and dopamine-depleted rats to systemically compare the impact of levodopa or apomorphine on neuronal population oscillations in three nodes of the cortico-basal ganglia loop circuit. Our results showed that levodopa had a higher potency than apomorphine to suppress the abnormal beta oscillations often associated with bradykinesia while simultaneously enhancing the gamma oscillations often associated with increased movement. Our data suggests that the higher clinical efficacy of levodopa as well as some of its side effects, as e.g. dyskinesias may be based on its characteristic ability to modulate beta-/gamma-oscillation dynamics in the cortico-basal ganglia loop circuit.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats.

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo.