Vertical locomotion improves horizontal locomotion: effects of climbing on gait and other mobility aspects in Parkinson's disease. A secondary analysis from a randomized controlled trial.

BACKGROUND: In the Climb Up! Head Up! trial, we showed that sport climbing reduces bradykinesia, tremor, and rigidity in mildly to moderately affected participants with Parkinson's disease. This secondary analysis aimed to evaluate the effects of sport climbing on gait and functional mobility in this cohort. METHODS: Climb Up! Head Up! was a 1:1 randomized controlled trial. Forty-eight PD participants (Hoehn and Yahr stage 2-3) either participated in a 12-week, 90-min-per-week sport climbing course (intervention group) or were engaged in regular unsupervised physical activity (control group). Relevant outcome measures for this analysis were extracted from six inertial measurement units placed on the extremities, chest, and lower back, that were worn during supervised gait and functional mobility assessments before and after the intervention. Assessments included normal and fast walking, dual-tasking walking, Timed Up and Go test, Instrumented Stand and Walk test, and Five Times Sit to Stand test. RESULTS: Compared to baseline, climbing improved gait speed during normal walking by 0.09 m/s (p = 0.005) and during fast walking by 0.1 m/s. Climbing also reduced the time spent in the stance phase during fast walking by 0.03 s. Climbing improved the walking speed in the 7-m- Timed Up and Go test by 0.1 m/s (p < 0.001) and the turning speed by 0.39 s (p = 0.052), the speed in the Instrumented Stand and Walk test by 0.1 m/s (p < 0.001), and the speed in the Five Times Sit to Stand test by 2.5 s (p = 0.014). There was no effect of sport climbing on gait speed or gait variables during dual-task walking. CONCLUSIONS: Sport climbing improves gait speed during normal and fast walking, as well as functional mobility in people with Parkinson's disease. Trial registration This study was registered within the U.S. National Library of Medicine (No: NCT04569981, date of registration September 30th, 2020).

Climb up! Head up! Climbing improves posture in Parkinson's disease. A secondary analysis from a randomized controlled trial.

OBJECTIVE: To investigate the effect of sport climbing on a biomechanical marker of axial posture in patients with Parkinson's disease, as well as its association with age, body mass index and health-related quality-of-life outcome measures. DESIGN: Pre-planned secondary analysis of our randomized controlled, semi-blind trial (unblinded patients, blinded assessors) comparing sport climbing to unsupervised exercise. SETTING: Single-centre study conducted at the Department of Neurology of the Medical University of Vienna, Austria. PARTICIPANTS: Forty-eight Parkinson's disease patients (aged 64 ± 8 years, Hoehn & Yahr stage 2-3) were included. INTERVENTION: Sport climbers (n = 24) followed a 12-week, 90 min/week supervised top-rope sport climbing course in an indoor climbing gym. The unsupervised training group (n = 24) independently followed the 'European Physiotherapy Guidelines for Parkinson's Disease' and World Health Organization recommendations for an active lifestyle for 12 weeks. MAIN MEASURES: Posture was assessed with the horizontal distance of the seventh cervical vertebra to the wall at baseline and after the intervention. RESULTS: Participating in the sport climbing group significantly predicted the biomechanical marker of axial posture (P = 0.044). The improvement in the biomechanical marker did not affect the quality of life, depression, fatigue, physical activity or fear of falling. Participants in the sport climbing group showed a significantly decreased horizontal distance of the seventh cervical vertebra to the wall after the intervention (-1.7 cm (95%CI [-2.6, -0.8]). In the unsupervised training group, no difference was found (-0.5 cm; 95%CI -1.3, 0.2]). CONCLUSIONS: We conclude that sport climbing improves a biomechanical marker of axial posture in Parkinson's disease.

Additive Effect of Dopaminergic Medication on Gait Under Single and Dual-Tasking Is Greater Than of Deep Brain Stimulation in Advanced Parkinson Disease With Long-Duration Deep Brain Stimulation.

INTRODUCTION: Patients with advanced Parkinson disease (PD) often experience problems with mobility, including walking under single- (ST) and dual-tasking (DT) conditions. The effects of deep brain stimulation in the subthalamic nucleus (DBS) versus dopaminergic medication (Med) on these conditions are not well investigated. MATERIALS AND METHODS: We used two ST and two DT-gait paradigms to evaluate the effect of DBS and dopaminergic medication on gait parameters in 14 PD patients (mean age 66 ± 8 years) under DBSOFF/MedON, DBSON/MedOFF, and DBSON/MedON conditions. They performed standardized 20-meter walks with convenient and fast speed. To test DT capabilities, they performed a checking-boxes and a subtraction task during fast-paced walking. Quantitative gait analysis was performed using a tri-axial accelerometer (Dynaport, McRoberts, The Netherlands). Dual-task costs (DTC) of gait parameters and secondary task performance were compared intraindividually between DBSOFF/MedON vs DBSON/MedON, and DBSON/MedOFF vs DBSON/MedON to estimate responsiveness. RESULTS: Dopaminergic medication increased gait speed and cadence at convenient speed. It increased cadence and decreased number of steps at fast speed, and improved DTC of cadence during the checking boxes and DTC of cadence and number of steps during the subtraction tasks. DBS only improved DTC of cadence during the checking boxes and DTC of gait speed during the subtraction task. CONCLUSION: Dopaminergic medication showed larger additional effects on temporal gait parameters under ST and DT conditions in advanced PD than DBS. These results, after confirmation in independent studies, should be considered in the medical management of advanced PD patients with gait and DT deficits.

Effects of dopamine on reinforcement learning in Parkinson's disease depend on motor phenotype.

Parkinson's disease is clinically defined by bradykinesia, along with rigidity and tremor. However, the severity of these motor signs is greatly variable between individuals, particularly the presence or absence of tremor. This variability in tremor relates to variation in cognitive/motivational impairment, as well as the spatial distribution of neurodegeneration in the midbrain and dopamine depletion in the striatum. Here we ask whether interindividual heterogeneity in tremor symptoms could account for the puzzlingly large variability in the effects of dopaminergic medication on reinforcement learning, a fundamental cognitive function known to rely on dopamine. Given that tremor-dominant and non-tremor Parkinson's disease patients have different dopaminergic phenotypes, we hypothesized that effects of dopaminergic medication on reinforcement learning differ between tremor-dominant and non-tremor patients. Forty-three tremor-dominant and 20 non-tremor patients with Parkinson's disease were recruited to be tested both OFF and ON dopaminergic medication (200/50 mg levodopa-benserazide), while 22 age-matched control subjects were recruited to be tested twice OFF medication. Participants performed a reinforcement learning task designed to dissociate effects on learning rate from effects on motivational choice (i.e. the tendency to 'Go/NoGo' in the face of reward/threat of punishment). In non-tremor patients, dopaminergic medication improved reward-based choice, replicating previous studies. In contrast, in tremor-dominant patients, dopaminergic medication improved learning from punishment. Formal modelling showed divergent computational effects of dopaminergic medication as a function of Parkinson's disease motor phenotype, with a modulation of motivational choice bias and learning rate in non-tremor and tremor patients, respectively. This finding establishes a novel cognitive/motivational difference between tremor and non-tremor Parkinson's disease patients, and highlights the importance of considering motor phenotype in future work.

Cognitive load amplifies Parkinson's tremor through excitatory network influences onto the thalamus.

Parkinson's tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson's disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson's patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson's tremor.

GABAergic changes in the thalamocortical circuit in Parkinson's disease.

Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma-aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine-dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine-resistant tremor (n = 17), dopamine-responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA-to-total-creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression.

Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson's tremor.

Rest tremor in Parkinson's disease is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. Clinically, there is strong interindividual variation in the therapeutic response of tremor to dopaminergic medication. This observation casts doubt on the idea that Parkinson's tremor has a dopaminergic basis. An interesting alternative explanation is that interindividual differences in the pathophysiology of tremor may underlie this clinical heterogeneity. Previous work showed that dopaminergic medication reduces Parkinson's tremor by inhibiting tremulous activity in the pallidum and thalamus, and this may explain why some tremors are dopamine-responsive. Here we test the hypothesis that dopamine-resistant resting tremor may be explained by increased contributions of non-dopaminergic brain regions, such as the cerebellum. To test this hypothesis, we first performed a levodopa challenge test in 83 tremulous Parkinson's disease patients, and selected 20 patients with a markedly dopamine-responsive tremor (71% reduction) and 14 patients with a markedly dopamine-resistant tremor (6% reduction). The dopamine response of other core motor symptoms was matched between groups. Next, in all 34 patients, we used combined EMG-functional MRI to quantify tremor-related brain activity during two separate sessions (crossover, double-blind, counterbalanced design): after placebo, or after 200/50 mg dispersible levodopa/benserazide. We compared tremor-related brain activity between groups and medication sessions. Both groups showed tremor amplitude-related brain activity in a cerebello-thalamo-cortical circuit. Dopamine-resistant tremor patients showed increased tremor-related activity in non-dopaminergic areas (cerebellum), whereas the dopamine-responsive group showed increased tremor-related activity in the thalamus and secondary somatosensory cortex (across medication sessions). Levodopa inhibited tremor-related thalamic responses in both groups, but this effect was significantly greater in dopamine-responsive patients. These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine.

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Seasonality of benign paroxysmal positional vertigo : A retrospective study from Central Europe.

BACKGROUND: Although benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in clinical practice, factors influencing the pathophysiology remain not fully understood. OBJECTIVE: Here we aim to investigate possible seasonal influences on the occurrence of BPPV in Vienna, a city located in a Central European country with pronounced seasonal fluctuations. METHODS: We retrospectively investigated data from 503 patients presenting with BPPV to the outpatient clinics of the Medical University of Vienna between 2007 and 2012. Analyses included age, gender, type of BPPV, seasonal assignment, as well as daylight hours and the temperature in Vienna at symptom onset. RESULTS: Out of 503 patients (159 male, 344 female, ratio 1:2.2; mean age 60 ± 15.80 years), most patients presented with posterior (89.7%) and left-sided (43.1%) BPPV. There was a significant seasonal difference (χ2 p = 0.036) with the majority of symptoms occurring in winter seasons (n = 142), followed by springtime (n = 139). Symptom onset did not correlate with the average temperature (p = 0.24) but on the other hand very well with daylight hours (p < 0.05), which ranged from 8.4 h per day in December, to an average of 15.6 h in July. CONCLUSION: Our results show a seasonal accumulation of BPPV during winter and springtime, which is in line with previous studies from other climatic zones, suggesting an association of this seasonality with varying vitamin D levels.

Therapeutic climbing in Parkinson's disease: Differences in self-reported health and well-being, feasibility and clinical changes.

BACKGROUND: Therapeutic climbing (TC) is a whole-body workout that stimulates and improves physical and psychosocial abilities. It has been used in neurological rehabilitation, but there is scarce evidence of specific benefits for people with Parkinson's (PwP). OBJECTIVE: To investigate and evaluate self-reported differences in health and well-being among trial participants, the overall feasibility of TC and clinical changes caused as a rehabilitation measure for PwP. METHODS: A 3-level Likert scale survey was completed by 26 PwP (100% response rate) after a TC course (mean 16 sessions) at the Neurological Rehabilitation Center assessing self-perceived differences in health and well-being in terms of physical, psychological, and social parameters. We investigated the feasibility of TC in terms of adherence, practicability and acceptability during a multidisciplinary inpatient rehabilitation program and determined several clinical outcomes (10-meter distance and 2-minute duration walking tests, Functional Gait Assessment, Nine-Hole-Peg tests, and Tinetti Assessment Tool). RESULTS: Improvements are based on self-reported perceptions of PwP. We observed an improvement of overall physical (average 65%), psychological (average 59%) and social (average 39%) aspects after TC. PwP improved strength (96%), balance (88%), range of motion (88%), body awareness (85%), physical well-being (77%), and fatigue (75%). Furthermore, they self-reported admiration in their social surrounding (42%) and felt more sociable and outgoing (40%). Concerning adherence, practicability and acceptability, TC seems to be feasible for PwP. Treatment adherence was 100%, 70% declared motivation to continue TC, and 96% intended to recommend TC to peers. Furthermore, PwP showed statistically significant improvements in 10-meter walking tests (T0: 7.5 (1.1-13.9), T1: 6.5 (0.1-12.9); p < .01; n = 16), 2-minute walking tests (T0: 149.5 (-111.0-410.0), T1: 177.0 (-140.7-494.7); p < .01; n = 19), Functional Gait Assessment (T0: 26.0 (-24.8-76.8), T1: 28.0 (2.6-53.4); p < .01; n = 15), and Nine-Hole-Peg tests (left: T0: 26.5 (24.3-28.7), T1: 24.1 (22.0-26.3); p < .01; n = 15; right: T0: 26.7 (24.1-29.2), T1: 23.3 (20.8-25.7); p < .01; n = 15). CONCLUSION: The preliminary findings suggest that TC offers an effective and feasible training method that may positively affect PwP overall perceptions of physical and psychosocial health status. The methodological limitations and small sample size limit the study's interpretability. More research is needed to definitely show the scientifically significant benefits of TC to PwP.

The therapeutic effects of climbing: A systematic review and meta-analysis.

OBJECTIVE: Several recent studies show a growing popularity of therapeutic climbing (TC) for patients with various conditions. This could be an attempt to fill the gap left by traditional exercises that do not always address physical, mental, and social well-being. This review provides an overview of the physical, mental, and social effects and safety aspects of climbing for different indications. LITERATURE SURVEY: A literature search was conducted on July 8, 2020 (update search August 26, 2021). We searched MEDLINE via Ovid, Embase, and PubMed and bibliographies of included studies, and we conducted a manual search. METHODOLOGY: Two independent reviewers evaluated the quality of the studies using appropriate Risk of Bias (RoB) tools, and the level of evidence for each domain was graded. Study characteristics and effectiveness data for TC were extracted and synthesized. Meta-analyses were conducted for the three dimensions (physical/mental/social health), using a random-effects model. SYNTHESIS: A total of 112 publications were reviewed, and 22 full-text articles were assessed regarding the eligibility criteria, of which 18 trials involving 568 patients were included. TC is safe and positively affects physical (e.g., fitness, motor control, movement velocity, dexterity, strength), mental (e.g., depressiveness, somatisation, psychoticism, emotion regulation, body perception, self-esteem, fatigue), and social (e.g., social functioning, trust, communication, sense of responsibility) health for individuals with neurological, orthopedic, psychiatric, and pediatric ailments. The meta-analysis showed a statistically significant improvement in the physical dimension favoring the climbing group. Improvements that were not statistically significant were found for the mental/social dimensions in the climbing group. The heterogeneity of data was moderate/high (social/mental dimension), and for the physical dimension, data were homogenous. CONCLUSIONS: The studies investigating TC outline its positive effects in various patient groups. TC is a safe and effective treatment for improving physical/mental/social well-being. This review is based on the best available evidence; however, significant gaps remain in providing sufficiently strong evidence.

How COVID-19 will boost remote exercise-based treatment in Parkinson's disease: a narrative review.

The lack of physical exercise during the COVID-19 pandemic-related quarantine measures is challenging, especially for patients with Parkinson's disease (PD). Without regular exercise not only patients, but also nursing staff and physicians soon noticed a deterioration of motor and non-motor symptoms. Reduced functional mobility, increased falls, increased frailty, and decreased quality of life were identified as consequences of increased sedentary behavior. This work overviews the current literature on problems of supplying conventional physiotherapy and the potential of telerehabilitation, allied health services, and patient-initiated exercise for PD patients during the COVID-19 period. We discuss recent studies on approaches that can improve remote provision of exercise to patients, including telerehabilitation, motivational tools, apps, exergaming, and virtual reality (VR) exercise. Additionally, we provide a case report about a 69-year-old PD patient who took part in a 12-week guided climbing course for PD patients prior to the pandemic and found a solution to continue her climbing training independently with an outdoor rope ladder. This case can serve as a best practice example for non-instructed, creative, and patient-initiated exercise in the domestic environment in difficult times, as are the current. Overall, many recent studies on telemedicine, telerehabilitation, and patient-initiated exercises have been published, giving rise to optimism that facilitating remote exercise can help PD patients maintain physical mobility and emotional well-being, even in phases such as the COVID-19 pandemic. The pandemic itself may even boost the need to establish comprehensive and easy-to-do telerehabilitation programs.

A randomised controlled trial on effectiveness and feasibility of sport climbing in Parkinson's disease.

Physical activity is of prime importance in non-pharmacological Parkinson's disease (PD) treatment. The current study examines the effectiveness and feasibility of sport climbing in PD patients in a single-centre, randomised controlled, semi-blind trial. A total of 48 PD patients without experience in climbing (average age 64 ± 8 years, Hoehn & Yahr stage 2-3) were assigned either to participate in a 12-week sport climbing course (SC) or to attend an unsupervised physical training group (UT). The primary outcome was the improvement of symptoms on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III). Sport climbing was associated with a significant reduction of the MDS-UPDRS-III (-12.9 points; 95% CI -15.9 to -9.8), while no significant improvement was to be found in the UT (-3.0 points; 95% CI -6.0 to 0.1). Bradykinesia, rigidity and tremor subscales significantly improved in SC, but not in the unsupervised control group. In terms of feasibility, the study showed a 99% adherence of participants to climbing sessions and a drop-out rate of only 8%. No adverse events occurred. This trial provides class III evidence that sport climbing is highly effective and feasible in mildly to moderately affected PD patients.

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.

Serum neurofilament light chain withstands delayed freezing and repeated thawing.

Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24 h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24 h (mean absolute difference 0.2 pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7 pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4-8 °C when samples are frozen within 24 h and single aliquots can be used up to three times. These observations should be considered for planning future studies.

The nature of postural tremor in Parkinson disease.

OBJECTIVE: To disentangle the different forms of postural tremors in Parkinson disease (PD). METHODS: In this combined observational and intervention study, we measured resting and postural tremor characteristics in 73 patients with tremulous PD by using EMG of forearm muscles. Patients were measured both "off" medication (overnight withdrawal) and after dispersible levodopa-benserazide 200/50 mg. We performed an automated 2-step cluster analysis on 3 postural tremor characteristics: the frequency difference with resting tremor, the degree of tremor suppression after posturing, and the dopamine response. RESULTS: The cluster analysis revealed 2 distinct postural tremor phenotypes: 81% had re-emergent tremor (amplitude suppression, frequency difference with resting tremor 0.4 Hz, clear dopamine response) and 19% had pure postural tremor (no amplitude suppression, frequency difference with resting tremor 3.5 Hz, no dopamine response). This finding was manually validated (accuracy of 93%). Pure postural tremor was not associated with clinical signs of essential tremor or dystonia, and it was not influenced by weighing. CONCLUSION: There are 2 distinct postural tremor phenotypes in PD, which have a different pathophysiology and require different treatment. Re-emergent tremor is a continuation of resting tremor during stable posturing, and it has a dopaminergic basis. Pure postural tremor is a less common type of tremor that is inherent to PD, but has a largely nondopaminergic basis.

The patient's perspective: The effect of levodopa on Parkinson symptoms.

BACKGROUND: Dopaminergic medication adjustments in Parkinson's disease are often solely based on patient reports. However, it is unclear how well patient-based ratings of the levodopa response correlate with clinician-based ratings, and whether this correlation differs between motor symptoms. Here we compare patient-clinician agreement for the effect of levodopa on resting tremor and bradykinesia/rigidity. Furthermore, given patients' reports that tremor is most troublesome during stress, we test for differences in patient-clinician agreement between tremor at rest and stress-induced tremor. METHODS: We included 42 tremulous Parkinson patients, who were clinically rated (using the MDS-UPDRS) in a practically defined OFF-state and after levodopa-benserazide 200/50 mg. Using accelerometry, we quantified the effect of dopaminergic medication and behavioral context (rest vs. cognitive stress) on tremor intensity. Patients rated medication effects on tremor and bradykinesia/rigidity using visual analogue scales. RESULTS: There was only moderate patient-clinician agreement for the effect of levodopa on bradykinesia/rigidity (R2 = 0.18; p < 0.01), and a tendency towards larger agreement for tremor (R2 = 0.44; p < 0.001; difference between correlation coefficients: z = 1.64; p = 0.051). Patient ratings of tremor changes correlated significantly better with accelerometry for tremor during cognitive stress (R2 = 0.35; p < 0.001) vs. tremor at rest (R2 = 0.12; p < 0.05; difference: z = -2.35, p < 0.01). CONCLUSION: The moderate correlations between patient ratings and clinical/accelerometry changes indicate the need for methods to better monitor symptom severity and impairments in daily life, for example wearable sensors. Our findings also suggest that context matters: Parkinson patients' subjective experience of levodopa effectiveness on tremor was largely based on the ability of levodopa to reduce tremor during cognitive stress.

Cognitive Stress Reduces the Effect of Levodopa on Parkinson's Resting Tremor.

AIMS: Resting tremor in Parkinson's disease (PD) increases markedly during cognitive stress. Dopamine depletion in the basal ganglia is involved in the pathophysiology of resting tremor, but it is unclear whether this contribution is altered under cognitive stress. We test the hypothesis that cognitive stress modulates the levodopa effect on resting tremor. METHODS: Tremulous PD patients (n = 69) were measured in two treatment conditions (OFF vs. ON levodopa) and in two behavioral contexts (rest vs. cognitive co-activation). Using accelerometry, we tested the effect of both interventions on tremor intensity and tremor variability. RESULTS: Levodopa significantly reduced tremor intensity (across behavioral contexts), while cognitive co-activation increased it (across treatment conditions). Crucially, the levodopa effect was significantly smaller during cognitive co-activation than during rest. Resting tremor variability increased after levodopa and decreased during cognitive co-activation. CONCLUSION: Cognitive stress reduces the levodopa effect on Parkinson's tremor. This effect may be explained by a stress-related depletion of dopamine in the basal ganglia motor circuit, by stress-related involvement of nondopaminergic mechanisms in tremor (e.g., noradrenaline), or both. Targeting these mechanisms may open new windows for treatment. Clinical tremor assessments under evoked cognitive stress (e.g., counting tasks) may avoid overestimation of treatment effects in real life.

The Clinical Evaluation of Parkinson's Tremor.

Parkinson's disease harbours many different tremors that differ in distribution, frequency, and context in which they occur. A good clinical tremor assessment is important for weighing up possible differential diagnoses of Parkinson's disease, but also to measure the severity of the tremor as a basis for further tailored treatment. This can be challenging, because Parkinson's tremor amplitude is typically very variable and context-dependent. Here, we outline how we investigate Parkinson's tremor in the clinic. We describe a simple set of clinical tasks that can be used to constrain tremor variability (cognitive and motor co-activation, several specific limb postures). This may help to adequately characterize the tremor(s) occurring in a patient with Parkinson's disease.