Bradykinesia in Neurodegenerative Disorders: A Blinded Video Analysis of Pathology-Proven Cases.

BACKGROUND: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. OBJECTIVE: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. METHODS: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. RESULTS: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05). CONCLUSIONS: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Shrew's venom quickly causes circulation disorder, analgesia and hypokinesia.

Multiple representatives of eulipotyphlan mammals such as shrews have oral venom systems. Venom facilitates shrews to hunt and/or hoard preys. However, little is known about their venom composition, and especially the mechanism to hoard prey in comatose states for meeting their extremely high metabolic rates. A toxin (BQTX) was identified from venomous submaxillary glands of the shrew Blarinella quadraticauda. BQTX is specifically distributed and highly concentrated (~ 1% total protein) in the organs. BQTX shares structural and functional similarities to toxins from snakes, wasps and snails, suggesting an evolutional relevancy of venoms from mammalians and non-mammalians. By potentiating thrombin and factor-XIIa and inhibiting plasmin, BQTX induces acute hypertension, blood coagulation and hypokinesia. It also shows strong analgesic function by inhibiting elastase. Notably, the toxin keeps high plasma stability with a 16-h half-life in-vivo, which likely extends intoxication to paralyze or immobilize prey hoarded fresh for later consumption and maximize foraging profit.

Long-Term Persistence of Increased Number of γH2AX+ Peripheral Blood Lymphocytes in Monkeys Exposed to Negative Factors of Space Flights: Ionizing Radiation and Simulated Hypogravity.

We studied the influence of ionizing radiation and hypogravity as negative factors of space flights on DNA damage in peripheral blood lymphocytes of rhesus monkeys at different times after exposure (from 1 to 446 days). The proportion of cells with high numbers of DNA double-strand breaks (DSB), positive for the surrogate DSB marker-protein γH2AX, was monitored using flow cytometry. Some animals were exposed to 7-day antiorthostatic hypokinesia simulating hypogravity, the others to a combined effect of antiorthostatic hypokinesia, whole-body γ-irradiation (2.34 cGy/h, dose 1 Gy), and irradiation of the head with 12C ions (450 MeV, dose 1 Gy). Exposure to antiorthostatic hypokinesia led to a significant increase in the proportion of γH2AX+ lymphocytes only on the first day after exposure, whereas after combined exposure, increased numbers of damaged lymphocytes were recorded up to 42 days after exposure.

Bradykinesia in motoneuron diseases.

OBJECTIVE: Only few studies investigated voluntary movement abnormalities in patients with motoneuron diseases (MNDs) or their neurophysiological correlates. We aimed to kinematically assess finger tapping abnormalities in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), as compared to healthy controls (HCs), and their relationship with motoneuron involvement. METHODS: Fourteen ALS and 5 PLS patients were enrolled. Finger tapping was assessed by a motion analysis system. Patients underwent a central motor conduction time assessment, a motor nerve conduction study, and needle electromyography. Data were compared to those of 79 HCs using non-parametric tests. Possible relationships between clinical, kinematic, and neurophysiological data were assessed in patients. RESULTS: As a major finding, ALS and PLS patients performed finger tapping slower than HCs. In both conditions, movement slowness correlated with muscle strength. In ALS, movement slowness also correlated with the amplitude of the compound muscle action potential recorded from the muscles involved in the task and with denervation activity. No correlations were found between slowness, measures of upper motoneuron involvement, and other clinical and neurophysiological data. CONCLUSIONS: This study provides novel information on voluntary movement abnormalities in MNDs. SIGNIFICANCE: The results highlight the pathophysiological role of motoneurons in generating movement slowness.

Comparison of the Parkinson's KinetiGraph to off/on levodopa response testing: Single center experience.

BACKGROUND AND OBJECTIVE: Levodopa off/on testing is frequently performed to assess medication response in patients with Parkinson's disease (PD) as an aid in determining best medical management or potential surgical candidacy. The Parkinson's Kinetigraph (PKG) is a wearable device which generates tremor, bradykinesia (BKS) and dyskinesia (DKS) scores representing motor symptoms over a six-day period. In this study, we compared off/on testing with PKG motor scores. METHODS: Patients were enrolled as part of an observational study: Assessing the Longitudinal Signs in PD, a three-year study evaluating clinical and biomarker evolution in patients with PD taking levodopa. Patients underwent off/on testing at baseline and 6-month visits. A greater than 30% improvement between off and on MDS-Unified Parkinson's Disease Rating Scale scores was considered a robust response. After each visit, patients wore the PKG for 6 days. A bradykinesia score (BKS) greater than 26 and dyskinesia score (DKS) greater than 9 were considered poorly controlled bradykinesia and dyskinesia, respectively. RESULTS: The median BKS at the baseline and 6-month visits were 27.15 and 27.55, respectively, despite a robust median off/on improvement at both visits. In addition, 10/18 (66%) and 7/13 (53.8%) patients with robust off/on improvement at the baseline and 6-month visits, respectively, demonstrated a BKS > 26 or DKS > 9. CONCLUSION: A robust off/on response during a clinic visit does not necessarily reflect adequately controlled motor symptoms. The PKG, by virtue of its continuous recording of motor movements, may provide additional clinically relevant data on motor symptoms which may be useful for prospective observational studies.

DNAJC6 mutation causing cranial-onset dystonia with tremor dominant levodopa non-responsive parkinsonism: A novel phenotype.

DNAJC6 mutation causes two types of phenotypes: slowly progressive parkinsonism with levodopa response and rapidly progressive parkinsonism with additional manifestations like intellectual disability, epilepsy etc. We report a new phenotype wherein an adolescent girl developed blepharospasm followed by jaw opening, lingual and cervical dystonia followed by tremors of limbs (rest and action) with rigidity, bradykinesia. The dystonia-parkinsonism phenotype has not been described. She had novel homozygous missense mutation in DNAJC6 gene.

Beta power and movement-related beta modulation as hallmarks of energy for plasticity induction: Implications for Parkinson's disease.

Extensive work on movement-related beta oscillations (~13-30 Hz) over the sensorimotor areas in both humans and animals has demonstrated that sensorimotor beta power decreases during movement and transiently increases after movement. This beta power modulation has been interpreted as reflecting interactions between sensory and motor cortical areas with attenuation of sensory afferents during movement and their subsequent re-activation for internal models updating. More recent studies in neurologically normal subjects have demonstrated that this movement-related modulation as well as mean beta power at rest increase with practice and that previous motor learning enhances such increases. Conversely, patients with Parkinson's disease (PD) do not show such practice-related increases. Interestingly, a 2-h inactivity period without sleep can restore beta power values to baseline in normal subjects. Based on these results and on those of biochemical and electrophysiological studies in animals, we expand the current interpretation of beta activity and propose that the practice-related increases of beta power over sensorimotor areas are local indices of energy used for engaging plasticity-related activity. This paper provides some preliminary evidence in this respect linking findings of biochemical and electrophysiological studies in both humans and animals. This novel interpretation may explain the high level of beta power at rest, the deficient modulation during movement as well as the decreased skill formation in PD as resulting from deficiency in energy consumption, availability and regulation that are altered in this disease.

Evaluation of neurogenic bladder outlet obstruction mimicking sphincter bradykinesia in male patients with Parkinson's disease.

BACKGROUND: Lower urinary tract symptoms are one of the most common groups of non-movement symptoms in patients with Parkinson's disease (PD). Storage symptoms are well-acknowledged, but neurogenic voiding dysfunction caused by PD remains a knowledge gap. This study aimed to evaluate the neurogenic bladder outlet obstruction in male patients with PD and its clinical significance. METHODS: Male patients who were diagnosed with PD and underwent urodynamic studies were retrospectively reviewed. The patients with prostate size < 30 ml and bladder outlet obstruction index ≥40 were included in the study. Lower urinary tract symptoms were evaluated by International Prostate Symptom Score (IPSS). Free flowmetry was performed and post void residual (PVR) volume was measured by ultrasound at follow-up. RESULTS: Six patients were included in the final analysis. The mean age was 68.2 and the mean movement symptom duration was 70.7 months. The patients had a mean IPSS of 12.5 and mean PVR volume of 70.8 ml. All patients had slow stream but none of them reported significant voiding difficulty. Urodynamic studies showed the delayed urinary sphincter relaxation and the special trace pattern. After a mean follow-up of 20 months, they had a mean IPSS of 12.5 and mean PVR volume of 73.3 ml. None of them complained of significant voiding difficulty at follow-up. CONCLUSION: The delayed urinary sphincter relaxation is a rare but repeatable phenomenon in male patients with PD. It is unlikely to cause disturbing voiding dysfunction, as reported by the patients, and does not progress prominently during the course of PD. Further studies are needed to investigate the nature of this special type of neurogenic BOO and whether it is peculiar to PD in a larger patient cohort.

Machine Learning-Based Automatic Rating for Cardinal Symptoms of Parkinson Disease.

OBJECTIVE: We developed and investigated the feasibility of a machine learning-based automated rating for the 2 cardinal symptoms of Parkinson disease (PD): resting tremor and bradykinesia. METHODS: Using OpenPose, a deep learning-based human pose estimation program, we analyzed video clips for resting tremor and finger tapping of the bilateral upper limbs of 55 patients with PD (110 arms). Key motion parameters, including resting tremor amplitude and finger tapping speed, amplitude, and fatigue, were extracted to develop a machine learning-based automatic Unified Parkinson's Disease Rating Scale (UPDRS) rating using support vector machine (SVM) method. To evaluate the performance of this model, we calculated weighted κ and intraclass correlation coefficients (ICCs) between the model and the gold standard rating by a movement disorder specialist who is trained and certified by the Movement Disorder Society for UPDRS rating. These values were compared to weighted κ and ICC between a nontrained human rater and the gold standard rating. RESULTS: For resting tremors, the SVM model showed a very good to excellent reliability range with the gold standard rating (κ 0.791; ICC 0.927), with both values higher than that of nontrained human rater (κ 0.662; ICC 0.861). For finger tapping, the SVM model showed a very good reliability range with the gold standard rating (κ 0.700 and ICC 0.793), which was comparable to that for nontrained human raters (κ 0.627; ICC 0.797). CONCLUSION: Machine learning-based algorithms that automatically rate PD cardinal symptoms are feasible, with more accurate results than nontrained human ratings. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that machine learning-based automated rating of resting tremor and bradykinesia in people with PD has very good reliability compared to a rating by a movement disorder specialist.

Continuous home monitoring of Parkinson's disease using inertial sensors: A systematic review.

Parkinson's disease (PD) is a progressive neurological disorder of the central nervous system that deteriorates motor functions, while it is also accompanied by a large diversity of non-motor symptoms such as cognitive impairment and mood changes, hallucinations, and sleep disturbance. Parkinsonism is evaluated during clinical examinations and appropriate medical treatments are directed towards alleviating symptoms. Tri-axial accelerometers, gyroscopes, and magnetometers could be adopted to support clinicians in the decision-making process by objectively quantifying the patient's condition. In this context, at-home data collections aim to capture motor function during daily living and unobstructedly assess the patients' status and the disease's symptoms for prolonged time periods. This review aims to collate existing literature on PD monitoring using inertial sensors while it focuses on papers with at least one free-living data capture unsupervised either directly or via videotapes. Twenty-four papers were selected at the end of the process: fourteen investigated gait impairments, eight of which focused on walking, three on turning, two on falls, and one on physical activity; ten articles on the other hand examined symptoms, including bradykinesia, tremor, dyskinesia, and motor state fluctuations in the on/off phenomenon. In summary, inertial sensors are capable of gathering data over a long period of time and have the potential to facilitate the monitoring of people with Parkinson's, providing relevant information about their motor status. Concerning gait impairments, kinematic parameters (such as duration of gait cycle, step length, and velocity) were typically used to discern PD from healthy subjects, whereas for symptoms' assessment, researchers were capable of achieving accuracies of over 90% in a free-living environment. Further investigations should be focused on the development of ad-hoc hardware and software capable of providing real-time feedback to clinicians and patients. In addition, features such as the wearability of the system and user comfort, set-up process, and instructions for use, need to be strongly considered in the development of wearable sensors for PD monitoring.

Modulation of beta bursts in subthalamic sensorimotor circuits predicts improvement in bradykinesia.

No biomarker of Parkinson's disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson's disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson's disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson's disease.

Objective measurement of limb bradykinesia using a marker-less tracking algorithm with 2D-video in PD patients.

BACKGROUND: Quantitative measurement of parkinsonian motor symptoms is crucial in clinical practice and in research. However, the widely used Unified PD Rating Scale (UPDRS) part III is based on a semi-quantitative evaluation with high inter- and intra-rater variability. Sensor-based measurements have been widely studied but are limited for their accessibility. METHODS: We analyzed 2D-RGB videos recording finger tapping and leg agility tests in 29 PD patients with a marker-less deep-learning based tracking algorithm. The tracking performance was validated with an accelerometer. Four parameters (mean amplitude, mean interpeak interval, amplitude variability and interpeak interval variability) were calculated from the position tracking. RESULTS: The performance of the video-tracking was in good agreement with the accelerometer-based tracking (Intra-class correlation coefficient > 0.9 for the peak amplitude, and >0.6 for the interpeak interval). The video-tracking successfully captured variable aspects of limb bradykinesia that have a distinct correlation with the general parkinsonian motor symptoms and gait. In the finger-tapping task, the mean amplitude (R = -0.6, p = 2.4 × 10-6), amplitude variability (R = 0.36, p = 0.0092), mean interpeak interval (R = 0.34, p = 0.014), and interpeak interval variability (R = 0.66, p = 1.4 × 10-7) was significantly correlated with the UPDRS scores. In leg agility test, the mean amplitude (R = -0.58, p = 1.7 × 10-5), mean interpeak interval (R = 0.37, p = 0.0088) and interpeak interval variability (R = 0.7, p = 6.2 × 10-8) were significantly correlated with the UPDRS scores, but not with amplitude variability (R = 0.17, p = 0.26). Limb rigidity was significantly correlated with the interpeak interval (R = 0.40, p = 0.0036) and its variability (R = 0.59, p = 4.2 × 10-6) in the leg agility test. CONCLUSION: The video-based tracking could objectively measure limb bradykinesia in PD patients.

Changes in Total Cholesterol and Heart Rate in Normotensive and Hypertensive Rats under Combined Influence of Cold Exposure and Hypokinesia.

We studied the effect of hypokinesia alone and in combination with cold exposure on HR and total cholesterol content in the blood serum of Wistar, WKY, and SHR rats. Irrespectively of the season, hypokinesia was associated with a decrease in HR, which is probably a result of reduced body needs due to deceleration of metabolic processes. A significant increase in total cholesterol was found under conditions of cold exposure combined with hypokinesia, which indicates qualitative structural rearrangement of energy metabolism under the influence of environmental factors. In winter, the increase in total cholesterol concentration was more pronounced (by 51.5%) in the group of hypertensive animals. Presumably, the increase in the serum concentration of total cholesterol under conditions of hypokinesia and cold exposure is a predictor of structural changes in the heart.

The evolution of parkinsonism in primary progressive apraxia of speech: A 6-year longitudinal study.

INTRODUCTION: Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome in which patients present with an isolated motor speech disorder. Some PPAOS patients develop parkinsonism and other features of progressive supranuclear palsy (PSP) and/or corticobasal syndrome (CBS) over time. We aimed to assess the evolution of parkinsonian characteristics in PPAOS patients who had been followed yearly for at least six years. METHODS: From a large cohort of 46 PPAOS patients, eight were followed yearly for > 6-years in multiple NIH-funded grants. Parkinsonian and other features, including bradykinesia, tremor, rigidity, postural instability, apraxia, ocular motor function and cognition were assessed at each visit, and research criteria applied for PSP and CBS diagnosis. Neurological, speech-language test scores, and [18F]fluorodeoxyglucose PET (FDG-PET) and MRI midbrain volumes were assessed. RESULTS: A Parkinson's plus syndrome developed in all eight patients (100%). Bradykinesia was the earliest feature, followed by rigidity and postural instability. Tremor was not a significant feature. Parkinsonism, limb apraxia and ocular motor impairment tended to develop four-to-five years after onset with some patients having slight asymmetric parkinsonism. Six patients (75%) met research criteria for probable PSP, although only one for PSP-Richardson's syndrome; three patients met criteria for possible CBS. Slightly asymmetric, left-sided, hypometabolism was observed on FDG-PET, not matching asymmetry of Parkinsonism. Midbrain hypometabolism was absent-minimal. Three patients had progressive midbrain volumes in the PSP-Richardson's syndrome range. CONCLUSIONS: A Parkinson's plus syndrome may inevitably develop in PPAOS supporting PPAOS as an early presentation of a Parkinson's plus disorder.

Localization of motor and verbal fluency effects in subthalamic DBS for Parkinson's disease.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN DBS) improves cardinal motor symptoms of Parkinson's disease (PD) but can worsen verbal fluency (VF). An optimal site of stimulation for overall motor improvement has been previously identified using an atlas-independent, fully individualized, field-modeling approach. This study examines if cardinal motor components (bradykinesia, tremor, and rigidity) share this identified optimal improvement site and if there is co-localization with a site that worsens VF. METHODS: An atlas-independent, field-modeling approach was used to identify sites of maximal STN DBS effect on overall and cardinal motor symptoms and VF in 60 patients. Anatomic coordinates were referenced to the STN midpoint. Symptom severity was assessed with the MDS-UPDRS part III and established VF scales. RESULTS: Sites for improved bradykinesia and rigidity co-localized with each other and the overall part III site (0.09 mm lateral, 0.93 mm posterior, 1.75 mm dorsal). The optimal site for tremor was posterior to this site (0.10 mm lateral, 1.40 mm posterior, 1.93 mm dorsal). Semantic and phonemic VF sites were indistinguishable and co-localized medial to the motor sites (0.32 mm medial, 1.18 mm posterior, 1.74 mm dorsal). CONCLUSION: This study identifies statistically distinct, maximally effective stimulation sites for tremor improvement, VF worsening, and overall and other cardinal motor improvements in STN DBS. Current electrode sizes and voltage settings stimulate all of these sites simultaneously. However, future targeted lead placement and focused directional stimulation may avoid VF worsening while maintaining motor improvements in STN DBS.

Effect of Anti-Glutamate Antibodies in Modeled Parkinsonian Syndrome.

We studied the effect of single and repeated intranasal administration of antibodies to glutamate in experimental parkinsonian syndrome induced by injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6J mice. Intranasal administration of anti-glutamate antibodies to mice in parallel with administration of MPTP over 10 days alleviated parkinsonian symptoms (oligokinesia and rigidity). In the serum of mice injected with antibodies to glutamate and/or MPTP, the titers of autoantibodies to glutamate and dopamine were higher than in control animals receiving saline. Single intranasal administration of anti-glutamate antibodies to mice with established parkinsonian syndrome did not affect the severity of parkinsonian symptoms.

Acute effects of adaptive Deep Brain Stimulation in Parkinson's disease.

BACKGROUND: Beta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson's disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed. METHODS: To determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson's Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT). RESULTS: Mean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p = .001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p = .002), and did not achieve significance during cDBS (p = .08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p = .009), but not in aDBS (p = .407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS. CONCLUSION: Beta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy.

Dopamine-responsive and dopamine-resistant resting tremor in Parkinson disease.

OBJECTIVE: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. METHODS: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected "off" and "on" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. RESULTS: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. CONCLUSION: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach.

The Clinical Features and Progression of Late-Onset Versus Younger-Onset in an Adult Cohort of Huntington's Disease Patients.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that typically manifests between the ages of 30 and 50 years. However, the disease can present at any age, and phenotypic differences between younger and later-onset patients have received limited attention. OBJECTIVE: To compare clinical features of late- (>70 years of age) and younger-onset (<30 years of age) HD patients. METHODS: Patients presenting to our regional NHS HD clinic with new-onset manifest HD diagnosed over the age of 70 years (LoHD) (n = 18) were compared with a younger cohort who developed disease under the age of 30 years (YoHD) (n = 12). Rate of progression over time on standard cognitive and motor measures was compared. RESULTS: At first clinic presentation, both groups had the same total UHDRS scores. However, the LoHD group had higher chorea scores (F (1,28) = 6.52, p = 0.016), while the YoHD group had more dystonia (F (1,28) = 8.69, p = 0.006) and eye movement abnormalities (F (1,28) = 16.991, p < 0.001). The YoHD group also had a greater rate of motor progression, especially for bulbar measures (F (1, 28) = 6.96, p = 0.013) and bradykinesia (F (1, 28) = 7.99, p = 0.009). No differences were found in the rate of cognitive change (F (1,21) = 1.727, p = 0.203) nor functional capacity (F (1,28) = 1.388, p = 0.249) between the groups. CONCLUSION: Phenotypic differences between YoHD and LoHD patients were found in terms of initial presentation and rate of motor progression. This has implications for therapeutic trials involving HD patients of different ages, given their different clinical features and progression.