Mitochondrial matrix-localized Src kinase regulates mitochondrial morphology.

The architecture of mitochondria adapts to physiological contexts: while mitochondrial fragmentation is usually associated to quality control and cell death, mitochondrial elongation often enhances cell survival during stress. Understanding how these events are regulated is important to elucidate how mitochondrial dynamics control cell fate. Here, we show that the tyrosine kinase Src regulates mitochondrial morphology. Deletion of Src increased mitochondrial size and reduced cellular respiration independently of mitochondrial mass, mitochondrial membrane potential or ATP levels. Re-expression of Src targeted to the mitochondrial matrix, but not of Src targeted to the plasma membrane, rescued mitochondrial morphology in a kinase activity-dependent manner. These findings highlight a novel function for Src in the control of mitochondrial dynamics.

Effects of 2 Years of Exercise on Gait Impairment in People With Parkinson Disease: The PRET-PD Randomized Trial.

BACKGROUND AND PURPOSE: This study presents a secondary analysis from the Progressive Resistance Exercise Training in Parkinson Disease (PRET-PD) trial investigating the effects of progressive resistance exercise (PRE) and a Parkinson disease (PD)-specific multimodal exercise program, modified Fitness Counts (mFC), on spatial, temporal, and stability-related gait impairments in people with PD. METHODS: Forty-eight people with PD were randomized to participate in PRE or mFC 2 times a week for 24 months; 38 completed the study. Gait velocity, stride length, cadence, and double-support time were measured under 4 walking conditions (off-/on-medication, comfortable/fast speed). Ankle strength was also measured off- and on-medication. Twenty-four healthy controls provided comparison data at one time point. RESULTS: At 24 months, there were no significant differences between exercise groups. Both groups improved fast gait velocity off-medication, cadence in all conditions, and plantarflexion strength off-/on-medication. Both groups with PD had more gait measures that approximated the healthy controls at 24 months than at baseline. Plantarflexion strength was significantly associated with gait velocity and stride length in people with PD at baseline and 24 months, but changes in strength were not associated with changes in gait. DISCUSSION AND CONCLUSIONS: Twenty-four months of PRE and mFC were associated with improved off-medication fast gait velocity and improved cadence in all conditions, which is important because temporal gait measures can be resistant to medications. Spatial and stability-related measures were resistant to long-term improvements, but did not decline over 24 months. Strength gains did not appear to transfer to gait.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A161).

Factors Associated With Ambulatory Activity in De Novo Parkinson Disease.

BACKGROUND AND PURPOSE: Objective ambulatory activity during daily living has not been characterized for people with Parkinson disease prior to initiation of dopaminergic medication. Our goal was to characterize ambulatory activity based on average daily step count and examine determinants of step count in nonexercising people with de novo Parkinson disease. METHODS: We analyzed baseline data from a randomized controlled trial, which excluded people performing regular endurance exercise. Of 128 eligible participants (mean ± SD = 64.3 ± 8.6 years), 113 had complete accelerometer data, which were used to determine daily step count. Multiple linear regression was used to identify factors associated with average daily step count over 10 days. Candidate explanatory variable categories were (1) demographics/anthropometrics, (2) Parkinson disease characteristics, (3) motor symptom severity, (4) nonmotor and behavioral characteristics, (5) comorbidities, and (6) cardiorespiratory fitness. RESULTS: Average daily step count was 5362 ± 2890 steps per day. Five factors explained 24% of daily step count variability, with higher step count associated with higher cardiorespiratory fitness (10%), no fear/worry of falling (5%), lower motor severity examination score (4%), more recent time since Parkinson disease diagnosis (3%), and the presence of a cardiovascular condition (2%). DISCUSSION AND CONCLUSIONS: Daily step count in nonexercising people recruited for this intervention trial with de novo Parkinson disease approached sedentary lifestyle levels. Further study is warranted for elucidating factors explaining ambulatory activity, particularly cardiorespiratory fitness, and fear/worry of falling. Clinicians should consider the costs and benefits of exercise and activity behavior interventions immediately after diagnosis of Parkinson disease to attenuate the health consequences of low daily step count.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A170).

Progressive resistance exercise restores some properties of the triphasic EMG pattern and improves bradykinesia: the PRET-PD randomized clinical trial.

In Parkinson's disease (PD), the characteristic triphasic agonist and antagonist muscle activation pattern during ballistic movement is impaired: the number of agonist muscle bursts is increased, and the amplitudes of the agonist and antagonist bursts are reduced. The breakdown of the triphasic electromyographic (EMG) pattern has been hypothesized to underlie bradykinesia in PD. Progressive resistance exercise has been shown to improve clinical measures of bradykinesia, but it is not clear whether the benefits for bradykinesia are accompanied by changes in agonist and antagonist muscle activity. This study examined the spatiotemporal changes in agonist and antagonist muscle activity following 24 mo of progressive resistance exercise and the combined relationship between spatiotemporal muscle activity and strength measures and upper limb bradykinesia. We compared the effects of progressive resistance exercise training (PRET) with a nonprogressive exercise intervention, modified Fitness Counts (mFC), in patients with PD. We randomized 48 participants with mild-to-moderate PD to mFC or PRET. At the study endpoint of 24 mo, participants randomized to PRET compared with mFC had significantly faster movement velocity, accompanied by significant increases in the duration, magnitude, and magnitude normalized to duration of the 1st agonist burst and fewer number of agonist bursts before peak velocity. The antagonist muscle activity was increased relative to baseline but did not differ between groups. Spatiotemporal EMG muscle activity and muscle strength were significantly associated with upper limb bradykinesia. These findings demonstrate that progressive resistance exercise improves upper limb movement velocity and restores some aspects of the triphasic EMG pattern.

Exercise improves cognition in Parkinson's disease: The PRET-PD randomized, clinical trial.

BACKGROUND: This article reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes that were gathered as part of the Progressive Resistance Exercise Training in Parkinson's disease (PD) randomized, controlled trial. METHODS: This study was a prospective, parallel-group, single-center trial. Fifty-one nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention (BTA). RESULTS: Eighteen patients in mFC and 20 patients in PRET completed the trial. At 12 and at 24 months, no differences between groups were observed. At 12 months, relative to baseline, mFC improved on the Digit Span (estimated change: 0.3; interquartile range: 0, 0.7; P = 0.04) and Stroop (0.3; 0, 0.6; P = 0.04), and PRET improved only on the Digit Span (0.7; 0.3, 1; P < 0.01). At 24 months, relative to baseline, mFC improved on the Digit Span (0.7; 0.3, 1.7; P < 0.01) and Stroop (0.3; 0.1, 0.5; P = 0.03), whereas PRET improved on the Digit Span (0.5; 0.2, 0.8; P < 0.01), Stroop (0.2; -0.1, 0.6; P = 0.048), and BTA (0.3; 0, 0.8; P = 0.048). No neurological or cognitive adverse events were observed. CONCLUSIONS: This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate Parkinson's disease.

A two-year randomized controlled trial of progressive resistance exercise for Parkinson's disease.

The effects of progressive resistance exercise (PRE) on the motor signs of Parkinson's disease have not been studied in controlled trials. The objective of the current trial was to compare 6-, 12-, 18-, and 24-month outcomes of patients with Parkinson's disease who received PRE with a stretching, balance, and strengthening exercise program. The authors conducted a randomized controlled trial between September 2007 and July 2011. Pairs of patients matched by sex and off-medication scores on the Unified Parkinson's Disease Rating Scale, motor subscale (UPDRS-III), were randomly assigned to the interventions with a 1:1 allocation ratio. The PRE group performed a weight-lifting program. The modified fitness counts (mFC) group performed a stretching, balance, and strengthening exercise program. Patients exercised 2 days per week for 24 months at a gym. A personal trainer directed both weekly sessions for the first 6 months and 1 weekly session after 6 months. The primary outcome was the off-medication UPDRS-III score. Patients were followed for 24 months at 6-month intervals. Of 51 patients, 20 in the PRE group and 18 in the mFC group completed the trial. At 24 months, the mean off-medication UPDRS-III score decreased more with PRE than with mFC (mean difference, -7.3 points; 95% confidence interval, -11.3 to -3.6; P<0.001). The PRE group had 10 adverse events, and the mFC group had 7 adverse events. PRE demonstrated a statistically and clinically significant reduction in UPDRS-III scores compared with mFC and is recommended as a useful adjunct therapy to improve Parkinsonian motor signs. © 2013 Movement Disorder Society.

Hepatic uptake and metabolism of phosphatidylcholine associated with high density lipoproteins.

BACKGROUND: Phosphatidylcholine (PC) is the predominant phospholipid associated with high density lipoproteins (HDL). Although the hepatic uptake of cholesteryl esters from HDL is well characterized, much less is known about the fate of PC associated with HDL. Thus, we investigated the uptake and subsequent metabolism of HDL-PC in primary mouse hepatocytes. METHODS AND RESULTS: The absence of scavenger receptor-BI resulted in a 30% decrease in cellular incorporation of [(3)H]PC whereas [(3)H]cholesteryl ether uptake was almost completely abolished. Although endocytosis is not involved in the uptake of cholesteryl esters from HDL, we demonstrate that HDL internalization accounts for 40% of HDL-PC uptake. Extracellular remodeling of HDL by secretory phospholipase A(2) significantly enhances HDL lipid uptake. HDL-PC taken up by hepatocytes is partially converted to triacylglycerols via PC-phospholipase C-mediated hydrolysis of PC and incorporation of diacylglycerol into triacylglycerol. The formation of triacylglycerol is independent of scavenger receptor-BI and occurs in extralysosomal compartments. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings indicate that HDL-associated PC is incorporated into primary hepatocytes via a pathway that differs significantly from that of HDL-cholesteryl ester, and shows that HDL-PC is more than a framework molecule, as evidenced by its partial conversion to hepatic triacylglycerol.

Effect of High-Intensity Treadmill Exercise on Motor Symptoms in Patients With De Novo Parkinson Disease: A Phase 2 Randomized Clinical Trial.

Importance: Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high-intensity exercise. Objectives: To examine the feasibility and safety of high-intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial. Design, Setting, and Participants: The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control). Interventions: High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months. Main Outcomes and Measures: Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score. Results: A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2%-67.7%) maximum heart rate in the moderate-intensity group (P < .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high-intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe. Conclusions and Relevance: High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease. Trial Registration: clinicaltrials.gov Identifier: NCT01506479.

Two-year exercise program improves physical function in Parkinson's disease: the PRET-PD randomized clinical trial.

Background. The progressive resistance exercise (PRE) in Parkinson's disease trial (PRET-PD) showed that PRE improved the motor signs of PD compared to a modified Fitness Counts (mFC) program. It is unclear how long-term exercise affects physical function in these individuals. Objective. To examine the effects of long-term PRE and mFC on physical function outcome measures in individuals with PD. Methods. A preplanned secondary analysis was conducted using data from the 38 patients with idiopathic PD who completed the PRET-PD trial. Participants were randomized into PRE or mFC groups and exercised 2 days/week up to 24 months. Blinded assessors obtained functional outcomes on and off medication at baseline, 6 and 24 months with the Modified Physical Performance Test, 5 times sit to stand test, Functional Reach Test, Timed Up and Go, Berg Balance Scale, 6 minute walk test (6MWT), and 50-ft walking speed (walk speed). Results. The groups did not differ on any physical function measure at 6 or 24 months (Ps > .1). Across time, all physical function measures improved from baseline to 24 months when tested on medication (Ps < .0001), except for 6MWT (P = .068). Off medication results were similar except that the 6MWT was now significant. Conclusions. Twenty-four months of supervised and structured exercise (either PRE or mFC) is effective at improving functional performance outcomes in individuals with moderate PD. Clinicians should strive to include structured and supervised exercise in the long-term plan of care for individuals with PD.

Spinal cord modulation associated with isometric contractions.

OBJECTIVE: The dual-strategy hypothesis explains single-joint voluntary movement by dividing movements into two different strategies and suggesting that different excitation pulses modulate these movements. The existence of this excitation pulse was evaluated by quantifying magnitude and timing changes in the H-reflex (changes in spinal excitability) prior to a voluntary contraction. These changes in spinal excitability were assessed during a ballistic plantar flexion isometric contraction, where both the target size and force level was manipulated. METHODS AND MATERIALS: Subjects were seated in a modified chair with a force transducer placed under the metatarsal heads to measure ankle force output. Following a visual stimulus subjects were trained to produce a plantar flexion force of 25% and 50% of a maximum voluntary contraction, within target sizes of 5% and 15% of the selected force level. Soleus motor neuron reflex excitability was analyzed by measuring changes in the H/M ratio. The H-reflex was randomly elicited by tibial nerve stimulations at 15, 30, 45, 60, 75 and 90 ms prior to the recorded average soleus premotor time for each of the force and target size conditions. RESULTS: A two-way repeated-measures analysis of variance indicated a significant effect among target sizes for the time of change in spinal excitability, slope of facilitation (rate of rise of spinal excitability), and peak facilitation. A significant difference was also established between force levels for the slope and peak facilitation, but there was no difference with time of facilitation. CONCLUSIONS: These results indicate that changes in both target size and force level can influence slope and peak of facilitation. However, only target size appears to affect the time of facilitation. Results clearly support the existence of an excitation pulse that is regulated by the type of movement.

Progressive resistance exercise and Parkinson's disease: a review of potential mechanisms.

This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.

Combined measures of movement and force variability distinguish Parkinson's disease from essential tremor.

OBJECTIVE: To examine whether behavioral and electrophysiological measures of motor performance accurately differentiate Parkinson's disease (PD) and essential tremor (ET). METHODS: Twenty-four patients (12 PD; 12 ET) performed isometric force, ballistic movements, and tremor tasks. Receiver operating characteristic (ROC) analyses were conducted on all dependent measures that were significantly different between the two patient groups. RESULTS: Patients with PD were more impaired on measures of movement deceleration than ET. Patients with ET were more impaired on measures of force variability than PD. ROC analyses revealed that sensitivity and specificity were excellent when combining measures during the isometric force task (torque rise time and force variability; 92% sensitivity and 92% specificity; AUC = 0.97). When combining measures across the force and movement tasks, the ROC analysis revealed improved sensitivity and specificity (force variability and peak deceleration; 92% sensitivity and 100% specificity; AUC = 0.99). CONCLUSIONS: Combining measures of force variability and movement deceleration accurately differentiate patients with PD from those with ET with high sensitivity and specificity. SIGNIFICANCE: If validated in a larger sample, these measures can serve as markers to confirm the diagnosis of PD or ET and thus, enhance decision making for appropriate treatments for patients with these respective diseases.

Variability of EMG patterns: a potential neurophysiological marker of Parkinson's disease?

OBJECTIVE: This study evaluated whether changes in the electromygraphic (EMG) pattern during rapid point-to-point movements in individuals diagnosed with PD can: (1) distinguish PD subjects from healthy subjects and (2) determine if differences in the EMG pattern reflect disease severity in PD. METHODS: Three groups of 10 PD subjects and 10 age/sex-matched healthy subjects performed rapid 72 degree point-to-point elbow flexion movements. PD subjects were divided, a priori, into three groups based upon off medication motor UPDRS score. RESULTS: Measures related to the EMG pattern distinguished all PD subjects and 9 out of 10 healthy subjects, resulting in 100% sensitivity. Further, significant correlations were shown between EMG measures and the motor UPDRS score. After 30 months, the one healthy subject whose EMG pattern was abnormal was reexamined. The EMG measures remained abnormal and the motor UPDRS score went from 0 to 10. Parkinson's disease was diagnosed. CONCLUSION: Measures related to the variability of the EMG pattern during rapid point-to-point movements provide neurophysiological measures that objectively distinguish PD subjects from healthy subjects. These measures also correlate with disease severity. SIGNIFICANCE: EMG measures may provide a non-invasive measure that is sensitive and specific for identifying individuals with PD.

A role for hepatic scavenger receptor class B, type I in decreasing high density lipoprotein levels in mice that lack phosphatidylethanolamine N-methyltransferase.

Phosphatidylethanolamine N-methyltransferase (PEMT) is a liver-specific enzyme that converts phosphatidylethanolamine to phosphatidylcholine (PC). Mice that lack PEMT have reduced plasma levels of PC and cholesterol in high density lipoproteins (HDL). We have investigated the mechanism responsible for this reduction with experiments designed to distinguish between a decreased formation of HDL particles by hepatocytes or an increased hepatic uptake of HDL lipids. Therefore, we analyzed lipid efflux to apoA-I and HDL lipid uptake using primary cultured hepatocytes isolated from Pemt(+/+) and Pemt(-/-) mice. Hepatic levels of the ATP-binding cassette transporter A1 are not significantly different between Pemt genotypes. Moreover, hepatocytes isolated from Pemt(-/-) mice released cholesterol and PC into the medium as efficiently as did hepatocytes from Pemt(+/+) mice. Immunoblotting of liver homogenates showed a 1.5-fold increase in the amount of the scavenger receptor, class B, type 1 (SR-BI) in Pemt(-/-) compared with Pemt(+/+) livers. In addition, there was a 1.5-fold increase in the SR-BI-interacting protein PDZK1. Lipid uptake experiments using radiolabeled HDL particles revealed a greater uptake of [(3)H]cholesteryl ethers and [(3)H]PC by hepatocytes derived from Pemt(-/-) compared with Pemt(+/+) mice. Furthermore, we observed an increased association of [(3)H]cholesteryl ethers in livers of Pemt(-/-) compared with Pemt(+/+) mice after tail vein injection of [(3)H]HDL. These results strongly suggest that PEMT is involved in the regulation of plasma HDL levels in mice, mainly via HDL lipid uptake by SR-BI.

Force control and disease severity in Parkinson's disease.

Several measures of isometric contractions reflect motor impairments in subjects with Parkinson's disease (PD), including long relaxation times and greater power in the 5 to 15 Hz electromyographic (EMG) bandwidth during the holding phase of contractions compared to those measures in healthy subjects. We sought to determine whether the impairments observed in subjects with PD in the performance of isometric contractions reflect disease severity. Twenty-eight subjects with PD performed isometric contractions at a torque level equal to 50% of the torque generated during a maximum voluntary contraction while off medication. Subjects were instructed to reach the target torque as fast as possible upon hearing the auditory "go" signal and to relax their muscles when a second auditory cue signaled the end of the hold phase. There was a significant positive correlation between torque relaxation time and Unified Parkinson's Disease Rating Scale (UPDRS)-Motor score. A significant positive correlation was also observed between the proportion of power in the 5 to 15 Hz frequency bin of the agonist EMG signal and UPDRS-Motor score, and a significant negative correlation between the proportion of power in the 15 to 30 Hz frequency bin and UPDRS-Motor score. These measures provide objective quantification of the severity of motor impairment that can be used to investigate the efficacy of different interventions in individuals with PD.

Greater impairment of extension movements as compared to flexion movements in Parkinson's disease.

Research on isometric contractions in subjects with Parkinson's disease (PD) has shown that anti-parkinsonian medication results in a greater increase in extensor strength than flexor strength. This finding is consistent with the hypothesis that there is a greater impairment in neural activation of extensor muscles as compared to flexor muscles in subjects with PD. Such a hypothesis is physiologically feasible given the known differences in the neural control of flexor and extensor muscles. If the above hypothesis is true for both phasic and tonic muscle activation, then differences between performance of rapid single-joint flexion and extension movements should exist in subjects with PD. Twelve subjects with PD, "off" and "on" medication, and 12 age-and sex-matched healthy control subjects performed rapid single-joint movements in flexion and extension over three distances. For neurologically healthy subjects, we did not identify any significant differences in either kinematic or EMG parameters between flexion and extension movements. In contrast, in the PD subjects extension movements were slower and associated with more agonist bursts when compared to flexion movements. The results are consistent with the hypothesis that there is a differential impairment of neural activation of extensor muscles of the arm as compared to flexor muscles in subjects with PD.

Effect of medication on EMG patterns in individuals with Parkinson's disease.

Individuals with Parkinson's disease show dramatic improvements in their ability to move when medicated. However, the neural cause of this improvement is unclear. One hypothesis is that neural activation patterns, as measured by surface electromyography (EMG), are normalized by medication. We tested this hypothesis by investigating the effect of medication on the electromyographic (EMG) patterns recorded when individuals with idiopathic Parkinson's disease performed elbow flexion movements over three movement distances while off and on antiparkinsonian medication. When the subjects were off medication, they lacked the ability to modulate the agonist EMG burst duration with changes in movement distance. The ability to modulate agonist EMG burst duration is characteristic of the EMG patterns observed in healthy subjects. Also, multiple agonist bursts were exhibited during the acceleration phase. As expected, medication diminished the clinical signs of Parkinson's disease, increased movement speed, and increased the magnitude of the first agonist burst. Medication did not restore agonist burst duration modulation with movement distance, did not change the frequency of agonist bursting, and did not alter the timing of the antagonist activation. These results show that medication does not alter the temporal profile of EMG activation.