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Plasma Phospho‐Tau Identifies Alzheimer's Co‐Pathology in Patients with Lewy Body Disease

2020-12-07T00:00

Background

Alzheimer's disease co‐pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives.

Objective

To investigate if plasma phospho‐tau217 and phospho‐tau181 can detect Alzheimer's pathology in Lewy body disease with dementia.

Methods

In this cross‐sectional study we investigated plasma phospho‐tau217 and phospho‐tau181 in 35 patients with Lewy body disease with dementia. Patients underwent tau‐PET imaging (¹⁸F‐RO948).

Results

Plasma phospho‐tau217 correlated with plasma phospho‐tau181, CSF phospho‐tau217 (r_s = 0.68, P < 0.001), and negatively with CSF β‐amyloid_42/40 (r_s = −0.52, P = 0.001). Plasma phospho‐tau217 and phospho‐tau181 correlated with tau‐PET signal in the temporal cortex (r_s > 0.56, P < 0.001) and predicted abnormal tau‐PET status and β‐amyloid status (area under the curve > 0.78 and > 0.81, respectively).

Conclusion

Plasma phospho‐tau might be a useful marker for Alzheimer's co‐pathology in Lewy body disease with dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Gain‐of‐Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype

2020-11-16T00:00

Background

We describe a 4‐generation Dutch pedigree with a unique dominantly inherited clinical phenotype of a combined progressive chorea and cervical dystonia carrying a novel heterozygous dopamine D2 receptor (DRD2) variant.

Objectives

The objective of this study was to identify the genetic cause of the disease and to further investigate the functional consequences of the genetic variant.

Methods

After detailed clinical and neurological examination, whole‐exome sequencing was performed. Because a novel variant in the DRD2 gene was found as the likely causative gene defect in our pedigree, we sequenced the DRD2 gene in a cohort of 121 Huntington‐like cases with unknown genetic cause (Germany). Moreover, functional characterization of the DRD2 variant included arrestin recruitment, G protein activation, and G protein‐mediated inhibition of adenylyl cyclase determined in a cell model, and G protein‐regulated inward‐rectifying potassium channels measured in midbrain slices of mice.

Result

We identified a novel heterozygous variant c.634A > T, p.Ile212Phe in exon 5 of DRD2 that cosegregated with the clinical phenotype. Screening of the German cohort did not reveal additional putative disease‐causing variants. We demonstrated that the D2_S/L‐I²¹²F receptor exhibited increased agonist potency and constitutive activation of G proteins in human embryonic kidney 239 cells as well as significantly reduced arrestin3 recruitment. We further showed that the D2_S‐I²¹²F receptor exhibited aberrant receptor function in mouse midbrain slices.

Conclusions

Our results support an association between the novel p.Ile212Phe variant in DRD2, its modified D2 receptor activity, and the hyperkinetic movement disorder reported in the 4‐generation pedigree. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long‐Term Safety and Clinical Effects of Nilotinib in Parkinson's Disease

2020-11-20T00:00

Background

Nilotinib is US Food and Drug Administration–approved for leukemia, and this open‐label study investigated the safety, tolerability, and potential clinical effects of nilotinib in medically optimized patients with Parkinson's disease.

Objectives

Safety and tolerability were the primary objectives, and clinical outcomes were exploratory.

Methods

A total of 63 patients completed a 15‐month phase 2, double‐blind, placebo‐controlled study and were rerandomized 1:1 into an open‐label study of nilotinib 150 mg versus 300 mg for 12 months.

Results

Nilotinib was safe and tolerated, and no adverse effects seemed to be related to the drug, and no differences in adverse events were observed between groups. Exploratory clinical outcomes showed that nilotinib 300 mg was remarkably stable from baseline to 27 months using partial and total Unified Parkinson's Disease Scale (UPDRS). Nilotinib 150 mg versus 300 mg, significantly declined using partial or the sum of UPDRS Parts I and II. There was no significant difference in nilotinib 150 mg versus 300 mg using UPDRS Part III (on levodopa) and total UPDRS Parts I to III. Subgroup analysis showed that late‐start nilotinib 150 mg significantly worsened using the sum of UPDRS Parts II + III and total UPDRS Parts I to III compared with late‐start nilotinib 300 mg. Quality of life using the Parkinson's Disease Questionnaire in nilotinib 150 mg significantly declined between 15 and 27 months compared with nilotinib 300 mg, and there was no change in cognition using the Montreal Cognitive Assessment between groups.

Conclusions

This study provides evidence that nilotinib is safe and tolerated in Parkinson's disease. The exploratory clinical data will inform an adequately powered larger study to evaluate the efficacy of nilotinib 300 mg in Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Levodopa Versus Dopamine Agonist after Subthalamic Stimulation in Parkinson's Disease

2020-11-09T00:00

Background

No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD).

Objective

Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD.

Methods

Thirty‐five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single‐blind study. All patients were reevaluated in short‐ (3 months), mid‐ (6 months), and long‐term (2.5 years) follow‐up after surgery. The primary outcome measure was the change in the Non‐Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non‐motor symptoms (NMS). Analysis was performed primarily in the intention‐to‐treat population.

Results

Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: −11.78–21.53, P = 0.566]). In short‐ and mid‐term follow‐up, monotherapy was safe and feasible in more than half of patients (60% in short‐ and 51.5% in mid‐term follow‐up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders.

Conclusions

This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Bilateral Pallidotomy for Dystonia: A Systematic Review

2020-11-20T00:00

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication‐refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre‐and postoperative Burke‐Fahn‐Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty‐five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median‐reported follow‐up was 12 months (n = 83; range: 2–180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication‐refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient‐Derived Neurons

2020-11-03T00:00

Background

VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria‐derived vesicles. The p.D620N mutation of VPS35 causes an autosomal‐dominant form of Parkinson's disease (PD), clinically representing typical PD.

Objective

Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient‐derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell‐derived neurons from a patient harboring the p.D620N mutation.

Methods

We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons.

Results

We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α‐synuclein in patient‐derived neurons compared to controls. Moreover, patient‐derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy.

Conclusion

We describe for the first time the impact of the p.D620N VPS35 mutation on autophago‐lysosome pathway and mitochondrial function in stem cell‐derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease

2020-12-31T00:00

Background

Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease‐specific gait impairment.

Objective

To evaluate associations between sub‐regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD.

Methods

99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub‐regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post‐mortem histology. Univariate analyses evaluated cross‐sectional associations between sub‐regional volumes and gait. Linear mixed‐effects models assessed whether volumes predicted longitudinal gait changes.

Results

There were no cross‐sectional, age‐independent relationships between sub‐regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041).

Conclusions

This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

March Infographic: Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease

Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease

2020-12-05T00:00

Background

Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.

Methods

We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as ¹¹C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with ¹⁸F‐dopa influx constants.

Results

The ¹¹C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased ¹¹C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral ¹¹C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal ¹⁸F‐dopa uptake was similar to healthy controls.

Conclusions

In vivo ¹¹C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Closed‐Loop Deep Brain Stimulation for Essential Tremor Based on Thalamic Local Field Potentials

2021-02-06T00:00

Background

High‐frequency thalamic stimulation is an effective therapy for essential tremor, which mainly affects voluntary movements and/or sustained postures. However, continuous stimulation may deliver unnecessary current to the brain due to the intermittent nature of the tremor.

Objective

We proposed to close the loop of thalamic stimulation by detecting tremor‐provoking movement states using local field potentials recorded from the same electrodes implanted for stimulation, so that the stimulation is only delivered when necessary.

Methods

Eight patients with essential tremor participated in this study. Patient‐specific support vector machine classifiers were first trained using data recorded while the patient performed tremor‐provoking movements. Then, the trained models were applied in real‐time to detect these movements and triggered the delivery of stimulation.

Results

Using the proposed method, stimulation was switched on for 80.37 ± 7.06% of the time when tremor‐evoking movements were present. In comparison, the stimulation was switched on for 12.71 ± 7.06% of the time when the patients were at rest and tremor‐free. Compared with continuous stimulation, a similar amount of tremor suppression was achieved while only delivering 36.62 ± 13.49% of the energy used in continuous stimulation.

Conclusions

The results suggest that responsive thalamic stimulation for essential tremor based on tremor‐provoking movement detection can be achieved without any requirement for external sensors or additional electrocorticography strips. Further research is required to investigate whether the decoding model is stable across time and generalizable to the variety of activities patients may engage with in everyday life. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Automated Analysis of Diffusion‐Weighted Magnetic Resonance Imaging for the Differential Diagnosis of Multiple System Atrophy from Parkinson's Disease

2020-09-16T00:00

Background

Manual region‐of‐interest analysis of putaminal and middle cerebellar peduncle diffusivity distinguishes patients with multiple system atrophy (MSA) and Parkinson's disease (PD) with high diagnostic accuracy. However, a recent meta‐analysis found substantial between‐study heterogeneity of diagnostic accuracy due to the lack of harmonized imaging protocols and standardized analyses pipelines.

Objective

Evaluation of diagnostic accuracy of observer‐independent analysis of microstructural integrity as measured by diffusion‐tensor imaging in patients with MSA and PD.

Methods

A total of 29 patients with MSA and 19 patients with PD (matched for age, gender, and disease duration) with 3 years of follow‐up were investigated with diffusion‐tensor imaging and T1‐weighted magnetic resonance imaging. Automated localization of relevant brain regions was obtained, and mean diffusivity and fractional anisotropy values were averaged within the regions of interest. The classification was performed using a C5.0 hierachical decision tree algorithm.

Results

Mean diffusivity of the middle cerebellar peduncle and cerebellar gray and white matter compartment as well as the putamen were significantly increased in patients with MSA and showed superior effect sizes compared to the volumetric analysis of these regions. A classifier model identified mean diffusivity of the middle cerebellar peduncle and putamen as the most predictive parameters. Cross‐validation of the classification model yields a Cohen's κ and overall diagnostic accuracy of 0.823 and 0.914, respectively.

Conclusion

Analysis of microstructural integrity within the middle cerebellar peduncle and putamen yielded a superior effect size compared to the volumetric measures, resulting in excellent diagnostic accuracy to discriminate patients with MSA from PD in the early to moderate disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

The Role of the Subthalamic Nucleus in Sequential Working Memory in De Novo Parkinson's Disease

2020-10-24T00:00

Background

Deficits in maintaining and manipulating sequential information online can occur even in patients with mild Parkinson's disease. The subthalamic nucleus may play a modulatory role in the neural system for sequential working memory, which also includes the lateral prefrontal cortex.

Objectives

The objective of this study was to investigate neural markers of sequential working memory deficits in patients with de novo Parkinson's disease.

Methods

A total of 50 patients with de novo Parkinson's disease and 50 healthy controls completed a digit ordering task during functional magnetic resonance imaging scanning. The task separated the maintenance (“pure recall”) and manipulation of sequences (“reorder & recall” vs “pure recall”).

Results

In healthy controls, individual participants' task accuracy was predicted by the regional activation and functional connectivity of the subthalamic nucleus. Healthy participants who showed lower subthalamic nucleus activation and stronger subthalamic nucleus connectivity with the putamen performed more accurately in maintaining sequences (“pure recall”). Healthy participants who showed greater ordering‐related subthalamic nucleus activation change exhibited smaller accuracy costs in manipulating sequences (“reorder & recall” vs “pure recall”). Patients performed less accurately than healthy controls, especially in “reorder & recall” trials, accompanied by an overactivation in the subthalamic nucleus and a loss of synchrony between the subthalamic nucleus and putamen. Individual patients' task accuracy was predicted only by the subthalamic nucleus connectivity. The contribution of the subthalamic nucleus activation or activation change was absent. We observed no change in the lateral prefrontal cortex.

Conclusions

The overactivation and weakened functional connectivity of the subthalamic nucleus are the neural markers of sequential working memory deficits in de novo Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

A New Approach to the Development of Disease‐Modifying Therapies for PD; Fighting Another Pandemic

2020-10-07T00:00

A disease‐modifying therapy that slows disease progression and development of disability is the major unmet need in the treatment of Parkinson's disease. Recent scientific advances suggest many promising and exciting new interventions. However, despite these opportunities, the cost, time and uncertainty of being able to receive an indication as a disease‐modifying therapy has caused many pharmaceutical companies to abandon development of potentially disease‐modifying drugs. We propose a new approach to development of these agents that will reduce the cost and facilitate approval of putative disease‐modifying drugs that should prove acceptable to pharmaceutical companies and regulatory agencies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Comparison of Patient and Expert Perceptions of the Attainment of Research Milestones in Parkinson's Disease

2020-10-01T00:00

Background

Commentators suggest that patients have unrealistic expectations about the pace of research advances and that such expectations interfere with patient decision‐making.

Objective

The objective of this study was to compare expert expectations about the timing of research milestone attainment with those of patients who follow Parkinson's disease (PD) research.

Methods

Patients with PD and experts were asked to provide forecasts about 11 milestones in PD research in an online survey. PD experts were identified from a Michael J. Fox Foundation database, highly ranked neurology centers in the United States and Canada, and corresponding authors of articles on PD in top medical journals. Patients with PD were recruited through the Michael J. Fox Foundation. We tested whether patient forecasts differed on average from expert forecasts. We also tested whether differences between patient forecasts and the average expert forecasts were associated with any demographic factors.

Results

A total of 256 patients and 249 PD experts completed the survey. For 9 of the 11 milestones, patients' forecasts were on average higher than those of experts. Only exercise therapy met our 10% difference threshold for practical significance. Education was the only demographic that predicted patient deviations from expert forecasts on milestone forecasts. Patients offered significantly higher forecasts than experts that the clinical trials used in milestone queries would report positive primary outcomes.

Conclusions

Differences between patient and expert expectations about research milestones were generally minor, suggesting that there is little cause for concern that patients who follow PD research are unduly swayed by inaccurate representations of research advancement in the media or elsewhere. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Hydrocephalus Complicating Intrathecal Antisense Oligonucleotide Therapy for Huntington's Disease

2020-10-30T00:00

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

2020-09-23T00:00

Background

Orthostatic hypotension is common in patients with Parkinson's disease (PD). However, it remains unknown whether orthostatic hypotension is a marker of prodromal PD or more advanced disease. The objectives of this study were to assess whether orthostatic hypotension is a prodromal marker of PD in the general population.

Methods

This study was embedded in the Rotterdam Study, a large prospective population‐based cohort in the Netherlands. We measured orthostatic hypotension in 6910 participants. First, we determined the relation between prevalent PD and orthostatic hypotension using logistic regression. Second, we followed PD‐free participants for the occurrence of PD until 2016 and studied the association between orthostatic hypotension and the risk of PD using Cox proportional hazards models. All models were adjusted for age and sex.

Results

At baseline, the mean age ± standard deviation of the study population was 69.0 ± 8.8 years, and 59.1% were women. Orthostatic hypotension was present in 1245 participants (19.8%), and 62 participants (1.0%) had PD at the time of orthostatic hypotension measurement. Participants with PD were significantly more likely to have orthostatic hypotension (odds ratio, 1.88; 95% confidence interval, 1.09–3.24). During a median (interquartile range) follow‐up of 16.1 years (8.5–22.7 years), 122 participants were diagnosed with incident PD. Orthostatic hypotension at baseline was not associated with an increased risk of PD (hazard ratio, 0.97; 95% confidence interval, 0.59–1.58).

Conclusions

Our study suggests that orthostatic hypotension is common in patients with PD, but that orthostatic hypotension is not associated with an increased risk of PD and thus is not a prodromal marker of PD in the general population. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Four‐Year Follow‐up of [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography–Based Parkinson's Disease–Related Pattern Expression in 20 Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression

2020-09-10T00:00

Background

Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha‐synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [¹⁸F]fluorodeoxyglucose‐positron emission tomography (PET)–based PD‐related brain pattern can be used to monitor disease progression.

Objective

We longitudinally investigated PD‐related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters.

Methods

Subjects underwent two [¹⁸F]fluorodeoxyglucose‐PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame.

Results

At baseline, 8 of 20 (40%) subjects significantly expressed the PD‐related brain pattern (with z scores above the receiver operating characteristic–determined threshold). At follow‐up, six additional subjects exhibited significant PD‐related brain pattern expression (70% in total). PD‐related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD‐related brain pattern expression, phenoconverted to clinical PD.

Conclusions

Suprathreshold PD‐related brain pattern expression and greater score rate of change may signify greater shorter‐term risk for phenoconversion. Our results support the use of serial PD‐related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

2020-09-25T00:00

Background

X‐linked dystonia‐parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full‐length mRNA transcript.

Objectives

The objective of this study was to discover cell‐based and biofluid‐based biomarkers for X‐linked dystonia‐parkinsonism.

Methods

RNA from patient‐derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet‐digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5′ and 3′ to the retrotransposon insertion and the disease‐specific splice variant TAF1‐32i in whole‐blood RNA. Plasma levels of neurofilament light chain were measured using single‐molecule array.

Results

In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1‐3′/5′ ratio was lower in patient samples, whereas TAF1‐32i expression is higher relative to controls. In whole‐blood RNA, both TAF1‐3′/5′ ratio and TAF1‐32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79.

Conclusions

TAF1 dysregulation in blood serves as a disease‐specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adenosine A_2A Receptor Occupancy by Long‐Term Istradefylline Administration in Parkinson's Disease

2020-11-16T00:00

Mediterranean Dietary Pattern at Middle Age and Risk of Parkinson's Disease: A Swedish Cohort Study

2020-10-20T00:00

Background

The Mediterranean diet has been proposed to protect against neurodegeneration.

Objectives

The aim of this study was to assess the association of adherence to Mediterranean dietary pattern (MDP) at middle age with risk for Parkinson's disease (PD) later in life.

Method

In a population‐based cohort of >47,000 Swedish women, information on diet was collected through a food frequency questionnaire during 1991–1992, from which adherence to MDP was calculated. We also collected detailed information on potential confounders. Clinical diagnosis of PD was ascertained from the Swedish National Patient Register through 2012.

Results

We observed an inverse association between adherence to MDP and PD, multivariable hazard ratio of 0.54 (95% confidence interval: 0.30–0.98), comparing high with low adherence. The association was noted primarily from age 65 years onward. One unit increase in the adherence score was associated with a 29% lower risk for PD at age ≥ 65 years (95% confidence interval: 0.57–0.89).

Conclusion

Higher adherence to a Mediterranean diet at middle age was associated with lower risk for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Stress and Mindfulness in Parkinson's Disease: Clinical Effects and Potential Underlying Mechanisms

2020-10-23T00:00

Patients with Parkinson's disease (PD) are very vulnerable to the negative effects of psychological distress: neuropsychiatric symptoms, such as anxiety and depression, are highly prevalent in PD; motor symptoms (such as tremor) typically worsen in stressful situations; and dopaminergic medication is less effective. Furthermore, animal studies of PD suggest that chronic stress may accelerate disease progression. Adequate self‐management strategies are therefore essential to reduce the detrimental effects of chronic stress on PD. Mindfulness‐based interventions encourage individuals to independently self‐manage and adapt to the challenges created by their condition. In PD, emerging clinical evidence suggests that mindfulness‐based interventions may reduce psychological distress and improve clinical symptoms, but insight into the underlying mechanisms is lacking. In this viewpoint, we provide a systematic overview of existing mindfulness trials in PD. Furthermore, we discuss the cerebral mechanisms involved in acute and chronic stress, and the impact of mindfulness‐based interventions on these networks. In addition, we delineate a hypothetical mechanistic framework of how chronic stress may increase the susceptibility for neuropsychiatric symptoms in PD and may potentially even influence disease progression. We end with offering recommendations for future research. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Serious Transport Accidents in Tourette Syndrome or Chronic Tic Disorder

2020-09-24T00:00

Background

It is unknown whether individuals with tic disorders are at increased risk for serious transport accidents.

Objectives

The aim of this study was to investigate the risk for injuries or death caused by transport and motor vehicle accidents in individuals with Tourette syndrome or chronic tic disorder.

Methods

This population‐based, sibling‐controlled cohort study included all individuals aged ≥18 years living in Sweden between 1997 and 2013 (N = 6,127,290). A total of 3449 individuals had a registered diagnosis of Tourette syndrome or chronic tic disorder in the Swedish National Patient Register. We also identified 2191 families with full siblings discordant for tic disorders. Cox proportional hazards regression modeling was used to estimate the risk for injuries or deaths as a result of transport accidents in individuals with a lifetime diagnosis of Tourette syndrome or chronic tic disorder compared with unexposed individuals and siblings.

Results

Individuals with tic disorders had a higher risk for transport injuries or death compared with the general population (adjusted hazard ratio, 1.50 [95% confidence interval: 1.33–1.69]) and their unaffected siblings (adjusted hazard ratio, 1.41 [95% confidence interval: 1.18–1.68]). The risks were similar across sexes. The exclusion of most psychiatric comorbidities did not alter the magnitude of the estimates. However, the risks were no longer significant after exclusion of individuals with comorbid attention deficit hyperactivity disorder.

Conclusions

The marginally increased risk for serious transport accidents in tic disorders is mainly driven by attention deficit hyperactivity disorder comorbidity. Improved detection and management of attention deficit hyperactivity disorder symptoms in this patient group are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Laryngeal Movement Disorders in Multiple System Atrophy: A Diagnostic Biomarker?

2020-08-05T00:00

Background

Multiple system atrophy (MSA) is a rare neurodegenerative disorder, and its parkinsonian variant can be difficult to delineate from Parkinson's disease (PD). Despite laryngeal dysfunction being associated with decreased life expectancy and quality of life, systematic assessments of laryngeal dysfunction in large cohorts are missing.

Objectives

The objective of this study was to systematically assess laryngeal dysfunction in MSA and PD and identify laryngeal symptoms that allow for differentiating MSA from PD.

Methods

Patients with probable or possible MSA underwent flexible endoscopic evaluation of swallowing performing a systematic task protocol. Findings were compared with an age‐matched PD cohort.

Results

A total of 57 patients with MSA (64 [59–71] years; 35 women) were included, and task assessments during endoscopic examination compared with 57 patients with PD (67 [60–73]; 28 women). Patients with MSA had a shorter disease duration (4 [3–5] years vs 7 [5–10]; P < 0.0001) and higher disease severity (Hoehn & Yahr stage 4 [3–4] vs 3 [2–4]; P < 0.0001). Of the patients with MSA, 43.9% showed clinically overt laryngeal dysfunction with inspiratory stridor. During endoscopic task assessment, however, 93% of patients with MSA demonstrated laryngeal dysfunction in contrast with only 1.8% of patients with PD (P < 0.0001). Irregular arytenoid cartilages movements were present in 91.2% of patients with MSA, but in no patients with PD (P < 0.0001). Further findings included vocal fold motion impairment (75.4%), paradoxical vocal fold motion (33.3%), and vocal fold fixation (19.3%). One patient with PD showed vocal fold motion impairment.

Conclusion

Laryngeal movement disorders are highly prevalent in patients with MSA when assessed by a specific task protocol despite the lack of overt clinical symptoms. Our data suggest that irregular arytenoid cartilage movements could be used as a clinical marker to delineate MSA from PD with a specificity of 1.0 and sensitivity 0.9. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Signs of Chronic Hypoxia Suggest a Novel Pathophysiological Event in α‐Synucleinopathies

2020-09-03T00:00

Background

Multiple system atrophy (MSA) and Parkinson's disease (PD) patients develop respiratory and cardiovascular disturbances including obstructive sleep apnea, orthostatic hypotension, and nocturnal stridor. We hypothesized that, associated with these respiratory and cardiovascular disturbances, hypoxic events may occur in MSA and PD brains that may play a role in disease progression. The objective of this study was to evaluate the presence of hypoxia in nonneurological controls and PD and MSA patients.

Methods

Molecular levels of hypoxia markers were measured in postmortem brain tissue from controls and PD and MSA cases.

Results

MSA brain showed signs of chronic hypoxia characterized by the significant accumulation of the hypoxic marker HIF2α as compared to PD patients and controls. We detected no differences between MSA subtypes. Signs of hypoxia were also observed in PD patients with a clinical presentation similar to the MSA cases.

Conclusions

The results obtained from this study suggest a new alternative pathway associated with α‐synucleinopathies that may contribute to the pathogenesis of these disorders. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Clinical Outcomes and Selection Criteria for Prodromal Huntington's Disease Trials

2020-07-20T00:00

Background

Huntington's disease (HD) develops in individuals with extended cytosine‐adenine‐guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability.

Objectives

The present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures.

Methods

Individual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN‐stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts.

Results

Longitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and >0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD.

Conclusions

These analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Diabetes Causes Dysfunctional Dopamine Neurotransmission Favoring Nigrostriatal Degeneration in Mice

2020-07-15T00:00

Background

Numerous studies indicate an association between neurodegenerative and metabolic diseases. Although still a matter of debate, growing evidence from epidemiological and animal studies indicate that preexisting diabetes increases the risk to develop Parkinson's disease. However, the mechanisms of such an association are unknown.

Objectives

We investigated whether diabetes alters striatal dopamine neurotransmission and assessed the vulnerability of nigrostriatal neurons to neurodegeneration.

Methods

We used streptozotocin‐treated and genetically diabetic db/db mice. Expression of oxidative stress and nigrostriatal neuronal markers and levels of dopamine and its metabolites were monitored. Dopamine release and uptake were assessed using fast‐scan cyclic voltammetry. 6‐Hydroxydopamine was unilaterally injected into the striatum using stereotaxic surgery. Motor performance was scored using specific tests.

Results

Diabetes resulted in oxidative stress and decreased levels of dopamine and its metabolites in the striatum. Levels of proteins regulating dopamine release and uptake, including the dopamine transporter, the Girk2 potassium channel, the vesicular monoamine transporter 2, and the presynaptic vesicle protein synaptobrevin‐2, were decreased in diabetic mice. Electrically evoked levels of extracellular dopamine in the striatum were enhanced, and altered dopamine uptake was observed. Striatal microinjections of a subthreshold dose of the neurotoxin 6‐hydroxydopamine in diabetic mice, insufficient to cause motor alterations in nondiabetic animals, resulted in motor impairment, higher loss of striatal dopaminergic axons, and decreased neuronal cell bodies in the substantia nigra.

Conclusions

Our results indicate that diabetes promotes striatal oxidative stress, alters dopamine neurotransmission, and increases vulnerability to neurodegenerative damage leading to motor impairment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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A Gain‐of‐Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype

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Automated Analysis of Diffusion‐Weighted Magnetic Resonance Imaging for the Differential Diagnosis of Multiple System Atrophy from Parkinson's Disease

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A New Approach to the Development of Disease‐Modifying Therapies for PD; Fighting Another Pandemic

Comparison of Patient and Expert Perceptions of the Attainment of Research Milestones in Parkinson's Disease

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Hydrocephalus Complicating Intrathecal Antisense Oligonucleotide Therapy for Huntington's Disease

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

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Four‐Year Follow‐up of [18F]Fluorodeoxyglucose Positron Emission Tomography–Based Parkinson's Disease–Related Pattern Expression in 20 Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression

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Four‐Year Follow‐up of [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography–Based Parkinson's Disease–Related Pattern Expression in 20 Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression

Adenosine A_2A Receptor Occupancy by Long‐Term Istradefylline Administration in Parkinson's Disease