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Acute kidney injury (AKI) is common after pediatric cardiac surgery (CS). Several urine biomarkers have been validated to detect AKI earlier. The objective of this study was to evaluate urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® as predictors for AKI ≥ 1 in pediatric CS after 48 h and AKI ≥ 2 after 12 h. Pediatric patients (age < 18 year; body weight ≥ 2 kg) requiring CS were prospectively included. Urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® were measured during surgery and intensive care unit (ICU) stay and corrected for urine dilution. One hundred and one pediatric patients were included. AKI ≥ 1 within 48 h after ICU admission occurred in 62.4% and AKI ≥ 2 within 12 h in 30.7%. All damage biomarkers predicted AKI ≥ 1 within 48 h after ICU admission, when corrected for urine dilution: CHI3L1 (AUC-ROC: 0.642 (95% CI, 0.535–0.741)), NGAL (0.765 (0.664–0.848)), TIMP-2 (0.778 (0.662–0.868)), IGFBP7 (0.796 (0.682–0.883)), NephroCheck® (0.734 (0.614–0.832)). Similarly, AKI ≥ 2 within 12 h was predicted by all damage biomarkers when corrected for urine dilution: uCHI3L1 (AUC-ROC: 0.686 (95% CI, 0.580–0.780)), NGAL (0.714 (0.609–0.804)), TIMP-2 (0.830 (0.722–0.909)), IGFBP7 (0.834 (0.725–0.912)), NephroCheck® (0.774 (0.658–0.865)). After pediatric cardiac surgery, the damage biomarkers urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® reliably predict AKI after correction for urine dilution. [ABSTRACT FROM AUTHOR]

Background: Development of disease‐modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11C‐UCB‐J, a radioligand for the brain‐wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18F‐fludeoxyglucose (18F‐FDG) PET, but longitudinal 11C‐UCB‐J PET data have not been reported. The aim of this study was to compare the sensitivity of 11C‐UCB‐J PET, 18F‐FDG PET, and volumetric MRI for detection of longitudinal changes in early HD. Methods: Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11C‐UCB‐J PET, 18F‐FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within‐group and between‐group longitudinal clinical and imaging changes were assessed. Results: The HD group showed significant 2‐year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (−4.5% ± 3.8%), putamen (−3.6% ± 3.5%), pallidum (−3.0% ± 2.7%), and frontal cortex (−2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (−2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions. Conclusions: Volumetric MRI may be more sensitive than 11C‐UCB‐J PET and 18F‐FDG PET for detection of 2‐year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

ABSTRACT Parkinson's disease (PD) affects driving ability. We aimed to determine the most critical impairments in specific road skills and in clinical characteristics leading to failure on a road test in PD. In this cross-sectional study, certified driving assessment experts evaluated specific driving skills in 104 active, licensed drivers with PD using a standardized, on-road checklist and issued a global decision of pass/fail. Participants also completed an off-road evaluation assessing demographic features, disease characteristics, motor function, vision, and cognition. The most important driving skills and off-road predictors of the pass/fail outcome were identified using multivariate stepwise regression analyses. Eighty-six (65%) passed and 36 (35%) failed the on-road driving evaluation. Persons who failed performed worse on all on-road items. When adjusted for age and gender, poor performances on lateral positioning at low speed, speed adaptations at high speed, and left turning maneuvers yielded the best model that determined the pass/fail decision (R2 = 0.56). The fail group performed poorer on all motor, visual, and cognitive tests. Measures of visual scanning, motor severity, PD subtype, visual acuity, executive functions, and divided attention were independent predictors of pass/fail decisions in the multivariate model (R2 = 0.60). Our study demonstrated that failure on a road test in PD is determined by impairments in specific driving skills and associated with deficits in motor, visual, executive, and visuospatial functions. These findings point to specific driving and off-road impairments that can be targeted in multimodal rehabilitation programs for drivers with PD. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT Background We previously developed a short clinical battery, consisting of contrast sensitivity, Clinical Dementia Rating, the Unified Parkinson's Disease Rating Scale-motor section ( UPDRS III), and disease duration, which correctly classified 90% of drivers with Parkinson's Disease ( PD). The aim of this study was to validate that screening battery in a different sample of PD drivers. Methods Sixty drivers with PD were enrolled to validate our original screening battery to predict driving fitness decisions (pass-fail) by a state agency where drivers underwent detailed visual, cognitive, and on-road testing. Results Twenty-four participants (40%) failed the driving evaluation. The screening battery correctly classified 46 (77%) participants (sensitivity and negative predictive value = 96%; specificity and positive predictive value = 64%). Adding other clinical predictors (e.g., age of onset, Hoehn-Yahr stage instead of UPDRS III) failed to improve the specificity of the model when the sensitivity was kept constant at 96%. However, a driving simulator evaluation improved the specificity of the model to 94%. Conclusions The original clinical battery proved to be a valid screening tool that accurately identifies fit drivers with PD and select those who need more detailed testing at specialized centers. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Orthostatic tremor is a rare and debilitating movement disorder. Its first-line treatment is pharmacological. For pharmaco-refractory patients, surgical treatment options such as deep brain stimulation (DBS) and spinal cord stimulation (SCS) have been investigated recently.Objectives: We conducted a systematic review of all published outcome and safety data on DBS and SCS for orthostatic tremor patients.Methods: We searched Pubmed and Embase for studies describing orthostatic tremor patients treated with DBS or SCS. We collected all available outcome and safety data and our primary endpoint was the change in unsupported stance duration 1 year postoperatively (±6 months).Results: We included 15 studies, reporting on 32 orthostatic tremor patients who underwent DBS, 4 patients SCS and 2 both. The ventral intermediate nucleus and the zona incerta were targeted in 25/34 and 9/34 DBS cases, respectively. The median stance time at 1 year follow-up was 240 s compared to 30 s pre-operatively (p < 0.001). Stimulation-induced side effects occurred in the majority of patients, but were often transient. Bilateral stimulation appeared more effective than unilateral and stimulation settings were comparable to thalamic DBS for essential tremor. There were insufficient data available to draw meaningful conclusions on the long-term effects of DBS. Due to insufficient data, no conclusions could be drawn on the effects of SCS on orthostatic tremor.Conclusion: DBS may be effective to increase stance time in orthostatic tremor patients in the first year, but further research is necessary to evaluate the long-term effects and the role of spinal cord stimulation. [ABSTRACT FROM AUTHOR]

SUMMARY Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by abnormal movement, cognitive decline, and psychiatric disturbance. HD is caused by a trinucleotide repeat expansion in the HTT gene and a corresponding neurotoxic polyglutamine expansion in the huntingtin protein. There is currently no therapy to modify the progressive course of the disease, and symptomatic treatment options are limited. In this review we describe a diverse set of emerging experimental therapeutic strategies for HD: deep brain stimulation; delivery of neurotrophic factors; cell transplantation; HTT gene silencing using RNA interference or antisense oligonucleotides; and delivery of intrabodies. The common feature of these experimental therapies is that they all require a neurosurgical intervention, either for implantation of an electrode or for brain delivery of molecules, viruses or cells that do not cross the blood-brain barrier upon oral or intravenous administration. We summarize available data on the rationale, safety, efficacy, and intrinsic limitations of each of these approaches, focusing mainly on studies in HD patients and genetic animal models of HD. Although each of these strategies holds significant promise, their efficacy remains to be proven in HD patients. [ABSTRACT FROM AUTHOR]

Measurement of striatal volume using magnetic resonance imaging (MRI) provides a marker of striatal degeneration in Huntington disease (HD). Recent evidence suggests that diffusion-weighted MRI (DWI) may also detect striatal damage in HD. Here, we compared the sensitivities of volumetric MRI and DWI at distinguishing 10 patients with early symptomatic HD from 12 agematched controls. Additionally, we assessed longitudinal changes in striatal volume and diffusivity in 8 of the HD patients over a 2-year period. At baseline, HD patients had significantly smaller volumes and significantly higher trace of the diffusion coefficient (Trace(D)) values of putamen and caudate than controls, but the volume differences were relatively larger than the Trace(D) differences. Putaminal and caudate volumes were outside the normal range in 9 of 10 HD patients, whereas Trace(D) values of putamen and caudate were abnormal in 8 and 6 of 10 HD subjects, respectively. During 2-year follow-up, there was significant volume loss of HD putamen (mean change: –8.0 %) and caudate (mean change: –12.7 %). By contrast, longitudinal Trace(D) changes of putamen (mean change: 4.0 %) and caudate (mean change: 3.8 %) did not reach statistical significance. Thus, volumetric MRI seems more sensitive to striatal degeneration in early symptomatic HD than DWI. [ABSTRACT FROM AUTHOR]

The article discusses the court case "European Parliament v. Commission." Details about the case, which was held in the European Court of Justice and explores the European policy on chemical substances, are provided. The use of the comitology procedure in the European Union (EU) is explained and its role in the case is also explored.

The article discusses a court case about the use and transposition of the European Commission (EC) Birds and Habitats Directives by Ireland. Details about the Birds and Habitats Directives and the history of infringement cases handled by the European Court of Justice (ECJ) are provided. The ECJ concluded that Ireland has neglected to sufficiently prevent the deterioration of birds and habitats.

The transmembrane protein stargazin enhances levels of functional AMPA receptors at the neuronal plasma membrane and at synapses. To clarify the mechanism for this effect, we studied trafficking of the AMPA receptor subunit glutamate receptor 1 (GluR1) in transfected COS7 cells. GluR1 expressed poorly on the surface of these cells and was primarily retained in the endoplasmic reticulum (ER). Stargazin expression strongly increased the surface fraction of GluR1. This effect was not reduced by a dominant-negative dynamin mutant, suggesting that stargazin does not inhibit AMPA receptor endocytosis. Interestingly, upregulation of ER chaperones as part of the unfolded protein response (UPR) both mimicked and occluded the effect of stargazin, suggesting a role for stargazin in ER processing of AMPA receptors. Consistent with this idea, we detected UPR induction in cerebellar granule cells lacking stargazin. Finally, residual AMPA receptor currents in stargazin-deficient neurons were suppressed by inhibition of the UPR. These findings uncover a role for stargazin in AMPA receptor trafficking through the early compartments of the biosynthetic pathway. Furthermore, they provide evidence for modulation of AMPA receptor trafficking by the UPR. [ABSTRACT FROM AUTHOR]

AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors mediate fast excitatory synaptic transmission in brain and underlie aspects of synaptic plasticity. Numerous AMPA receptor-binding proteins have been implicated in AMPA receptor trafficking and anchoring. However, the relative contributions of these proteins to the composition of native AMPA receptor complexes in brain remain uncertain. Here, we use blue native gel electrophoresis to analyze the composition of native AMPA receptor complexes in cerebellar extracts. We identify two receptor populations: a functional form that contains the transmembrane AMPA receptor- regulatory protein stargazin and an apo-form that lacks stargazin. Limited proteolysis confirms assembly of stargazin with a large proportion of native AMPA receptors. In contrast, other AMPA receptor-interacting proteins, such as synapse-associated protein 97, glutamate receptor-interacting protein 1, protein kinase Ca binding protein, N-ethylmaleimide-sensitive fusion protein, AP2, and protein 4.1N, do not show significant association with AMPA receptor complexes on native gels. These data identify stargazin as an auxiliary subunit for a neurotransmitter-gated ion channel. [ABSTRACT FROM AUTHOR]

Glutamate receptors are the primary mediators of excitatory synaptic transmission in the mammalian central nervous system. Activity-dependent changes in the number of postsynaptic glutamate receptors underlie aspects of synaptic plasticity and provide a mechanism for information storage in the brain. Recent work shows that receptor exit from the endoplasmic reticulum represents a critical regulatory step in glutamate receptor trafficking to the neuronal cell surface. [Copyright &y& Elsevier]

Abstract Activation of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been linked to potent effects on survival and dendritic outgrowth of spinal motoneurons. Ca2+ permeability of AMPA receptors is controlled by the GluR2 subunit. Whole-cell electrophysiological studies have suggested that GluR2-containing and GluR2-lacking AMPA receptors may coexist in individual motoneurons. However, there has not been a direct demonstration of heterogeneity in AMPA receptor subunit composition in single motoneurons, nor of distinct subcellular distributions of GluR2-containing and GluR2-lacking receptors. In the present study, we have used confocal microscopy, immunocytochemistry and Ca2+ imaging to characterize the subcellular localization of AMPA receptors in cultured rat spinal motoneurons. Immunoreactivity for GluR2 and GluR4 was concentrated in clusters, the vast majority of which were found in dendrites at synapses. Double-labelling for GluR2 and GluR4 revealed variability in relative expression of GluR2 and GluR4 between clusters within individual motoneurons; most AMPA receptor clusters were immunoreactive for both GluR2 and GluR4, but a significant minority of clusters were immunoreactive for GluR2 only or for GluR4 only. The majority of GluR2-immunonegative AMPA receptor clusters was present in dendrites, but the relative proportion of GluR2-immunonegative and GluR2-immunopositive clusters was similar in dendrites and soma. Imaging of [Ca2+]i rises triggered by AMPA receptor activation confirmed Ca2+ influx in motoneuron dendrites. These findings strongly support a model in which GluR2-containing and GluR2-lacking AMPA receptors coexist in motoneurons, clustered at synapses, and mixed in a relative proportion that varies considerably between cell membrane microdomains. [ABSTRACT FROM AUTHOR]

Background: Imaging tools that allow quantification of Parkinson's disease (PD) progression could facilitate the development of disease-modifying therapies. Cross-sectional studies have shown presynaptic terminal damage in PD patients, but longitudinal data are limited.Objectives: The aim of this study was to longitudinally assess loss of presynaptic terminals in general and dopaminergic presynaptic terminals in particular as measures of disease progression in early PD.Methods: A total of 27 patients with early PD and 18 age- and sex-matched healthy controls underwent positron emission tomography (PET) with 11 C-UCB-J, a ligand for the brain-wide presynaptic terminal marker SV2A, and with 18 F-FE-PE2I, a highly selective dopamine transporter ligand, in combination with a comprehensive motor and non-motor clinical assessment at baseline (BL) and after 26.5 ± 2.1 months (Y2). SUVR-1 images were calculated and volumes of interest were delineated based on individual 3D T1 magnetic resonance imaging (MRI).Results: PD patients showed significant 2-year worsening of Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) (off medication) scores, but not of non-motor scores. Motor and non-motor scores in controls did not change significantly over 2 years. 18 F-FE-PE2I binding in caudate and putamen showed significant 2-year decline in the PD group and remained unchanged in controls. Longitudinal decline of striatal 18 F-FE-PE2I binding in PD did not correlate with longitudinal changes in MDS-UPDRS-III scores. 11 C-UCB-J PET did not show any region with significant 2-year change in PD or controls.Conclusions: 18 F-FE-PE2I PET showed robust 2-year decline in early PD, but 11 C-UCB-J PET did not. Longitudinal changes in 18 F-FE-PE2I binding did not correlate with clinical motor progression. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

This article discusses a case of chorea with slow saccades caused by a mutation in the NKX2-1 gene. Chorea is characterized by involuntary movements, and slow saccades refer to slow eye movements. The patient in this case study experienced chorea and slow saccades, along with other symptoms such as delayed motor and speech milestones, mild asthma, and mildly elevated thyroid stimulating hormone levels. The article highlights that slow saccades are not typically associated with NKX2-1-related disorder, but this case suggests that it should be considered as a possible cause. [Extracted from the article]

Neuroimaging is increasingly being included in clinical trials of Huntington’s disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD. [ABSTRACT FROM AUTHOR]

Background: Preserved cycling capabilities in patients with Parkinson's disease, especially in those with freezing of gait are still poorly understood. Previous research with invasive local field potential recordings in the subthalamic nucleus has shown that cycling causes a stronger suppression of β oscillations compared to walking, which facilitates motor continuation. Methods: We recorded local field potentials from 12 patients with Parkinson's disease (six without freezing of gait, six with freezing of gait) who were bilaterally implanted with deep brain stimulation electrodes in the subthalamic nucleus. We investigated β (13–30 Hz) and high γ (60–100 Hz) power during both active and passive cycling with different cadences and compared patients with and without freezing of gait. The passive cycling experiment, where a motor provided a fixed cadence, allowed us to study the effect of isolated sensory inputs without physical exercise. Results: We found similarly strong suppression of pathological β activity for both active and passive cycling. In contrast, there was stronger high γ band activity for active cycling. Notably, the effects of active and passive cycling were all independent of cadence. Finally, β suppression was stronger for patients with freezing of gait, especially during passive cycling. Conclusions: Our results provide evidence for a link between proprioceptive input during cycling and β suppression. These findings support the role of continuous external sensory input and proprioceptive feedback during rhythmic passive cycling movements and suggest that systematic passive mobilization might hold therapeutic potential. © 2023 International Parkinson and Movement Disorder Society. Cycling's impact on Parkinson's disease, particularly freezing of gait, is poorly understood. Invasive subthalamic recordings from 12 deep brain stimulation patients show equivalent β suppression during active and passive cycling, independent of cadence, with a stronger effect in freezing of gait patients. Proprioceptive input during cycling links to β suppression. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease 2019 (COVID-19) leads to thoracic complications requiring surgery. This is challenging, particularly in patients supported with venovenous extracorporeal membrane oxygenation (VV-ECMO) due to the need for continuous therapeutic anticoagulation. We aim to share our experience regarding the safety and perioperative management of video-assisted thoracic surgery for this specific population. Methods: Retrospective, single-center study between November 2020 and January 2022 at the ICU department of a 1.061-bed tertiary care and VV-ECMO referral center during the COVID-19 pandemic. Results: 48 COVID-19 patients were supported with VV-ECMO. A total of 14 video-assisted thoracic surgery (VATS) procedures were performed in seven patients. Indications were mostly hemothorax (85.7%). In eight procedures heparin was stopped at least 1 h before incision. A total of 10 circuit changes due to clot formation or oxygen transfer failure were required in six patients (85.7%). One circuit replacement seemed related to the preceding VATS procedure, although polytransfusion might be a contributing factor. None of the mechanical complications was fatal. Four VATS-patients (57.1%) died, of which two (50%) immediately perioperatively due to uncontrollable bleeding. All three survivors were treated with additional transarterial embolization. Conclusion: (1) Thoracic complications in COVID-19 patients on VV-ECMO are common. (2) Indication for VATS is mostly hemothorax (3) Perioperative mortality is high, mostly due to uncontrollable bleeding. (4) Preoperative withdrawal of anticoagulation is not directly related to a higher rate of ECMO circuit-related complications, but a prolonged duration of VV-ECMO support and polytransfusion might be. (5) Additional transarterial embolization to control postoperative bleeding may further improve outcomes. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether mild motor signs (MMS) in old age correlate with synaptic density in the brain. Background: Normal aging is associated with a decline in movement quality and quantity, commonly termed "mild parkinsonian signs" or more recently MMS. Whether MMS stem from global brain aging or pathology within motor circuits remains unresolved. The synaptic vesicle glycoprotein 2A positron emission tomography (PET) ligand 11C‐UCB‐J allows the investigation of brain‐motor associations at the synaptic level in vivo. Method: Fifty‐eight healthy older adults (≥50 years) were included from two monocentric control cohorts. Brain magnetic resonance imaging and 11C‐UCB‐J PET data were available in 54 participants. 11C‐UCB‐J PET binding was quantified by standardized uptake value ratio (SUVR) values in grey matter (GM) volumes of interest (VOIs): caudate, putamen, globus pallidus, substantia nigra, thalamus, cerebellum, and the frontal, parietal, temporal, and occipital cortex. Multiple linear regression analyses were performed with Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) part III score measuring MMS as the dependent variable and mean SUVR values in each VOI as the independent variable with age, Fazekas score (white matter lesion [WML] load), VOI and cohort as covariates. Results: Participants (68 ± 7.5 years; 52% female) had an average MDS‐UPDRS part III score of 3.3 ± 2.8. The MDS‐UPDRS part III score was inversely associated with synaptic density, independently of WML load or GM volume, in the caudate, substantia nigra, thalamus, cerebellum, and parietal, occipital, temporal cortex. Cohen's f2 showed moderate effect sizes for subcortical (range, 0.30–0.35), cortical (0.28–0.35) and cerebellar VOIs (0.31). Conclusion: MMS in healthy aging are associated with lower synaptic density throughout the brain. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Amyotrophic Lateral Sclerosis" by L. P. Rowland and N. A. Shneider in the May 31, 2001 issue.

Parkinson's disease, one of the most common neurodegenerative diseases, may not only affect the motor system, but also the physiology of the gastrointestinal tract. Delayed gastric emptying, impaired motility and altered intestinal bacteria are well-established consequences of the disease, which can have a pronounced effect on the absorption of orally administered drugs. In contrast, no studies have been performed into the composition of intestinal fluids. It is not unlikely that Parkinson's disease also affects the composition of intestinal fluids, a critical factor in the in vitro and in silico simulation of drug dissolution, solubilization and absorption. In the current study, duodenal fluids were aspirated from Parkinson's disease (PD) patients and age-matched healthy controls (healthy controls, HC) consecutively in fasted and fed conditions. The fluids were then characterized for pH, buffer capacity, osmolality, total protein, phospholipids, bile salts, cholesterol and lipids. In a fasted state, the intestinal fluid composition was highly similar in PD patients and healthy controls. In general, the same was true for fed-state fluids, apart from a slightly slower and less pronounced initial change in factors directly affected by the meal (i.e., buffer capacity, osmolality, total protein and lipids) in PD patients. The absence of a fast initial increase for these factors immediately after meal intake, as was observed in healthy controls, might result from slower gastric emptying in PD patients. Irrespective of the prandial state, a higher relative amount of secondary bile salts was observed in PD patients, potentially indicating altered intestinal bacterial metabolism. Overall, the data from this study indicate that only minor disease-specific adjustments in small intestinal fluid composition should be considered when simulating intestinal drug absorption in PD patients. [ABSTRACT FROM AUTHOR]

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. Methods: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. Results: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. Conclusion: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. Trial registration : EudraCT number 2020-002129-27. Clinicaltrials.gov NCT05224115 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson's disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson's disease, are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and iPSC-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization, but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and iPSC-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity with optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Our earlier work showed that automaticity and retention of writing skills improved with intensive writing training in Parkinson's disease (PD). However, whether this training changed the resting-state networks in the brain and how these changes underlie retention of motor learning is currently unknown. Objective: To examine changes in resting-state functional connectivity (rs-FC) and their relation to behavioral changes immediately after writing training and at 6 week follow-up. Methods: Twenty-five PD patients underwent resting-state fMRI (ON medication) before and after 6 weeks writing training. Motor learning was evaluated with a dual task paradigm pre- and post-training and at follow-up. Next, pre-post within-network changes in rs-FC were identified by an independent component analysis. Significant clusters were used as seeds in ROI-to-ROI analyses and rs-FC changes were correlated with changes in behavioral performance over time. Results: Similar to our larger cohort findings, writing accuracy in single and dual task conditions improved post-training and this was maintained at follow-up. Connectivity within the dorsal attentional network (DAN) increased pre-post training, particularly with the right superior and middle temporal gyrus (rS/MTG). This cluster also proved more strongly connected to parietal and frontal areas and to cerebellar regions. Behavioral improvements from pre- to post-training and follow-up correlated with increased rs-FC between rS/MTG and the cerebellum. Conclusions: Training-driven improvements in dual task writing led to functional reorganization within the DAN and increased connectivity with cerebellar areas. These changes were associated with the retention of writing gains and could signify task-specific neural changes or an inability to segregate neural networks. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. Objectives: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. Methods: We transiently expressed wild‐type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK‐293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. Results: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. Conclusions: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off‐label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty‐two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease‐modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Discusses the judgments of the European Court of Justice in Commission v. Germany and Radlberger GmbH & Co., S. Spitz KG v. Land Baden-Württemberg, concerning the German preference for reusable beverage packaging and the way in which Germany givest it preferential treatment. Relevant provisions of the Packaging and Waste Packaging Directive; Opinion of the Advocate-General in the Danish bottles case; Criticism of Europe on Germany's quota system.

Keywords: PARK7, DJ-1, Parkinson's disease, juvenile, hyposmia EN PARK7, DJ-1, Parkinson's disease, juvenile, hyposmia 149 152 4 01/06/21 20210101 NES 210101 Mutations in the I PARK7 i gene, which encodes DJ-1, are a rare cause of autosomal recessive Parkinson's disease (PD).1 Only approximately 30 I PARK7 i -linked PD cases have been reported.2 I PARK7 i mutations typically cause levodopa-responsive parkinsonism with early or even juvenile age at onset (AAO) (median AAO, 27 years) and slow progression.2 However, detailed phenotype descriptions are scarce. The majority (83%) of I PARK7 i -linked PD cases have an AAO between 20 and 40 years, whereas only 13% have an AAO below 20.2 The youngest AAO reported in a patient with I PARK7 i mutations was 16 years.6 Intuitively, one would expect a neurodegenerative process that already manifests itself at such a young age to be more aggressive and more rapidly progressive. This is true for Huntington's disease, where long CAG repeat lengths cause both younger AAO and more rapid progression.7 Similarly, PD attributed to I SNCA i triplications has both a younger AAO and more aggressive course than PD with I SNCA i duplications.8 In contrast, autosomal recessive PD caused by I PRKN, PINK1 i , and I PARK7 i mutations typically combines young AAO with very slow progression, as illustrated to an extreme degree by our current case. [Extracted from the article]

Background: It has been hypothesized that the pathology of Parkinson's disease (PD) primarily affects presynaptic terminals and spreads trans‐synaptically. Objectives: The main objective of this study was to assess the magnitude and anatomical extent of presynaptic terminal loss across the brain in early PD. A second objective was to compare loss of presynaptic terminals and cell bodies within the nigrostriatal tract. Methods: A total of 30 patients with early PD and 20 age‐ and gender‐matched healthy controls underwent positron emission tomography with 11C‐UCB‐J, a ligand for the universal presynaptic terminal marker synaptic vesicle protein 2A (SV2A), and with the dopamine transporter ligand 18F‐FE‐PE2I, as well as a detailed clinical assessment. Volumes of interest were delineated based on individual 3‐dimensional T1 magnetic resonance imaging. BPND images were calculated. Results: Patients with PD showed significant loss of SV2A binding in the substantia nigra only. Loss of dopamine transporter binding in the PD group was much greater in the putamen than in the substantia nigra. We found no correlations between SV2A or dopamine transporter binding and any of the clinical motor or nonmotor scores. Homologous voxel‐based analysis in the PD group showed significant correlations between SV2A and dopamine transporter binding in the caudate and substantia nigra. Conclusions: Presynaptic terminals appear to be the most heavily affected subcellular compartment of nigrostriatal neurons in early PD. Moreover, early PD causes loss of presynaptic terminals that innervate the nigrostriatal neurons. This loss of presynaptic boutons in the substantia nigra may reflect an axonal response to target deprivation or could possibly point to a trans‐synaptic mode of propagation of the disease process. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Rationale: Dopamine transporter (DAT) imaging is an important adjunct in the diagnostic workup of patients with Parkinsonism. 18F-FE-PE2I is a suitable PET radioligand for DAT quantification and imaging with good pharmacokinetics. The aim of this study was to determine a clinical optimal simplified reference tissue-based image acquisition protocol and to compare the discriminatory value and effect size for 18F-FE-PE2I to that for 123I-FP-CIT scan currently used in clinical practice. Methods: Nine patients with early Parkinson's disease (PD, 64.3 ± 6.8 years, 3M), who had previously undergone a 123I-FP-CIT scan as part of their diagnostic workup, and 34 healthy volunteers (HV, 47.7 ± 16.8 years, 13M) underwent a 60-min dynamic 18F-FE-PE2I PET-MR scan on a GE Signa 3T PET-MR. Based on dynamic data and MR-based VOI delineation, BPND, semi-quantitative uptake ratio and SUVR[t1–t2] images were calculated using either occipital cortex or cerebellum as reference region. For start-and-end time of the SUVR interval, three time frames [t1–t2] were investigated: [15–40] min, [40–60] min, and [50–60] min postinjection. Data for putamen (PUT) and caudate nucleus-putamen ratio (CPR) were compared in terms of quantification bias versus BPND and discriminative power. Results: Using occipital cortex as reference region resulted in smaller bias of SUVR with respect to BPND + 1 and higher correlation between SUVR and BPND + 1 compared with using cerebellum, irrespective of SUVR [t1–t2] interval. Smallest bias was observed with the [15–40]-min time window, in accordance with previous literature. The correlation between BPND + 1 and SUVR was slightly better for the late time windows. Discriminant analysis between PD and HV using both PUT and CPR SUVRs showed an accuracy of ≥ 90%, for both reference regions and all studied time windows. Semi-quantitative 123I-FP-CIT and 18F-FE-PE2I values and relative decrease in the striatum for patients were highly correlated, with a higher effect size for 18F-FE-PE2I for PUT and CPR SUVR. Conclusion: 18F-FE-PE2I is a suitable radioligand for in vivo DAT imaging with high discriminative power between early PD and healthy controls. Whereas a [15–40]-min window has lowest bias with respect to BPND, a [50–60]-min time window at pseudoequilibrium can be advocated in terms of clinical feasibility with optimal discriminative power. The occipital cortex may be slightly preferable as reference region because of the higher time stability, stronger correlation of SUVR with BPND + 1, and lower bias. Moreover, the data suggest that the diagnostic accuracy of a 10-min static 18F-FE-PE2I scan is non-inferior compared with 123I-FP-CIT scan used in standard clinical practice. [ABSTRACT FROM AUTHOR]

Background: The onset of freezing of gait (FOG) represents a turning point in the lives of patients with Parkinson's disease (PD). FOG increases fall risk and is associated with worse physical and mental health related quality of life, thus increasing disease burden. Moreover, therapeutic studies aiming to ameliorate freezing have had limited success. In a step towards pre-emptive therapy to delay or prevent the onset of FOG, this prospective cohort study set out to uncover clinical markers of conversion to FOG. Objective: Investigate clinical markers of conversion to FOG. Methods: Sixty PD patients without FOG were followed up for two years and underwent extensive clinical testing each year. FOG classification was made with the New Freezing of Gait Questionnaire. Clinical predictors of conversion to FOG were investigated using univariate analysis and through building a multivariable model using all measured components. Results: Twelve patients developed FOG during the study (Incidence: 11.5% per year). Due to the large number of predictors, univariate analyses did not survive multiple comparison correction, precluding strong inference on any one predictor. Overall, the effect sizes suggested that motor deficits including difficulties with repetitive movement scaling (AUC: 0.71), coordination (AUC: 0.73) and consistency (AUC: 0.76) as well as gait asymmetry (AUC: 0.79) and variability (AUC: 0.71) were most predictive of conversion. Further, converters reported more subjective cognitive difficulty (AUC: 0.74), although their measured performance was similar to non-converters. Multivariable analyses further showed that the two components most consistently selected in the predictive model were: 1) an MDS-UPDRS component with worse axial motor, hand use and non-motor symptoms; and 2) finger tapping abnormalities. Conclusion: Conversion to FOG was predicted mainly by objective and clinical measures of motor dyscontrol, as non-motor disturbances were surfacing. Although based on a small cohort with limited converters, this novel finding informs future studies aimed at FOG prevention. [ABSTRACT FROM AUTHOR]

Purpose: The endocannabinoid system plays a regulatory role in a number of physiological functions, including motor control but also mood, emotion, and cognition. A number of preclinical studies in Parkinson's disease (PD) models demonstrated that modulating the type 1 cannabinoid receptor (CB1R) may improve motor symptoms and components of cognitive processing. However, the relation between CB1R, cognitive decline and behavioral symptoms has not been investigated in PD patients so far. The aim of this study was to examine whether CB1R availability is associated with measures of cognitive and behavioral function in PD patients. Methods: Thirty-eight PD patients and ten age- and gender-matched controls underwent a [18F]MK-9470 PET scan to assess CB1R availability, as well as volumetric MR imaging. Neuropsychological symptoms were evaluated using an extensive cognitive and behavioral battery covering the five cognitive domains, depression, anxiety, apathy, and psychiatric complications, and were correlated to CB1R availability using vowel-wise regression analysis (P < 0.05, corrected for familywise error). Results: PD patients with poorer performance in episodic memory, executive functioning, speed and mental flexibility (range P 0.003–0.03) showed lower CB1R availability in predominantly the midcingulate cortex and middle to superior frontal gyrus (Tpeak-level > 4.0). Also, PD patients with more severe visuospatial dysfunction showed decreased CB1R availability in the precuneus, midcingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (Tpeak-level = 5.5). These correlations were not related to cortical gray matter atrophy. No relationship was found between CB1R availability and mood or behavioral symptom scores. Conclusions: Decreased CB1R availability in the prefrontal and midcingulate cortex in PD patients is strongly correlated with disturbances in executive functioning, episodic memory, and visuospatial functioning. Further investigation of regional CB1R expression in groups of PD patients with mild cognitive impairment or dementia is warranted in order to further investigate the role of CB1R expression in different levels of cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

Purpose: The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [11C]JNJ54173717 ([11C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test–retest variation (TRV), as well as possible genotype effects, were investigated. Methods: Biodistribution and radiation dosimetry studies were performed in three HV (mean age 30 ± 2 years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11 HV (mean age 62 ± 10 years, six women) and 10 PD patients (mean age 64 ± 8 years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (VT) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13 years, four HV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study. Results: The mean effective dose was 4.47 ± 0.32 μSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous VT values in the grey and white matter. Average VT values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect VT. Average TRV was 10–15%. The stability of VT over time allowed a reduction in scan time to 70 min. Conclusion: [11C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses. [ABSTRACT FROM AUTHOR]

Exaggerated activity in the beta band (13–35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment. [ABSTRACT FROM AUTHOR]

Keywords: Parkinson's disease; Dopa-responsive dystonia; GTP cyclohydrolase 1; Tetrahydrobiopterin; Nitric oxide synthase EN Parkinson's disease Dopa-responsive dystonia GTP cyclohydrolase 1 Tetrahydrobiopterin Nitric oxide synthase 10 12 3 01/09/21 20210101 NES 210101 GCH1 encodes GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis [[1]]. The higher O SB 2 sb SP - sp levels in IFN- -treated GCH1 mutant fibroblasts compared with IFN- -treated control cells could result from loss of the direct O SB 2 sb SP - sp scavenging effect of BH4 [[4]]. In conclusion, IFN- -treated fibroblasts from 4 GCH1 mutation carriers all displayed increased O SB 2 sb SP - sp , and fibroblasts from 3 of the 4 carriers showed increased staurosporine-induced apoptosis. [Extracted from the article]

Symmetric biphasic pulses have been shown to acutely increase the therapeutic window of ventralis intermedius deep brain stimulation (Vim-DBS) for essential tremor (ET) compared to cathodic pulses. Acute supratherapeutic stimulation can induce ataxic side effects in Vim-DBS. To investigate the effect on tremor, ataxia and dysarthria of 3 h of biphasic stimulation in patients with DBS for ET. A randomized, doubled-blind, cross-over design was used to compare standard cathodic pulses with symmetric biphasic pulses (anode-first) during a 3-h period per pulse shape. During each 3-h period, all stimulation parameters were identical, except for the pulse shape. Tremor (Fahn-Tolosa-Marin Tremor Rating Scale), ataxia (International Cooperative Ataxia Rating Scale) and speech (acoustic and perceptual measures) were assessed hourly during the 3-h periods. Twelve ET patients were included. During the 3-h stimulation period, tremor control was equivalent between the two pulse shapes. Biphasic pulses elicited significantly less ataxia than cathodic pulses (p = 0.006). Diadochokinesis rate of speech was better for the biphasic pulse (p = 0.048), but other measures for dysarthria were not significantly different between the pulses. Symmetric biphasic pulses induce less ataxia than conventional pulses after 3 h of stimulation DBS in ET patients. • When compared for 3 h, at supratherapeutic thresholds: • Biphasic pulses induce less stimulation-induced ataxia compared to cathodic pulses. • Biphasic pulses induce equivalent tremor control compared to cathodic pulses. • Diadochokinesis rate of speech was better for biphasic than cathodic pulses. [ABSTRACT FROM AUTHOR]

A common motor symptom of Parkinson’s disease (PD) is micrographia, characterized by a decrease in writing amplitude. Despite the relevance of this impairment for activities of daily living, the underlying neural network abnormalities and the impact of cueing strategies on brain connectivity are unknown. Therefore, we investigated the effects of visual cues on visuomotor network interactions during handwriting in PD and healthy controls (HCs). Twenty-eight patients with early disease, ON dopaminergic medication, and 14 age-matched controls performed a pre-writing task with and without visual cues in the scanner. Patients displayed weaker right visuo-parietal coupling than controls, suggesting impaired visuomotor integration during writing. Surprisingly, cueing did not have the expected positive effects on writing performance. Patients and controls, however, did activate similar networks during cued and uncued writing. During cued writing, the stronger influence of both visual and motor areas on the left superior parietal lobe suggested that visual cueing induced greater visual steering. In the absence of cues, there was enhanced coupling between parietal and supplementary motor areas (SMA) in line with previous findings in HCs during uncued motor tasks. In conclusion, the present study showed that patients with PD, despite their compromised brain function, were able to shift neural networks similar to controls. However, it seemed that visual cues provided a greater accuracy constraint on handwriting rather than offering unequivocal beneficial effects. Altogether, the results suggest that the effectiveness of using compensatory neural networks through applying external stimuli is task dependent and may compromise motor control during writing. [ABSTRACT FROM AUTHOR]

Recently, it was shown that patients with Parkinson’s disease (PD) and freezing of gait (FOG) can also experience freezing episodes during handwriting and present writing problems outside these episodes. So far, the neural networks underlying increased handwriting problems in subjects with FOG are unclear. This study used dynamic causal modeling of fMRI data to investigate neural network dynamics underlying freezing-related handwriting problems and how these networks changed in response to visual cues. Twenty-seven non-freezers and ten freezers performed a pre-writing task with and without visual cues in the scanner with their right hand. The results showed that freezers and non-freezers were able to recruit networks involved in cued and uncued writing in a similar fashion. Whole group analysis also revealed a trend towards altered visuomotor integration in patients with FOG. Next, we controlled for differences in disease severity between both patient groups using a sensitivity analysis. For this, a subgroup of ten non-freezers matched for disease severity was selected by an independent researcher. This analysis further exposed significantly weaker coupling in mostly left hemispheric visuo-parietal, parietal – supplementary motor area, parietal – premotor, and premotor–M1 pathways in freezers compared to non-freezers, irrespective of cues. Correlation analyses revealed that these impairments in connectivity were related to writing amplitude and quality. Taken together, these findings show that freezers have reduced involvement of the supplementary motor area in the motor network, which explains the impaired writing amplitude regulation in this group. In addition, weaker supportive premotor connectivity may have contributed to micrographia in freezers, a pattern that was independent of cueing. [ABSTRACT FROM AUTHOR]

Background: In previous work, we found that intensive amplitude training successfully improved micrographia in Parkinson’s disease (PD). Handwriting abnormalities in PD also express themselves in stroke duration and writing fluency. It is currently unknown whether training changes these dysgraphic features. Objective: To determine the differential effects of amplitude training on various hallmarks of handwriting abnormalities in PD. Methods: We randomized 38 right-handed subjects in early to mid-stage of PD into an experimental group (n = 18), receiving training focused at improving writing size during 30 minutes/day, five days/week for six weeks, and a placebo group (n = 20), receiving stretch and relaxation exercises at equal intensity. Writing skills were assessed using a touch-sensitive tablet pre- and post-training, and after a six-week retention period. Tests encompassed a transfer task, evaluating trained and untrained sequences, and an automatization task, comparing single- and dual-task handwriting. Outcome parameters were stroke duration (s), writing velocity (cm/s) and normalized jerk (i.e. fluency). Results: In contrast to the reported positive effects of training on writing size, the current results showed increases in stroke duration and normalized jerk after amplitude training, which were absent in the placebo group. These increases remained after the six-week retention period. In contrast, velocity remained unchanged throughout the study. Conclusion: While intensive amplitude training is beneficial to improve writing size in PD, it comes at a cost as fluency and stroke duration deteriorated after training. The findings imply that PD patients can redistribute movement priorities after training within a compromised motor system. [ABSTRACT FROM AUTHOR]

Background and Objectives: Many controversies surround the usefulness of dual-task training in Parkinson's disease (PD). This study (1) compared the efficacy of two different dual-task training programs for improving dual-task gait and (2) assessed the possible fall risk of such training.Methods: Patients (N = 121) with a diagnosis of PD (aged 65.93 [±9.22] years, Hoehn and Yahr stage II-III on-medication) were randomized to (1) a consecutive group in which gait and cognitive tasks were trained separately or (2) an integrated group in which gait and cognitive tasks were trained simultaneously. Both interventions involved 6 weeks of at-home physiotherapist-led training. Two baseline tests were performed as a 6-week control period before training. Posttests were performed immediately after training and at 12-week follow-up. Dual-task gait was assessed during trained and untrained secondary tasks to assess consolidation of learning. Fall risk was determined by a weekly telephone call for 24 weeks.Results: No significant time by group interactions were found, suggesting that both training modes had a similar effect on dual-task gait. Immediately after training, and not after the control period, significant improvements (P < .001) in dual-task gait velocity were found in all trained and untrained dual tasks. Improvements ranged between 7.75% and 13.44% when compared with baseline values and were retained at 12-week follow-up. No significant change in fall risk occurred in both study arms (P = .84).Conclusions: Consecutive and integrated dual-task training led to similar and sustained improvements in dual-task gait velocity without increasing fall risk. These novel findings support adoption of dual-task training in clinical practice. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease with motor and non-motor symptoms, including constipation. Therefore, several studies have investigated the gastrointestinal tract, and more specifically the enteric nervous system (ENS), in search of an early biomarker of PD. Besides a-synuclein aggregation, mitochondrial dysfunction and dysregulation of intracellular Ca2+ concentration probably contribute to the pathogenesis of PD. Here we assessed neuronal and mitochondrial functioning in primary enteric neurons of PD patients and their healthy partners as controls. Using a unique combination of live microscopy techniques, applied to routine duodenum biopsies, we were able to record neuronal Ca2+ responses and mitochondrial membrane potential in these nerve tissues. We found that submucous neurons were not affected in PD patients, which suggests that these neurons are not involved in the pathogenesis or the gastrointestinal symptoms of PD. Our study provides for the first time functional information on live neurons in PD patients. [ABSTRACT FROM AUTHOR]

Background: Handwriting in Parkinson’s disease (PD) features specific abnormalities which are difficult to assess in clinical practice since no specific tool for evaluation of spontaneous movement is currently available. Objective: This study aims to validate the ‘Systematic Screening of Handwriting Difficulties’ (SOS-test) in patients with PD. Methods: Handwriting performance of 87 patients and 26 healthy age-matched controls was examined using the SOS-test. Sixty-seven patients were tested a second time within a period of one month. Participants were asked to copy as much as possible of a text within 5 minutes with the instruction to write as neatly and quickly as in daily life. Writing speed (letters in 5 minutes), size (mm) and quality of handwriting were compared. Correlation analysis was performed between SOS outcomes and other fine motor skill measurements and disease characteristics. Intrarater, interrater and test-retest reliability were assessed using the intraclass correlation coefficient (ICC) and Spearman correlation coefficient. Results: Patients with PD had a smaller (p = 0.043) and slower (p<0.001) handwriting and showed worse writing quality (p = 0.031) compared to controls. The outcomes of the SOS-test significantly correlated with fine motor skill performance and disease duration and severity. Furthermore, the test showed excellent intrarater, interrater and test-retest reliability (ICC > 0.769 for both groups). Conclusion: The SOS-test is a short and effective tool to detect handwriting problems in PD with excellent reliability. It can therefore be recommended as a clinical instrument for standardized screening of handwriting deficits in PD. [ABSTRACT FROM AUTHOR]

Background: Micrographia occurs in approximately 60% of people with Parkinson's disease (PD). Although handwriting is an important task in daily life, it is not clear whether relearning and consolidation (ie the solid storage in motor memory) of this skill is possible in PD. The objective was to conduct for the first time a controlled study into the effects of intensive motor learning to improve micrographia in PD.Methods: In this placebo-controlled study, 38 right-handed people with PD were randomized into 2 groups, receiving 1 of 2 equally time-intensive training programs (30 min/day, 5 days/week for 6 weeks). The experimental group (n = 18) performed amplitude training focused at improving writing size. The placebo group (n = 20) received stretch and relaxation exercises. Participants' writing skills were assessed using a touch-sensitive writing tablet and a pen-and-paper test, pre- and posttraining, and after a 6-week retention period. The primary outcome was change in amplitude during several tests of consolidation: (1) transfer, using trained and untrained sequences performed with and without target zones; and (2) automatization, using single- and dual-task sequences.Results: The group receiving amplitude training significantly improved in amplitude and variability of amplitude on the transfer and automatization task. Effect sizes varied between 7% and 17%, and these benefits were maintained after the 6-week retention period. Moreover, there was transfer to daily life writing.Conclusions: These results show automatization, transfer, and retention of increased writing size (diminished micrographia) after intensive amplitude training, indicating that consolidation of motor learning is possible in PD. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]