Motor Unified Parkinson's Disease Research Articles

Migraine, Tension-Type Headache and Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background and Objectives: The relationship between migraine and tension-type headache (TTH) with Parkinson's disease (PD) is controversial, while a common pathophysiological link remains obscure. The aim of this systematic review is to investigate the association between PD, migraine and TTH. Materials and Methods: Following PRISMA, we searched MEDLINE, WebofScience, Scopus, CINAHL, Cochrane Library and ClinicalTrials.gov up to 1 July 2022 for observational studies examining the prevalence and/or associations of PD with migraine and TTH. We pooled proportions, standardized mean differences (SMD) and odds ratios (OR) with random effects models. The risk of bias was assessed with the Newcastle-Ottawa scale (PROSPERO CRD42021273238). Results: Out of 1031 screened studies, 12 were finally included in our review (median quality score 6/9). The prevalence of any headache among PD patients was estimated at 49.1% (760 PD patients; 95% CI 24.8-73.6), migraine prevalence at 17.2% (1242 PD patients; 95% CI 9.9-25.9), while 61.5% (316 PD patients; 95% CI 52.6-70.1) of PD patients with migraine reported headache improvement after PD onset. Overall, migraine was not associated with PD (302,165 individuals; ORpooled = 1.11; 95% CI 0.72-1.72).However, cohort studies demonstrated a positive association of PD among lifetime migraineurs (143,583 individuals; ORpooled = 1.54, 95% CI 1.28-1.84), while studies on 12-month migraine prevalence yielded an inverse association (5195 individuals; ORpooled = 0.64, 95% CI 0.43-0.97). Similar findings were reported by 3 studies with data on the TTH-PD relationship (high prevalence, positive association when examined prospectively and an inverse relationship on 12-month prevalence). These data were not quantitatively synthesized due to methodological differences among the studies. Finally, PD patients suffering from any headache had a lower motor unified Parkinson's disease rating scale (UPDRS) score (503 PD patients; SMD -0.39; 95% CI -0.57 to -0.21) compared to PD patients not reporting headache. There is an unclear association of headaches in genetic PD cohorts. Conclusions: Observational data suggest that migraine and TTH could be linked to PD, but the current literature is conflicting.

Initial Clinical Outcome With Bilateral, Dual-Target Deep Brain Stimulation Trial in Parkinson Disease Using Summit RC + S.

Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism. To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study. We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power. Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively. Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.

Prediction of motor Unified Parkinson's Disease Rating Scale scores in patients with Parkinson’s disease using surface electromyography

ObjectiveParkinson's disease (PD) is a chronic neurodegenerative disorder with increasing prevalence in the elderly. Especially patients with advanced PD often require complex medication regimens due to fluctuations, that is abrupt transitions from ON to OFF or vice versa. Current gold standard to quantify PD-patients’ motor symptoms is the assessment of the Unified Parkinson's Disease Rating Scale (UPDRS), which, however, is cumbersome and may depend upon investigators. This work aimed at developing a mobile, objective and unobtrusive measurement of motor symptoms in PD. MethodsData from 45 PD-patients was recorded using surface electromyography (sEMG) electrodes attached to a wristband. The motor paradigm consisted of a tapping task performed with and without dopaminergic medication. Our aim was to predict UPDRS scores from the sEMG characteristics with distinct regression models and machine learning techniques. ResultsA random forest regression model outnumbered other regression models resulting in a correlation of 0.739 between true and predicted UPDRS values. ConclusionsPD-patients’ motor affection can be extrapolated from sEMG data during a simple tapping task. In the future, such records could help determine the need for medication changes in telemedicine applications. SignificanceOur findings support the utility of wearables to detect Parkinson's symptoms and could help in developing tailored therapies in the future.

Weight loss and weight gain in Parkinson disease

IntroductionParkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change. MethodsIn this longitudinal analysis, weight at baseline and follow-up was used to classify patients into groups of weight loss, stable, and weight gain. Differences between these groups at baseline and then with change over time were tested. ResultsThe sample was 668 patients with mean(SD) age 66.1(10) and disease duration 5.3(5.4) years. Using 3% weight change criteria: 32.6% lost, 23.1% gained, and 55.7% had stable weight. Using 5% criteria: 22.6% lost, 15.7% gained, and 61.7% had stable weight. Age was associated with both 3% and 5% change in weight. Other associations with 5% weight change were disease duration, Total and Motor Unified Parkinson's Disease Rating Scale, Older Americans Resource and Services disability, and Hoehn & Yahr staging. The effects of 3% weight loss on Motor UPDRS, IADLs, and depression, and the effects of 5% weight loss on IADLs remained statistically significant when controlling for baseline differences in age, levodopa use, and Total UPDRS. ConclusionPD patients are more likely to experience 3% than 5% weight change and this lower threshold of weight change was associated with greater disease severity and disability over time. Attention to more subtle weight change may help identify those at greater risk of disability.

Estimation of Parkinson's disease severity using speech features and extreme gradient boosting.

In recent years, there is an increasing interest in building e-health systems. The systems built to deliver the health services with the use of internet and communication technologies aim to reduce the costs arising from outpatient visits of patients. Some of the related recent studies propose machine learning-based telediagnosis and telemonitoring systems for Parkinson's disease (PD). Motivated from the studies showing the potential of speech disorders in PD telemonitoring systems, in this study, we aim to estimate the severity of PD from voice recordings of the patients using motor Unified Parkinson's Disease Rating Scale (UPDRS) as the evaluation metric. For this purpose, we apply various speech processing algorithms to the voice signals of the patients and then use these features as input to a two-stage estimation model. The first step is to apply a wrapper-based feature selection algorithm, called Boruta, and select the most informative speech features. The second step is to feed the selected set of features to a decision tree-based boosting algorithm, extreme gradient boosting, which has been recently applied successfully in many machine learning tasks due to its generalization ability and speed. The feature selection analysis showed that the vibration pattern of the vocal fold is an important indicator of PD severity. Besides, we also investigate the effectiveness of using age and years passed since diagnosis as covariates together with speech features. The lowest mean absolute error with 3.87 was obtained by combining these covariates and speech features with prediction level fusion. Graphical Abstract Framework for the proposed UPDRS estimation model.

Estimation of Parkinson's disease severity from voice features of vowels and consonant.

This study has investigated the efficiency of voice features in estimating the motor Unified Parkinson's Disease Rating Scale (UPDRS) score in Parkinson's disease (PD) patients. A total of 26 PD patients (mean age = 72) and 22 control subjects (mean age = 66.91) were recruited for the study. The sustained phonation /a/, /u/ and /m/ were collected in both off-state and on-state of Levodopa medication. The average motor UPDRS for PD off-state patients was 27.31, on-state was 20.42 and that of controls was 2.63. Voice features were extracted from the phonation tasks and were reduced to the most relevant 6 features for each phonation task using the Least Absolute Shrinkage and Selection Operator (LASSO) feature ranking method. The correlation between the reduced features and motor UPDRS was tested using the Spearman correlation coefficient test. AdaBoost regression learner was trained and used for automatically estimating the motor UPDRS score using the voice features. The results show that the vocal features for /m/ performed best by estimating the motor UPDRS score for PD off-state with the mean absolute error (MAE) of 3.52 and 5.90 for PD on-state. This study shows that assessment of voice can be used for day to day remote monitoring of PD patients.

Early Impairment of Chopsticks Skills in Parkinsonism Suggests Progressive Supranuclear Palsy.

Background and PurposeChopsticks are a primary eating utensil in East Asia, but systematic assessments of chopsticks skills in parkinsonian disorders is lacking. We aimed to identify any differences in chopsticks skills in the early stages of Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS).MethodsWe consecutively recruited 111 patients with PD and 74 with AP (40 with PSP, 30 with MSA, and 4 with CBS) who were in a drug-naïve state. The motor and cognitive functions of the patients were evaluated using a standardized protocol. Everyday chopsticks skills were evaluated using a chopsticks questionnaire developed in-house. The chopsticks skills test (CST) involved counting the number of pills that the subject was able to carry using chopsticks between two dishes separated by 20 cm within 20 seconds.ResultsPatient responses to the questionnaire indicating poor chopsticks skills (“I cannot pick up some of the food items” or “I cannot use chopsticks anymore”) were present in 23.0% of AP patients and 30% of PSP patients, compared to only 5.6% of PD patients [odd ratio (OR)=5.07 and OR=7.29, p≤0.001 in both]. The performance in the CST was worse in PSP than in PD (p<0.001). The CST results were correlated with hand motor skills including in the coinrotation test, timed figure-tapping test, and motor Unified Parkinson's Disease Rating Scale scores in all of the patient groups (p<0.001). In PSP, a decline in visuospatial function and frontal executive function was associated with a poor performance in the CST in addition to poor motor performance (p<0.05).ConclusionsImpairments in chopsticks skills were more common in PSP than in PD during the early stages of parkinsonism. This suggests that early functional impairment of chopsticks skills can be used as a warning sign for PSP.

On the (Non-)equivalency of monopolar and bipolar settings for deep brain stimulation fMRI studies of Parkinson's disease patients.

The majority of Parkinson's disease patients with deep brain stimulation (DBS) use a monopolar configuration, which presents challenges for EEG and MRI studies. The literature reports algorithms to convert monopolar to bipolar settings. To assess brain responses of Parkinson's disease patients implanted with DBS during fMRI studies using their clinical and presumed equivalent settings using a published conversion recipe. Prospective. Thirteen DBS patients. 1.5T and 3T, fMRI using gradient echo-planar imaging. Patients underwent 30/30sec ON/OFF DBS fMRI scans using monopolar and bipolar settings. To convert to a bipolar setting, the negative contact used for the monopolar configuration remained constant and the adjacent dorsal contact was rendered positive, while increasing the voltage by 30%. fMRI activation/deactivation maps and motor Unified Parkinson's Disease Rating Scale (UPDRS-III) scores were compared for patients in both configurations. T-tests were used to compare UPDRS scores and volumes of tissue activated (VTA) diameters in monopolar and bipolar configurations. The patterns of fMRI activation in the monopolar and bipolar configurations were generally different. The thalamus, pallidum, and visual cortices exhibited higher activation using the patient's clinical settings than the presumed equivalent settings. VTA diameters were lower (7 mm vs. 6.3 mm, P = 0.047) and UPDRS scores were generally higher in the bipolar (33.2 ± 16) than in the monopolar configuration (28.3 ± 17.4), without reaching statistical significance (P > 0.05). Monopolar and bipolar configurations result in different patterns of brain activation while using a previously published monopolar-bipolar conversion algorithm. Clinical benefits may be achieved with varying patterns of brain responses. Blind conversion from one to the other should be avoided for purposes of understanding the mechanisms of DBS. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Instrumented Test of Sensory Integration for Balance: A Validation Study.

Abnormal postural sway is associated with an increase in risk of falls but is difficult for clinicians to accurately quantify without access to laboratory equipment. Instrumenting clinical outcome measures using body-worn movement monitors is a low-cost alternative. This is the first study to compare the modified Clinical Test of Sensory Integration for Balance (i-mCTSIB) to the laboratory test of the Sensory Organization Test (SOT) with dynamic posturography in a group of participants with Parkinson's disease (PD) and subtle balance limitations. The purpose of this study was to (1) determine the concurrent validity of the i-mCTSIB with the SOT (6 and 4 conditions) and (2) compare the i-mCTSIB and the SOT to differentiate between individuals with and without recent falls within the previous 6 months. This cross-sectional study examined 26 participants with idiopathic PD who had a Motor Unified Parkinson's Disease Rating Scale score of 32.7 (13.5) out of 108. The composite and conditions 1 and 4 of the i-mCTSIB and SOT scores were significantly correlated: composite scores r = -0.64 (P ≤ .001), C1 r = -0.43 (P = .03), C3 r = -0.60 (P ≤ .01), and C4 r = -0.54 (P ≤ .001). A significant difference was observed in mean i-mCTSIB composite scores between fallers and nonfallers (P = .04). In contrast, the SOT composite was not significantly different between fallers and nonfallers (P = 0.31). The results suggest that the i-mCTSIB may be a valid and clinically meaningful measure of sensory organization in persons with PD, even those with mild postural instability as measured by the median Hoehn and Yahr score (2.0). Future research should evaluate predictive validity of the i-mCTSIB for prospective falls. The instrumented mCTSIB with portable, body-worn movement allows clinicians to quantify abnormal postural sway without the ceiling effects of clinical balance testing or the expense and importability of force plate technology in the SOT. Instrumenting mCTSIB may also distinguish between fallers and nonfallers.

The Dominant-Subthalamic Nucleus Phenomenon in Bilateral Deep Brain Stimulation for Parkinson's Disease: Evidence from a Gait Analysis Study.

It has been suggested that parkinsonian [Parkinson's disease (PD)] patients might have a "dominant" (DOM) subthalamic nucleus (STN), whose unilateral electrical stimulation [deep brain stimulation (DBS)] could lead to an improvement in PD symptoms similar to bilateral STN-DBS. Since disability in PD patients is often related to gait problems, in this study, we wanted to investigate in a group of patients bilaterally implanted for STN-DBS: (1) if it was possible to identify a subgroup of subjects with a dominant STN; (2) in the case, if the unilateral stimulation of the dominant STN was capable to improve gait abnormalities, as assessed by instrumented multifactorial gait analysis, similarly to what observed with bilateral stimulation. We studied 10 PD patients with bilateral STN-DBS. A clinical evaluation and a kinematic, kinetic, and electromyographic (EMG) analysis of overground walking were performed-off medication-in four conditions: without stimulation, with bilateral stimulation, with unilateral right or left STN-DBS. Through a hierarchical agglomerative cluster analysis based on motor Unified Parkinson's Disease Rating Scale scores, it was possible to separate patients into two groups, based on the presence (six patients, DOM group) or absence (four patients, NDOM group) of a dominant STN. In the DOM group, both bilateral and unilateral stimulation of the dominant STN significantly increased gait speed, stride length, range of motion of lower limb joints, and peaks of moment and power at the ankle joint; moreover, the EMG activation pattern of distal leg muscles was improved. The unilateral stimulation of the non-dominant STN did not produce any significant effect. In the NDOM group, only bilateral stimulation determined a significant improvement of gait parameters. In the DOM group, the effect of unilateral stimulation of the dominant STN determined an improvement of gait parameters similar to bilateral stimulation. The pre-surgical identification of these patients, if possible, could allow to reduce the surgical risks and side effects of DBS adopting a unilateral approach.

Vestibulo-ocular reflex abnormality in Parkinson's disease detected by video head impulse test.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by dopaminergic neuronal loss. The underlying cause of PD is unknown. To assess the clinical relevance of vestibular-ocular reflex (VOR) gain in patients with PD, especially those in the early stages. Sixty-three PD patients and 56 control healthy individuals were enrolled in this study between Mar 2015 and Aug 2015. VOR gains were determined by video head impulse test (vHIT) device. Statistical analysis was performed to assess the difference in VOR gains between PD patients and normal people. The relationship of VOR gain with age, duration and severity of disease was also assessed. In the control group, average VOR gain was 0.98±0.09 on the left side and 0.99±0.16 on the right side. No statistically significant difference was observed between the two sides in the control group (P>0.05). In the PD group, average VOR gain was 1.20±0.22 on the left side and 1.23±0.23 on the right side. No statistically significant difference was observed between the two sides in the PD group (P>0.05). There was a significant difference in VOR gain between the PD (both in early and mid-late stages) and the control group (P<0.05). A weak correlation was observed between VOR gain and the motor Unified Parkinson Disease Rating Scale score. No correlation of VOR gain with age, duration of disease or the Hoehn and Yahr Scale score was observed. VOR gains in PD patients were found to be higher than normal, especially in the early stages of the disease. vHIT is a potential tool to determine the VOR gain in PD patients and may help detect PD at an early stage.

The effect of aerobic exercise on dual-task gait in individuals with Parkinson's disease

Background/Aims: Dual tasking exacerbates gait deficits in people with Parkinson's disease. This pilot study aimed to examine the effect of aerobic exercise on dual-task gait in individuals with Parkinson's disease and begin to identify the impact of volitional pedal rate. Methods: Twenty people with Parkinson's disease were recruited and tested at baseline, post-intervention, and follow-up for motor (Unified Parkinson's Disease Rating Scale) and cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status) and dual-task gait (Time Up and Go) conditions (manual and cognitive). A 12-week aerobic exercise intervention of cycle ergometry was carried out three times a week for 60 minutes each session. To assess our intervention, separate repeated measures of analysis of variance were conducted. As determined a priori, to assess the impact of volitional pedal rate, participants were divided after the intervention into a high-pedal rate group (&gt;60 rpm) and a low-pedal rate group (≤60 rpm) based upon average maximal pedal rate throughout the intervention and analysed with the Mann Whitney U test and Related Samples Wilcoxon Signed Rank Test. Findings: Overall, motor function (P=0.580), cognitive function (P=0.077), and motor-cognitive interplay (P=0.168) did not improve after aerobic exercise. However, pedal rate groups were different for TUGmanual and TUGcognitive, but not on motor or cognitive function. Only low-pedal rate group improved over time (P=0.028 on TUGmanual) and demonstrated reduced dual task cost after the aerobic exercise (&gt;Minimal Detectible Change of 18.1%). Conclusions: Though the low-pedal rate group experienced greater motor-cognitive interference, persons who pedalled at the slower rate demonstrated the most improvement in dual-task activities.

Greater improvement in LRRK2 G2019S patients undergoing Subthalamic Nucleus Deep Brain Stimulation compared to non-mutation carriers.

BackgroundBilateral subthalamic nucleus deep brain stimulation (STN-DBS) of parkinson’s disease (PD) patients has demonstrated to improve motor performance and to reduce dopa-induced dyskinesia. An association between the occurrence of dyskinesias and LRRK2 (leucine-rich repeat kinase 2) G2019S gene mutations has recently been suggested. The aim of this study is to discover the impact of the G2019S mutation (with high incidence in the authors’ native Algeria) on the symptom response of PD in patients who underwent STN-DBS.MethodsWe carried out a comparative statistical study for the clinical evaluation and neuropsychological assessment of 27 Algerian PD STN-DBS patients, both G2019S mutation carriers (MC) and non-carriers (NC). A multiple correspondence analysis (MCA) was then conducted to compare the results with those from groups of individuals with similar modalities.ResultsThe MCA revealed that MC and NC PD patients showed two different patterns of clinical evaluations. The group of idiopathic patients showed some differences compared to the clinical evaluations, depending on gender. No association was found between the G2019S mutation and the Mini Mental State Examination scores (MMSE), and MC patients appeared more susceptible to dyskinesia than NC patients. In NC patients, we found two cases with Parkin mutations who had a different “honeymoon” period and different initial symptoms. The results showed considerable improvement of motor unified parkinson’s disease rating scale III (UPDRS-III) in a situation of stimulation without medication in the MC patients with a percentage of improvement (51.1 %) over the required 30 % compared to the NC patients (25.5 %). The same result was observed for the Schwab and England’s activities of daily living scale (S and E scale), which thus demonstrated a greater effectiveness of DBS for MC patients than for NC patients. However, the Hoehn and Yahr scale (H and Y Scale) showed the same significance in a situation of stimulation for MC and NC patients. In this later group, the best scores of UPDRS-III were observed for patients with the Parkin mutation before they underwent surgery.ConclusionsThis study shows that surgical treatment probably has a more significant impact on LRRK2 G2019S MC than on idiopathic patients.

Predicting Falls in Parkinson Disease Patients

Background: Falls are a major risk for Parkinson disease patients (PD). Single falls, in older people may be related to the underlying disease or may be accidental. Recurrent falls are more likely to be related to the underlying disease. Objectives: To predict falls in patients with Parkinson disease. Patients and Methods: Between July 1, 2011 and June 30, 2012 we examined 452 persons with PD in the Muhammad Ali Parkinson Clinic during their outpatient visits. Results: We followed 401 persons with PD for a year, 205 of whom, 51.0% fell: 161 fell once and 44 fell more than once (recurrent fallers). Recurrent fallers had PD significantly longer, 12.6 + 7.0 versus 5.9 + 4.5 years, had significantly higher, worse, motor unified parkinson disease rating scale (UPDRS) scores” 31.2 + 12.7 versus 19.7 + 8.3. The major difference between recurrent and single fallers was an inability of recurrent fallers to stand on one leg for < 3 seconds: 95% versus 11%, odds ratio 178 CI 95% 39.5 - 801.2. Conclusions: Single fallers who are unable to stand on one foot for < 3 seconds may be at risk for recurrent falls. Gait and balance training focused on improving a patient’s ability to stand on one leg may decrease the risk of recurrent falls in PD.

Validity, Reliability, and Insights from Applying the McGill Quality of Life Questionnaire to People Living with Parkinson's Disease (MQoL-PD).

Existing quality-of-life instruments for Parkinson's disease (PD) may not fully assess quality of life (QoL) for people with PD in a holistic and multidimensional manner. This study examines the subscale structure, validity, and internal-consistency reliability of the McGill Quality of Life (MQoL) Questionnaire in a sample of people with PD. This cross-sectional study evaluates the MQoL-PD by using Cronbach's alpha and principal components analysis. A total of 81 consenting people with PD from a tertiary care outpatient clinic were studied. Scores were tabulated for the motor Unified Parkinson's Disease Rating Scale (mUPDRS), the Short Form Health Survey (SF-36), the Parkinson's Disease Questionnaire (PDQ-39), the MQoL Single-Item Scale (MQoL-SIS), and the MQoL Questionnaire (MQoL). Cronbach's alpha for the MQoL-PD was: physical symptoms, 0.83; psychological symptoms, 0.59; and existential/support symptoms, 0.76. Important contributors to QoL in PD include mobility, bowel and bladder function, fatigue, and pain. The MQoL Questionnaire is a valid and reliable measure of physical, psychological, and existential/support symptoms for people with PD.

Repetitive deep transcranial magnetic stimulation for motor symptoms in Parkinson's disease: A feasibility study

ObjectivesRepetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial.To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. Patients and methodsAn open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n=9) or combined with HF PFC rDTMS (M1-PFC, n=10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. ResultsFor the M1+PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p=0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p=0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. ConclusionrDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

Vitamin D deficiency and its relationship with endothelial dysfunction in patients with early Parkinson's disease.

Increasing evidence has shown that individuals with Parkinson's disease (PD) have lower levels of 25-hydroxyvitamin D (25[OH]D) than healthy controls. Low vitamin D has been associated with endothelial dysfunction which may play a role in the pathogenesis and progression of PD. Flow-mediated dilation (FMD) is widely used as a clinical marker of overall endothelial function. We evaluated the relationship between serum 25(OH)D levels and FMD in PD. We enrolled 81 patients with early PD and 52 healthy controls, and we evaluate endothelial function based on vitamin D status and identify the association between FMD and vitamin D status in patients with early PD. The mean serum 25(OH)D levels were significantly lower in the PD patients than in the controls (21.8 ± 9.5 vs. 25.2 ± 9.3 ng/mL, p < 0.05). FMD was significantly lower in the PD patients (7.1 ± 1.8 %) than in the controls (8.1 ± 2.1 %, p < 0.05). The serum 25(OH)D was significantly associated with FMD independently of age, cardiovascular disease risk factors, body mass index, motor Unified PD Rating Scale status and homocysteine levels (adjusted R (2) = 0.331, β = 0.494, p < 0.001). These findings provide evidence of a possible association between endothelial dysfunction as assessed by FMD and low vitamin D status in patients with early PD.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

Cannabis (Medical Marijuana) Treatment for Motor and Non–Motor Symptoms of Parkinson Disease

The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001). There was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.