Mid-stage Parkinson's Disease Research Articles

Pharmacotherapy of motor symptoms in early and mid-stage Parkinson's disease: guideline "Parkinson's disease" of the German Society of Neurology.

There are multiple pharmacological treatment options for motor symptoms of Parkinson's disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson's Guideline Group, and publicly released in November 2023. In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise "Parkinson medication", "Initial monotherapy", "Early combination therapy", "Fluctuations and dyskinesia", and "Parkinsonian tremor". Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

Exploring Analysis Approaches for Using the Dopamine Transporter Striatal Binding Ratio in Early- to Mid-Stage Parkinson's Disease Modification Trials.

The dopamine transporter striatal binding ratio (DAT SBR) has been used as an outcome measure in Parkinson's disease (PD) trials of potential disease-modifying therapies; however, both patient characteristics and analysis approach potentially complicate its interpretation. The aim was to explore how well DAT SBR reflects PD motor severity across different striatal subregions and the relationship to disease duration, and side of onset. DAT SBR for the anterior and posterior putamen and caudate in both hemispheres was obtained using validated automated quantitative software on baseline scans of 132 patients recruited for the Exenatide PD2 and PD3 trials. Associations between mean and lateralized SBR subregions (posterior and anterior putamen and caudate) and summed and lateralized motor characteristics were explored using regression analysis. Analyses were repeated considering disease duration and limiting analysis to the less-affected hemisphere. Lateralized bradykinesia was most consistently associated with the loss of DAT uptake in the contralateral anterior putamen. There was much higher variance in the posterior putamen, and in all regions in those with longer duration disease, although bradykinesia remained robustly associated with anterior putaminal DAT uptake even in longer-duration patients. Restricting analyses to the less-affected side did not usefully reduce the variance compared to the overall cohort. These data suggest that DAT SBR could be a useful biomarker in disease-modifying trials, but a focus on anterior striatal subregions and incorporating disease duration into analyses may improve its utility.

Metacognitive accuracy differences in Parkinson's disease and REM sleep behavioral disorder relative to healthy controls.

Metacognition is the ability to monitor and self-assess cognitive performance. It can be impaired in neurodegenerative diseases, with implications for daily function, and the ability of patients to reliably report their symptoms to health professionals. However, metacognition has not been systematically assessed in early-mid stage Parkinson's disease (PD) and REM sleep behavioral disorder (RBD), a prodrome of PD. This study aimed to evaluate metacognitive accuracy and self-confidence in PD and RBD patients across various cognitive tasks. We conducted detailed computerized cognitive assessments with 19 cognitive tasks within an established PD and RBD cohort. Participants self-rated their performance post-task. Metacognitive accuracy was calculated by comparing these ratings against objective performance and further analyzed against clinical and mental health factors. PD and RBD patients' metacognitive accuracy aligned with control subjects. However, they exhibited lower confidence across cognitive domains, reflecting their reduced cognitive performance. A notable inverse correlation was observed between their confidence and MDS-UPDRS I and II scales and HADS anxiety and depression scores. Our findings indicate that patients with early to mid-stage PD and RBD are generally aware of their cognitive status, differing from other neurological disorders. The inverse relationship between patient confidence and symptoms of depression, anxiety, and daily life challenges underscores the impact of emotional and functional difficulties on their self-perception of cognitive abilities. This insight could be significant for understanding how these conditions affect mental health, aiding clinicians in developing more effective patient care strategies.

Vocal and tongue exercise in early to mid-stage Parkinson disease using the Pink1-/- rat

Vocal and swallowing deficits are common in Parkinson disease (PD). Because these impairments are resistant to dopamine replacement therapies, vocal and lingual exercise are the primary treatment, but not all individuals respond to exercise and neural mechanisms of treatment response are unclear. To explore putative mechanisms, we used the progressive Pink1-/- rat model of early to mid-stage PD and employed vocal and lingual exercises at 6- and 10-months of age in male Pink1-/- and wild type (WT) rats. We hypothesized that vocal and lingual exercise would improve vocal and tongue use dynamics and increase serotonin (5HT) immunoreactivity in related brainstem nuclei. Rats were tested at baseline and after 8 weeks of exercise or sham exercise. At early-stage PD (6 months), vocal exercise resulted in increased call complexity, but did not change intensity, while at mid-stage (10 months), vocal exercise no longer influenced vocalization complexity. Lingual exercise increased tongue force generation and reduced relative optical density of 5HT in the hypoglossal nucleus at both time points. The effects of vocal and lingual exercise at these time points are less robust than in prodromal stages observed in previous work, suggesting that early exercise interventions may yield greater benefit. Future work targeting optimization of exercise at later time points may facilitate clinical translation.

White Matter Microstructural Underpinnings of Mild Behavioral Impairment in Parkinson's Disease.

Patients with Parkinson's disease (PD) experience changes in behavior, personality, and cognition that can manifest even in the initial stages of the disease. Previous studies have suggested that mild behavioral impairment (MBI) should be considered an early marker of cognitive decline. However, the precise neurostructural underpinnings of MBI in early- to mid-stage PD remain poorly understood. The aim was to explore the changes in white matter microstructure linked to MBI and mild cognitive impairment (MCI) in early- to mid-stage PD using diffusion magnetic resonance imaging (dMRI). A total of 91 PD patients and 36 healthy participants were recruited and underwent anatomical MRI and dMRI, a comprehensive neuropsychological battery, and the completion of the Mild Behavioral Impairment-Checklist. Metrics of white matter integrity included tissue fractional anisotropy (FAt) and radial diffusivity (RDt), free water (FW), and fixel-based apparent fiber density (AFD). The connection between the left amygdala and the putamen was disrupted when comparing PD patients with MBI (PD-MBI) to PD-non-MBI, as evidenced by increased RDt (η2 = 0.09, P = 0.004) and both decreased AFD (η2 = 0.05, P = 0.048) and FAt (η2 = 0.12, P = 0.014). Compared to controls, PD patients with both MBI and MCI demonstrated increased FW for the connection between the left orbitofrontal gyrus (OrG) and the hippocampus (η2 = 0.22, P = 0.008), augmented RDt between the right OrG and the amygdala (η2 = 0.14, P = 0.008), and increased RDt (η2 = 0.25, P = 0.028) with decreased AFD (η2 = 0.10, P = 0.046) between the right OrG and the caudate nucleus. MBI is associated with abnormal microstructure of connections involving the orbitofrontal cortex, putamen, and amygdala. To our knowledge, this is the first assessment of the white matter microstructure in PD-MBI using dMRI. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluation of Nocturnal Symptoms in Chinese Parkinson's Disease Patients Based on the PDSS-2 Scale: A Multicenter Cross-Sectional Study.

Nocturnal symptoms have a significant effect on the quality of life in Parkinson's disease (PD) patients. This study aimed to investigate the prevalence and associated factors of nocturnal symptoms in Chinese PD patients. This multicenter cross-sectional study included 1,500 patients with primary PD from 18 centers in China was carried out between February 2019 and February 2020. Questionnaires including Parkinson's disease sleep scale 2 (PDSS-2), Parkinson's disease questionnaire 8 (PDQ-8), Beck depression inventory (BDI), and generalized anxiety disorder scale 7 (GAD-7) were used to assess nocturnal symptoms, quality of life, depression, and anxiety. Among 1,500 Chinese PD patients, 576 (38.4%) reported nocturnal symptoms. Of them, 59.2% were older than 65 years. The PDQ-8 total score was higher in patients with nocturnal symptoms (p < 0.01). Moderate and severe depression was reported more often in patients with nocturnal symptoms (p < 0.01), and the occurrence and severity of anxiety were higher as well (p < 0.01). Longer disease duration and higher Hoehn-Yahr (HY) stage were independently associated with nocturnal symptoms (p < 0.01). Education level, depression, disease course, HY stage, and nocturnal symptoms were related to the quality of life in Chinese PD patients (p < 0.01). Our study found that 38.4% of Chinese PD patients have nocturnal symptoms, even in early and mid-stage PD. Nocturnal symptoms were associated with worse quality of life and higher incidences of depression and anxiety. Nocturnal symptoms should be included in the assessment and care plan, especially in patients with longer disease courses and higher HY stages.

Self-directed physical activity interventions for motor symptoms and quality of life in early and mid-stage Parkinson's disease: A systematic review and meta-analysis

BackgroundSelf-directed physical activity (SDPA) has been found in previous research to alleviate some of the symptoms of early and mid-stage Parkinson's disease (PD) patients. So, this study aimed to determine the impact of SDPA on these patients in the areas of motor symptoms, and quality of life (QoL). MethodPubMed, Embase, the Cochrane Library, the Web of Science, Scopus, and ProQuest were all searched. The risk-of-bias tool of Cochrane for randomized trials, Version 2 (RoB 2), was also used to assess the credibility of studies in terms of their procedures. Results15 eligible studies were analyzed. SDPA improved motor function and mobility, including timed up and go (TUG) test [standardized mean difference (SMD), −0.55 (95% CI, −0.91 – −0.18), p = 0.003], 6-minute walking (6MW) test [1.11 (0.75 − 1.47), p < 0.00001], stride length [0.45 (0.18 – 0.72), p = 0.001], gait velocity [0.42 (0.04 – 0.81 p = 0.03], Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III) [−0.76 (−1.18 – −0.33), p = 0.0005] and enhanced Berg Balance Scale (BBS) [0.88 (0.50 – 1.27), p < 0.00001]). Despite engaging in SDPA, there was no significant improvement observed in freezing of gait (FOG) [0.23 (−0.11 – 0.56), p = 0.18] as well as the Parkinson's Disease Questionnaire-39 (PDQ-39) [0.04 (−0.55 – 0.62), p = 0.90]). ConclusionThe motor symptoms of those with early to mid-stage PD improved with SDPA, however the research found no enhancement in FOG or QoL.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. White matter hyperintensity burden at baseline predicted cognitive butnotmotordecline inearly to mid-stage PD. The motor decline observed after 2 years in these olderadultswithPDis probably related to the primary neurodegenerative process than comorbid white matter pathology.

Evaluation of the efficacy of physical therapy on cognitive decline at 6-month follow-up in Parkinson disease patients with mild cognitive impairment: a randomized controlled trial.

In Parkinson's disease (PD), physical activity may represent a possible non-pharmacological intervention not only for improving motor symptoms but also for modulating cognitive impairment. To evaluate the efficacy of an intensive physical program on cognitive functions in mid-stage PD patients with mild cognitive impairment (PD-MCI) over a 6-month follow-up. This is a 6-month randomized controlled follow-up study. 40 PD-MCI patients were randomized to receive physical therapy (PT) or no specific intervention beside drug treatment (CT). Cognitive and motor assessments were performed at baseline (T0), 4weeks after baseline (T1) and 6months after T0. In a previous study, we reported a significant improvement in global cognitive functioning and attention/working-memory at T1. Here, we evaluated the residual effect of the training intervention at 6months on both cognitive and motor performances. Intra-group analysis showed that at T2 most of cognitive and motor performances remained stable in the PT when compared to T0, while a significant worsening was observed in the CT. Between-group comparison at T2 showed significantly better results in PT than CT as regards MoCA and motor scales. The percentage change of cognitive and motor performances between T1 and T2 confirmed the benefit of physical therapy on global cognitive functioning scores (MMSE and MoCA). In this follow-up extension of a longitudinal randomized controlled study, we demonstrated that physical therapy has a positive effect on cognitive functions, which extends beyond the duration of the treatment itself to, at least temporarily, reducing cognitive decline. Trial registration number (ClinicalTrials.gov): NCT04012086 (9th July 2019).

Are there any differences between the tongue and posterior pharyngeal wall movement patterns during normal and Masako swallow?—An ultrasound analysis

Parkinson's disease (PD) is a neurodegenerative movement disorder affecting volitional movement due to Dopamine-producing neuron death in the substantia nigra. Impaired swallow function is highly prevalent with nearly 100% involvement in PD during the disease course and involves all three phases of swallowing. The oral stage of swallowing is impaired first. Reduced bolus control and reduced interior-to-posterior movement of the bolus transfer lead to delayed swallowing response, premature spillage, decreased base of tongue (BOT) retraction and strength, decreased hyolaryngeal elevation and excursion, and reduced action of pharyngeal constrictors. Together, these result in bolus retention, residue throughout the pharynx, and reduced airway protection leading to significant aspiration. To target these deficits we have designed an exercise regime to teach early to mid-stage PD patients to do the Masako swallow maneuver of saliva (swallow with tongue-tip held between teeth), with high intensity and frequency (i.e., 120 repetitions per day) in one month. The preliminary results are very promising. All participants demonstrated positive changes. To understand the underlying mechanism, we used Ultrasound and recorded 20 normal subjects while they did three normal swallows and 3 Masako swallow maneuvers. The initial observations indicated the tongue and pharyngeal movement patterns differ between the two maneuvers.

GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes.

Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Respiratory-Swallow Coordination Training and Voluntary Cough Skill Training: A Single-Subject Treatment Study in a Person With Parkinson's Disease.

Purpose Airway protective disorders are common in Parkinson's disease (PD), yet effective methods to rehabilitate these life-threatening impairments are limited. This study examined the effects of two skill-based treatments aimed at improving swallowing and cough in a severely dysphagic person with PD: respiratory-swallow coordination training (RSCT) and voluntary cough skill training (VCST). It was hypothesized that (a) RSCT would improve respiratory-swallow coordination and swallowing safety and efficiency and (b) VCST would improve reflex and voluntary cough effectiveness. Method An 81-year-old man with midstage PD and severe dysphagia was recruited for study participation. The study utilized a multiple-baseline ABACA experimental design with a 2-month delayed retention assessment. Measures of respiratory-swallow coordination, swallowing safety and efficiency, and cough effectiveness were collected at each assessment using respiratory inductive plethysmography, flexible endoscopic evaluations of swallowing, and spirometry. Data were analyzed descriptively using baseline corrected tau and standard mean difference effect sizes (d). Results Large effect sizes were observed immediately following RSCT for respiratory-swallow coordination (d = 9.17), penetration-aspiration (d = 12.88), vallecular residue (d = 1.75), piriform residue (d = 4.15), and overall dysphagia severity (d = 1.83). Large effect sizes were also observed immediately following VCST for single voluntary cough (d = 4.30), sequential voluntary cough (d = 3.28), and reflex cough (d = 5.58). Improvements were maintained 2 months later for all outcome measures except single voluntary cough. Discussion This is the first study to examine the effects of RSCT and VCST in a person with PD. Robust improvements in respiratory-swallow coordination and swallowing safety and efficiency were achieved following four sessions of RSCT, and significant improvements in reflex and voluntary cough strength were seen following four sessions of VCST. Future work is needed to study these treatments in larger cohorts of people with PD.

Nilotinib Safety and Clinical Effects on 'ON' Disability in Parkinson's Disease Patients

Background: Parkinson's disease (PD) involves motor and non-motor symptoms and loss of brain dopamine neurons. Nilotinib is a tyrosine kinase inhibitor that may alter brain dopamine metabolism. Methods: A phase II randomized, double-blind, placebo controlled trial to evaluate Nilotinib effects on safety, tolerability and clinical outcomes in PD. Seventy-five participants were randomized 1:1:1 into placebo, 150mg or 300mg Nilotinib once daily for 12 months. This study evaluated Nilotinib effects on top of the optimal standard of care in mid-stage PD (H&Y 2.5-3) at 6 and 12 months. Findings: Participants well tolerated Nilotinib and rare hematological, hepatic and other systems disorders were observed. Cardiovascular events were seen in all groups. Prior to randomization all participants were stabilized on either Levodopa and/or dopamine agonists and were tested ON time. As expected, all 3 groups were stable at 6 months, indicating the effects of PD medications. However, the placebo group declined on UPDRS II (2.39 points, p=0.007), total UPDRS I-III (4.78 points, p=0.031) and UPDRS I-IV (4.47 points, p=0.038) at 6-12 months but Nilotinib groups remained stable. Similarly, all groups were stable on PDQ39 SI and the emotional well-being subscale at 6 months but the placebo group declined (8.17 points, p=0.001 and 1.7 points, p=0.003, respectively) at 6-12 months, while Nilotinib groups remained stable. Interpretation: Nilotinib is well tolerated and appears to be safe in PD patients. Nilotinib appears to stop the decline in motor and non-motor functions up to 12 months, while the effects of optimized PD medications significantly wear off six months after treatment. Nilotinib may have a significant impact on the care and management of PD patients, leading to delay or elimination of dose adjustment of PD-medications, thus avoiding their side effects. Trial Registration: The study was conducted under FDA Investigational New Drug (IND) # 123183, and registered in ClinicalTrials.gov (NCT02954978). Funding Statement: Lasky and Barajas Family Fund and other philanthropies. Novartis Pharmaceuticals Corporation provided the study drug. Declaration of Interests: Charbel Moussa is an inventor on several US and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study. Ethics Approval Statement: This study was conducted in accordance with Good Clinical Practice guidelines and was approved by the Institutional Review Board (IRB# 2016-0380) at Georgetown University Medical Center as well as by Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) scientific review board. Informed consent was obtained from all participants and study partners

Predictors of Residue and Airway Invasion in Parkinson's Disease.

Dysphagia is a highly prevalent disorder in Parkinson's Disease (PD) characterized by changes in swallowing kinematics, residue, and airway invasion. These changes can lead to serious medical morbidities including malnutrition, aspiration pneumonia, and death. However, little is known about the most predictive causes of residue and airway invasion in this patient population. Therefore, the aims of this study were to (1) assess how disease severity affects residue, airway invasion, and swallowing kinematics in PD; and (2) determine which swallowing kinematic variables were most predictive of residue and airway invasion. A secondary analysis of forty videofluoroscopic swallow studies (VFSS) from individuals with early through mid-stage PD was performed. Airway invasion (Penetration-Aspiration Scale 'PAS'), residue (Bolus Clearance Ratio 'BCR'), and ten spatiotemporal swallowing kinematic variables were analyzed. Statistical analyses were used to determine if disease severity predicted residue, depth of airway invasion, and swallowing kinematics, and to examine which swallowing kinematic variables were most predictive of residue and the presence of airway invasion. Results revealed that residue and the presence of airway invasion were significantly predicted by swallowing kinematics. Specifically, airway invasion was primarily influenced by the extent and timing of airway closure, while residue was primarily influenced by pharyngeal constriction. However, disease severity did not significantly predict changes to swallowing kinematics, extent of residue, or depth of airway invasion during VFSS assessment. This study comprehensively examined the pathophysiology underlying dysphagia in people with early to mid-stage PD. The results of the present study indicate that disease severity alone does not predict swallowing changes in PD, and therefore may not be the best factor to identify risk for dysphagia in PD. However, the swallowing kinematics most predictive of residue and the presence of airway invasion were identified. These findings may help to guide the selection of more effective therapy approaches for improving swallowing safety and efficiency in people with early to mid-stage PD.

Progressive Gait Deficits in Parkinson's Disease: A Wearable-Based Biannual 5-Year Prospective Study.

Background: Gait changes occur during all Parkinson’s disease (PD) stages and wearable sensor-derived gait parameters may quantify PD progression. However, key aspects that may qualify quantitative gait parameters as progression markers in PD remain elusive.Objectives: Longitudinal changes in gait parameters from a lower-back sensor under convenient and challenging walking conditions in early- and mid-stage PD patients (E-PD, M-PD) compared to controls were investigated.Methods: Normal- and fast-pace parameters (step: number, time, velocity, variability) were assessed every 6 months for up to 5 years in 22 E-PD (<4 years baseline disease duration), 18 M-PD (>5 years) and 24 controls. Parameter trajectories and associations with MDS-UPDRS-III were tested using generalized estimating equations.Results: Normal-pace step number (annual change in E-PD: 2.1%, Time∗Group: p = 0.001) and step time variability (8.5%, p < 0.05) longitudinally increased in E-PD compared to controls (0.7%, -12%). For fast pace, no significant progression differences between groups were observed. Longitudinal changes in M-PD did not differ significantly from controls. MDS-UPDRS-III was largely associated with normal-pace parameters in M-PD.Conclusion: Wearables can quantify progressive gait deficits indicated by increasing step number and step time variability in E-PD. In M-PD, and for fast-pace, gait parameters possess limited potential as PD progression markers.

Could istradefylline be a treatment option for postural abnormalities in mid-stage Parkinson's disease?

BasegroundPostural abnormalities are refractory complications observed in mid- to late-stage Parkinson's disease (PD). MethodsWe analyzed the effects of istradefylline, a selective adenosine A2A receptor antagonist, on posture in 21 levodopa-treated PD patients from the subanalysis of a three-month open-label study. ResultsThe subitem score of posture (3.13) on the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III significantly improved following istradefylline treatment (baseline, 1.3±1.0 points vs 3months, 0.9±0.9 points; p<0.05). Among 18 patients who had postural abnormalities at baseline, defined as 1 point or greater on MDS-UPDRS part III subitem 3.13, posture improved in 9 (50%) and was unchanged in 9 (50%) patients after istradefylline treatment. Improved and unchanged groups did not show differences in baseline characteristics, except for tendency for a higher rate of Hoehn and Yahr stage IV and V (Off state) observed in the improved group. Changes in scores of posture (3.13) did not correlate with those of other MDS-UPDRS part III items, PD Questionnaire-8, PD Sleep Scale-2 and Epworth Sleepiness Scale. ConclusionBased on our preliminary findings, istradefylline could be an effective treatment option for postural abnormalities in mid-stage PD patients.

Identification of swallowing disorders in early and mid-stage Parkinson's disease using pattern recognition of pharyngeal high-resolution manometry data.

Parkinson's disease (PD) can cause severe dysphagia, especially later in disease progression. Early identification of swallowing dysfunction may lead to earlier intervention. Pharyngeal high-resolution manometry (HRM) provides complementary information to videofluoroscopy, with advantages of being quantitative and objective. Artificial neural network (ANN) classification can examine non-linear relationships among multiple variables with relatively low bias. We evaluated if ANN techniques could differentiate between patients with PD and healthy controls. Simultaneous videofluoroscopy and pharyngeal HRM were performed on 31 patients with early to mid-stage PD and 31 age- and sex-matched controls during thin-liquid swallows of 2cc, 10cc and comfortable sip volume. We performed multilayer-perceptron analyses on only videofluoroscopic data, only HRM data or a combination of the two. We also evaluated variability-based parameters, representing variability in manometric parameters across multiple swallows. We hypothesized that patients with PD and controls would be classified with at least 80% accuracy, and that combined videofluoroscopic and HRM data would classify participants better than either alone. Classification rates were highest with all parameters considered. Maximum classification rate was 82.3±5.2%, recorded for 2cc swallows. Inclusion of variability-based parameters improved classification rates. Classification rates using only manometric parameters were similar to those using all parameters, and rates were substantially lower for the comfortable sip volumes. Results from these classifications highlight the differences between swallowing function in patients with early and mid-stage PD and healthy controls. Early identification of swallowing dysfunction is key to developing preventative swallowing treatments for those with PD.

Cognitive performance in mid-stage Parkinson's disease: functional connectivity under chronic antiparkinson treatment.

Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.

Slowed Prosaccades and Increased Antisaccade Errors As a Potential Behavioral Biomarker of Multiple System Atrophy.

Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson’s disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD (N = 21), MSA (N = 11), and age-matched controls (C, N = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders.

Striatal and Hippocampal Atrophy in Idiopathic Parkinson's Disease Patients without Dementia: A Morphometric Analysis.

Analyses of subcortical gray structure volumes in non-demented idiopathic Parkinson's disease (PD) often, but not always, show volume loss of the putamen, caudate nucleus, nucleus accumbens, and hippocampus. There is building evidence that structure morphometry might be more sensitive to disease-related processes than volume. To assess morphometric differences of subcortical structures (putamen, caudate nucleus, thalamus, globus pallidus, nucleus accumbens, and amygdala) as well as the hippocampus in non-demented individuals with PD relative to age and education matched non-PD peers. Prospective recruitment of idiopathic no-dementia PD and non-PD peers as part of a federally funded investigation. T1-weighted isovoxel metrics acquired via 3-T Siemens Verio for all individuals [PD n = 72 (left side onset n = 27, right side onset n = 45); non-PD n = 48]. FIRST (FMRIB Software Library) applications provided volumetric and vertex analyses on group differences for structure size and morphometry. Group volume differences were observed only for putamen and hippocampi (PD < non-PD) with hippocampal volume significantly associating with disease duration. Group shape differences were observed for bilateral putamen, caudate nucleus, and hippocampus with greater striatal atrophy contralateral to side of motor symptom onset. Hippocampal shape differences disappeared when removing the effects of volume. The putamen was the primary structure to show both volume and shape differences in PD, indicating that the putamen is the predominant site of basal ganglia atrophy in early- to mid-stage PD. Side of PD symptom onset associates with contralateral striatal atrophy. Left-onset PD might experience more extensive striatal atrophy than right-onset PD. Hippocampus morphometric results suggest possible primary atrophy of CA3/4 and dentate gyrus.