Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.

A study of the reliability and validity of the Six-Spot Step Test Cognitive in ambulatory persons with Parkinson's disease.

INTRODUCTION: Although dual-task walking deficits challenge ambulatory function in persons with Parkinson's disease (PwPD), ambulation measures that incorporate cognitive dual-task loads seem scarce. In its construct and instruction, the Six-Spot Step Test Cognitive (SSSTcog) ensures an equal focus on cognitive and motor tasks. The present study investigated the construct validity and test-retest reliability of the SSSTcog in PwPD. METHODS: Seventy-eight PwPD were recruited from outpatient clinics. The SSSTcog was completed twice within the same day and again three to seven days later. In addition, the cognitive Timed "Up and Go" test (TUGcog) and the Mini-BESTest were also conducted on the last day. Reliability and validity were estimated using Bland-Altman statistics, the minimal difference (MD), Intraclass Correlation Coefficient (ICC), and Spearman's rank correlation coefficient (ρ). RESULTS: The SSSTcog was found reliable (ICC: 0.84-0.89; MD: 23.7%-30.2%) and showed moderate construct validity to the TUGcog (ρ = 0.62, p < 0.001). Weak correlations to the Mini-BESTest (ρ = -0.33, p < 0.003) indicated low construct validity. Significantly (p < 0.001) higher dual-task costs were seen when performing the SSSTcog (77.6%) compared to the TUGcog (24.3%). CONCLUSIONS: In PwPD, the SSSTcog showed promising construct validity, acceptable to excellent reliability, making it a valid measure of functional mobility, including cognitive dual-tasking. Higher dual-task cost for the SSSTcog indicated actual cognitive-motor interference while performing the test.

Spinal cord stimulation therapy for patients with Parkinson's disease and gait problems (STEP-PD): study protocol for an exploratory, double-blind, randomised, placebo-controlled feasibility trial.

Introduction: Gait difficulties are common in Parkinson's disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection. Methods and analysis: A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18F-deoxyglucose and 18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months. Ethics and dissemination: This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number: NCT05110053; ClinicalTrials.gov Identifier.

STN-DBS affects language processing differentially in Parkinson's disease: Multiple-case MEG study.

OBJECTIVES: In this study, we investigated the effects of bilateral and unilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) in PD patients on neural responses associated with two aspects of spoken language processing: semantics of action-related verbs and morphosyntactic processing. MATERIALS AND METHODS: Using a passive unattended paradigm to present spoken linguistic stimuli, we recorded magnetoencephalographic (MEG) responses in three PD patients in four DBS conditions: left unilateral STN-DBS, right unilateral STN-DBS, bilateral STN-DBS, and no STN-DBS. To ensure that any observed effects of DBS on the neuromagnetic responses could be attributed to the linguistic context per se and were not merely induced by the electrical stimulation, we assessed the effects of STN-DBS on linguistic contrasts within each stimulation condition. Hence, we contrasted the processing of action vs. abstract verbs as well as the processing of correct vs. incorrect morphosyntactic inflections within each DBS condition. RESULTS: The results revealed that, compared to the DBS-off state, both bilateral and right unilateral stimulation of the STN yielded significant dissociations in the processing of action and abstract verbs, with greater neuromagnetic responses for action verbs compared to abstract verbs. For morphosyntax processing, only left unilateral stimulation yielded significant dissociations (relative to the DBS-off state), with greater neuromagnetic responses to the incorrect inflections compared to the correct inflections. CONCLUSION: The results reflect differential effects of unilateral and bilateral STN-DBS on neuromagnetic responses associated with the processing of spoken language. They suggest that different specific aspects of linguistic information processing in PD are affected differently by STN-DBS.

Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: a trial design.

BACKGROUND: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood-brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. METHODS/DESIGN: In total, 90 subjects aged 18-70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. DISCUSSION: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014-000520-14 and 2017-000163-32.

Axial motor clues to identify atypical parkinsonism: A multicentre European cohort study.

OBJECTIVE: Differentiating Parkinson's disease (PD) from atypical parkinsonian disorders (APD) such as Multiple System Atrophy, parkinsonian type (MSA-p) or Progressive Supranuclear Palsy (PSP-RS) can be challenging. Early signs of postural Instability and gait disability (PIGD) are considered clues that may signal presence of APD. However, it remains unknown which PIGD test - or combination of tests - can best distinguish PD from APD. We evaluated the discriminative value of several widely-used PIGD tests, and aimed to develop a short PIGD evaluation that can discriminate parkinsonian disorders. METHODS: In this multicentre cohort study patients were recruited by 11 European MSA Study sites. Patients were diagnosed using standardized criteria. Postural instability and gait disability was evaluated using interviews and several clinical tests. RESULTS: Nineteen PD, 21 MSA-p and 25 PSP-RS patients were recruited. PIGD was more common in APD compared to PD. There was no significant difference in axial symptoms between PSP-RS and MSA-p, except for self-reported falls (more frequent in PSP-RS patients). The test with the greatest discriminative power to distinguish APD from PD was the ability to perform tandem gait (AUC 0.83; 95% CI 71-94; p < 0.001), followed by the retropulsion test (AUC 0.8; 95% CI 0.69-0.91; p < 0.001) and timed-up-and-go test (TUG) (AUC 0.77; 95% CI 0.64-0.9; p = 0.001). The combination of these three tests yielded highest diagnostic accuracy (AUC 0.96; 95% CI 0.92-1.0; p < 0.001). CONCLUSIONS: Our study suggests that simple "bedside" PIGD tests - particularly the combination of tandem gait performance, TUG and retropulsion test - can discriminate APD from PD.

Improved asymmetry of gait in Parkinson's disease with DBS: gait and postural instability in Parkinson's disease treated with bilateral deep brain stimulation in the subthalamic nucleus.

Postural instability is a sign of progression of Parkinson's disease (PD) and often resistant to levodopa treatment. To explore the effect of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) on postural stability and gait, full body gait analyses were performed without medication, OFF and ON DBS in eight PD patients and 12 healthy age-matched controls. DBS setting was changed at least 3 hours before gait analysis. To describe asymmetry most and least affected sides (MAS and LAS) were rated with the Unified Parkinson's Disease Rating Scale, motor part and quantitative gait analysis with the Vicon 612 gait analysis system. Stride length and gait velocity but not cadence improved ON DBS. The distances between the heel markers and center of mass (COM) were asymmetric and reduced OFF DBS. STN DBS increased the distances significantly and reduced asymmetry. The improvement in heel to COM distance was larger on the MAS compared with the LAS. OFF DBS knee momentum asymmetry was inversed so that LAS was more impaired than MAS. ON DBS asymmetry improved. PD patients OFF DBS place the heel too close to COM. The most affected body side has the most impaired swing and the result is a smaller knee moment on the opposite and least affected body side and an asymmetric gait pattern with disturbed balance OFF STN DBS. The asymmetry OFF DBS improved ON DBS. We suggest that DBS facilitates symmetric gait and thereby improves balance during gait.