The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Tekin I
PROVIDER: S-EPMC4770791 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
Publications
The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease.
Tekin Izel I Carkaci-Salli Nurgul N Lewis Mechelle M MM Mailman Richard B RB Huang Xuemei X Vrana Kent E KE
Parkinsonism & related disorders 20151223
<h4>Introduction</h4>Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis.<h4>Methods</h4>We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme.<h4>Results</h4>PD subjects homozygous for the common V ...[more]
Similar Datasets
Project description:This study investigated the turning characteristics of the more-affected limbs in Parkinson's disease (PD) patients in comparison with that of a control group, and in PD patients with freezing of gait (FOG; freezers) in comparison with those without FOG (non-freezers) for 360° and 540° turning tasks at the maximum speed. A total of 12 freezers, 12 non-freezers, and 12 controls participated in this study. The PD patients showed significantly longer total durations, shorter inner and outer step lengths, and greater anterior-posterior (AP) root mean square (RMS) center of mass (COM) distances compared to those for the controls. The freezers showed significantly greater AP and medial-lateral (ML) RMS COM distances compared to those of non-freezers. The turning task toward the inner step of the more-affected side (IMA) in PD patients showed significantly greater step width, total steps, and AP and ML RMS COM distances than that toward the outer step of the more-affected side (OMA). The corresponding results for freezers revealed significantly higher total steps and shorter inner step length during the 540° turn toward the IMA than that toward the OMA. Therefore, PD patients and freezers exhibited greater turning difficulty in performing challenging turning tasks such as turning with an increased angle and speed and toward the more-affected side.
| S-EPMC7309092 | biostudies-literature
Project description:BackgroundThe relationship between freezing of gait (FOG) and levodopa response is complex. Some patients respond, some have no response and in some patients levodopa causes FOG. We present 2 cases demonstrating a diphasic worsening of FOG after levodopa dosing.CasesTwo PD patients with FOG were examined during the practically defined off state, the transition from off to on (15 and 22 minutes postdose), and in the full on state (45 and 60 minutes postdose). FOG was measured using Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, item 11: freezing of gait. Both patients experienced worsening of FOG during the transition followed by improvement during the on state. Case 1 had serum levodopa levels measured. Videos are provided.ConclusionsTo our knowledge, this diphasic pattern of worsening of FOG has not been previously reported. The cause of this phenomenon is unknown but may relate to an inhibitory action of subthreshold levels of levodopa.
| S-EPMC7111566 | biostudies-literature
Project description:Freezing of gait (FOG) is arguably the most severe symptom associated with Parkinson's disease (PD), and often occurs while performing dual tasks or approaching narrowed and cluttered spaces. While it is well known that visual cues alleviate FOG, it is not clear if this effect may be the result of cognitive or sensorimotor mechanisms. Nevertheless, the role of vision may be a critical link that might allow us to disentangle this question. Gaze behaviour has yet to be carefully investigated while freezers approach narrow spaces, thus the overall objective of this study was to explore the interaction between cognitive and sensory-perceptual influences on FOG. In experiment #1, if cognitive load is the underlying factor leading to FOG, then one might expect that a dual-task would elicit FOG episodes even in the presence of visual cues, since the load on attention would interfere with utilization of visual cues. Alternatively, if visual cues alleviate gait despite performance of a dual-task, then it may be more probable that sensory mechanisms are at play. In compliment to this, the aim of experiment#2 was to further challenge the sensory systems, by removing vision of the lower-limbs and thereby forcing participants to rely on other forms of sensory feedback rather than vision while walking toward the narrow space. Spatiotemporal aspects of gait, percentage of gaze fixation frequency and duration, as well as skin conductance levels were measured in freezers and non-freezers across both experiments. Results from experiment#1 indicated that although freezers and non-freezers both walked with worse gait while performing the dual-task, in freezers, gait was relieved by visual cues regardless of whether the cognitive demands of the dual-task were present. At baseline and while dual-tasking, freezers demonstrated a gaze behaviour that neglected the doorway and instead focused primarily on the pathway, a strategy that non-freezers adopted only when performing the dual-task. Interestingly, with the combination of visual cues and dual-task, freezers increased the frequency and duration of fixations toward the doorway, compared to non-freezers. These results suggest that although increasing demand on attention does significantly deteriorate gait in freezers, an increase in cognitive demand is not exclusively responsible for freezing (since visual cues were able to overcome any interference elicited by the dual-task). When vision of the lower limbs was removed in experiment#2, only the freezers' gait was affected. However, when visual cues were present, freezers' gait improved regardless of the dual-task. This gait behaviour was accompanied by greater amount of time spent looking at the visual cues irrespective of the dual-task. Since removing vision of the lower-limbs hindered gait even under low attentional demand, restricted sensory feedback may be an important factor to the mechanisms underlying FOG.
| S-EPMC4682987 | biostudies-literature
Project description:BACKGROUND:The etiology of freezing of gait in Parkinson's disease (PD) is yet to be clarified. Non-motor risk factors including cognitive impairment, sleep disturbance and mood disorders have been shown in freezing of gait. RESEARCH QUESTION:We aimed to determine the predictive value of non-motor features in freezing of gait development. METHODS:Data were obtained from the Parkinson's Progression Markers Initiative. Fifty PD patients with self-reported freezing of gait, and 50 PD patients without freezing of gait at the fourth year visit were included. Groups were matched for Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III scores. Several cognitive and non-cognitive tests were used for non-motor features at baseline and over time. Executive function, visuospatial function, processing speed, learning and memory tests were used for cognition. Non-cognitive tests included sleepiness, REM sleep behavior disorder, depression and anxiety scales. RESULTS:Patients with freezing of gait had higher scores on sleepiness, REM sleep behavior disorder, depression and anxiety scales. However, predictor model analysis revealed that baseline processing speed, learning and sleepiness scores were predictive of self-reported freezing of gait development over time. SIGNIFICANCE:Our findings suggest that specific cognitive deficits and sleep disorders are predictive of future freezing of gait. These features may be helpful in identifying underlying networks in freezing of gait and should be further investigated with neuroimaging studies.
| S-EPMC6773271 | biostudies-literature
Project description:IntroductionFreezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life.Materials and methodsClinical-anatomical correlations, electrophysiology, and functional imaging have generated several mechanistic hypotheses, ranging from the most distal (abnormal central pattern generators of the spinal cord) to the most proximal (frontal executive dysfunction). Here, we review the neuroanatomy and pathophysiology of gait initiation in the context of FoG, and we discuss targets of central nervous system neuromodulation and their outcomes so far. The PubMed database was searched using these key words: neuromodulation, freezing of gait, Parkinson's disease, and gait disorders.ConclusionDespite these investigations, the pathogenesis of this process remains poorly understood. The evidence presented in this review suggests FoG to be a heterogenous phenomenon without a single unifying pathologic target. Future studies rigorously assessing targets as well as multimodal approaches will be essential to define the next generation of therapeutic treatments.
| S-EPMC8233405 | biostudies-literature
Project description:BackgroundFreezing of gait is a debilitating symptom of Parkinson's disease associated with high risks of falls and poor quality of life. While productive therapy for FoG is still underway, early prediction of FoG could help high-risk PD patients to take preventive measures. In this study, we predicted the onset of FoG in de novo PD patients using a battery of risk factors from patients enrolled in PPMI cohort.MethodsBaseline characteristics were compared between subjects who developed FoG (68 patients, 37.2%, pre-FoG group) during the five-year follow up and subjects who did not (115 patients, 62.8%, non-FoG group). A multivariate logistic regression model was built based on backward stepwise selection of factors that were associated with FoG onset in the univariate analysis. ROC curves were used to assess sensitivity and specificity of the predictive model.ResultsAt baseline, age, PIGD score, cognitive functions, autonomic functions, sleep behavior, fatigue and striatal DAT uptake were significantly different in the pre-FoG group relative to the non-FoG group. However, there was no difference in genetic characteristics between the two patient sets. Univariate analysis showed several motor and non-motor factors that correlated with FoG, including PIGD score, MDS-UPDRS part II score, SDMT score, HVLT Immediate/Total Recall, MOCA, Epworth Sleepiness Scale, fatigue, SCOPA-AUT gastrointestinal score, SCOPA-AUT urinary score and CSF biomarker Abeta42. Multivariate logistic analysis stressed that high PIGD score, fatigue, worse SDMT performance and low levels of Abeta42 were independent risk factors for FoG onset in PD patients.ConclusionsCombining motor and non-motor features including PIGD score, poor cognitive functions and CSF Abeta can identify PD patients with high risk of FoG onset.
| S-EPMC9172010 | biostudies-literature
Project description:This study investigated longitudinal clinical, structural and functional brain alterations in Parkinson's disease patients with freezing of gait (PD-FoG) and in those developing (PD-FoG-converters) and not developing FoG (PD-non-converters) over two years. Moreover, this study explored if any clinical and/or MRI metric predicts FoG development. Thirty PD-FoG, 11 PD-FoG-converters and 11 PD-non-converters were followed for two years. Thirty healthy controls were included at baseline. Participants underwent clinical and MRI visits. Cortical thickness, basal ganglia volumes and functional network graph metrics were evaluated at baseline and over time. In PD groups, correlations between baseline MRI and clinical worsening were tested. A ROC curve analysis investigated if baseline clinical and MRI measures, selected using a stepwise model procedure, could differentiate PD-FoG-converters from PD-non-converters. At baseline, PD-FoG patients had widespread cortical/subcortical atrophy, while PD-FoG-converters and non-converters showed atrophy in sensorimotor areas and basal ganglia relative to controls. Over time, PD-non-converters accumulated cortical thinning of left temporal pole and pallidum without significant clinical changes. PD-FoG-converters showed worsening of disease severity, executive functions, and mood together with an accumulation of occipital atrophy, similarly to PD-FoG. At baseline, PD-FoG-converters relative to controls and PD-FoG showed higher global and parietal clustering coefficient and global local efficiency. Over time, PD-FoG-converters showed reduced parietal clustering coefficient and sensorimotor local efficiency, PD-non-converters showed increased sensorimotor path length, while PD-FoG patients showed stable graph metrics. Stepwise prediction model including dyskinesia, postural instability and gait disorders scores and parietal clustering coefficient was the best predictor of FoG conversion. Combining clinical and MRI data, ROC curves provided the highest classification power to predict the conversion (AUC = 0.95, 95%CI: 0.86-1). Structural MRI is a useful tool to monitor PD progression, while functional MRI together with clinical features may be helpful to identify FoG conversion early.
| S-EPMC9666554 | biostudies-literature
Project description:IntroductionParkinson's disease patients with freezing of gait also experience sudden motor blocks (freezing) during other repetitive motor tasks. We assessed the proportion of patients with advanced PD and freezing of gait who also displayed segmental "freezing" in tapping tasks.MethodsFifteen Parkinson's disease patients with freezing of gait were assessed. Freezing of gait was evaluated using a standardized gait trajectory with the usual triggers. Patients performed repetitive tapping movements (as described in the MDS-UPDRS task) with the hands or the feet in the presence or absence of a metronome set to 4 Hz. Movements were recorded with a video motion system. The primary endpoint was the occurrence of segmental freezing in these tapping tasks. The secondary endpoints were (i) the relationship between segmental episodic phenomena and FoG severity, and (ii) the reliability of the measurements.ResultsFor the upper limbs, freezing was observed more frequently with a metronome (21% of trials) than without a metronome (5%). For the lower limbs, the incidence of freezing was higher than for the upper limbs, and was again observed more frequently in the presence of an auditory cue (47%) than in its absence (14%).ConclusionAlthough freezing of the lower limbs was easily assessed during an MDS-UPDRS task with a metronome, it was not correlated with the severity of freezing of gait (as evaluated during a standardized gait trajectory). Only this latter was a reliable measurement in patients with advanced Parkinson's disease.
| S-EPMC5590736 | biostudies-literature
Project description:Freezing of gait is the most severe gait deficit associated with Parkinson's disease and significantly affects patients' independence and consequently their quality of life. The lack of a clear understanding of its underlying neurophysiological mechanism has resulted in limited effectiveness of the current treatment options. In this study, we investigated EEG features over (pre-)supplementary motor area and primary motor cortex during a simple cue-based ankle dorsiflexion movement. These features include movement-related cortical potentials (0.05-5 Hz) and brain oscillations (1-50 Hz). Electromyogram signal from the tibialis anterior muscle of the dominant foot was used to determine the movement onset. The EEG features before, during and following the onset of the movement were compared among three groups of participants: patients with freezing (N = 14, 11 males), patients without freezing (N = 14, 13 males) and healthy age-matched controls (N = 13, 10 males) with 15 recorded trials for each individual. Additionally, Parkinson's disease patients with freezing of gait were separated into mild (N = 7) and severe cases (N = 5), so that EEG features associated with freezing severity could be investigated. The results indicated significant differences between patients with severe freezing of gait compared to healthy controls and patients without freezing of gait. In addition, patients with mild and severe freezing represented cortical activity differences. For patients with freezing, the initial component of movement-related cortical potential is significantly lower than that of the healthy controls (P = 0.002) and is affected by the severity of freezing. Furthermore, a striking absence of beta frequency band (12-35 Hz) desynchronization was observed in patients with freezing, especially low-beta frequency band over Cz, before the movement, which was also associated with the severity of the freezing of gait. Low-beta (13-20 Hz) and high-beta (21-35 Hz) frequency band activities represented unique features for each group. Beta event-related desynchronization over Cz present in healthy controls prior to movement onset, was partially replaced by the theta band (4-8 Hz) synchrony in patients with freezing. Patients with severe freezing also represented some level of theta band synchronization over contralateral supplementary motor area. This suggests the involvement of cognitive processing over the motor cortex in controlling cue-based voluntary movement as a compensatory mechanism associated with freezing of gait. The EEG features identified in this study are indicative of important freezing of gait clinical characteristics such as severity and contribute to a better understanding of the underlying neurophysiology of the mysterious phenomenon of freezing of gait.
| S-EPMC8643573 | biostudies-literature
Project description:Background:Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD), but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers. The main focus of this review is to summarize the possible mechanisms underlying FOG, the risk factors for screening and predicting the onset of FOG, and the clinical trials involving various therapeutic strategies. In addition, the limitations and recommendations for future research design are also discussed. Main body:In the mechanism section, we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG. In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. In the treatment section, we summarized the clinical trials of pharmacological and non-pharmacological treatments. Despite the limited effectiveness of current medications for FOG, especially levodopa resistant FOG, there were some drugs that showed promise such as istradefylline and rasagiline. Non-pharmacological treatments encompass invasive brain and spinal cord stimulation, noninvasive repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS), and physiotherapeutic approaches including cues and other training strategies. Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), dual-site DBS, spinal cord stimulation (SCS) and VNS. Of physiotherapy, wearable cueing devices seem to be generally effective and promising. Conclusion:FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration. Several risk factors of FOG have been identified, but need combinatorial optimization for predicting FOG more precisely. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggested that some therapeutic strategies showed promise.
| S-EPMC7161193 | biostudies-literature