Sandra K. Kostyk

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial

BACKGROUND Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinsons disease. METHODS Patients aged 30-75 years who had progressive levodopa-responsive Parkinsons disease and an overnight off-medication unified Parkinsons disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. FINDINGS Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two). INTERPRETATION The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinsons disease and shows the promise for gene therapy for neurological disorders. FUNDING Neurologix.

Reliability and Validity of the Tinetti Mobility Test for Individuals With Parkinson Disease

Background and Purpose: This study examined the interrater and intrarater reliability, concurrent validity, and criterion validity of the Tinetti Mobility Test (TMT) as a fall risk screening tool in individuals with Parkinson disease (PD). Subjects: Thirty individuals with PD voluntarily participated in the study, and data from a retrospective review of 126 patient records were included. Methods: Physical therapists and physical therapist students rated live and videotaped performances of the TMT. Tinetti Mobility Test scores were correlated with Unified Parkinsons Disease Rating Scale (UPDRS) motor scores and comfortable gait speed. The ability of the TMT to accurately assess fall risk was determined. Results: Interrater and intrarater reliability was good to excellent (intraclass correlation coefficient of >.80). Tinetti Mobility Test scores correlated with UPDRS motor scores (rs=−.45) and gait speed (rs=.53). The sensitivity and specificity of the TMT to identify fallers were 76% and 66%, respectively. Discussion and Conclusion: The TMT is a reliable and valid tool for assessing the mobility status of and fall risk for individuals with PD.

A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease

We examined the effects of 3 dosages of pridopidine, a dopamine‐stabilizing compound, on motor function and other features of Huntingtons disease, with additional evaluation of its safety and tolerability. This was a randomized, double‐blind, placebo‐controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty‐seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntingtons Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was −1.2 points (95% confidence interval [CI], −2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was −2.8 points (95% CI, −5.4 to −0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntingtons disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated.

Fall risk assessment using the Tinetti mobility test in individuals with Huntington's disease†

The Tinetti Mobility Test (TMT) is a clinical balance and gait test that predicts fall risk in the elderly. This study examined the concurrent validity, usefulness of the TMT as a fall risk screening tool, and the potential ability of the TMT to predict falls in individuals with Huntingtons disease (HD). Data from a retrospective review of 94 patient records were used. TMT scores were correlated with Unified Huntington Disease Rating Scale (UHDRS) motor scores. The ability of the TMT to accurately assess fall risk was determined using validity index measures. Logistic regression was used to assess the ability of the TMT to predict falls. TMT scores correlated with UHDRS motor scores (rs = −0.751, P < 0.0001). Using a cutoff value of 21, the TMT had a sensitivity of 74% and a specificity of 60% to identify fallers. Lower TMT scores and younger age were significant predictors of falls. The TMT is a valid tool for assessing balance and gait status and fall risk of individuals with HD.

Video game play (Dance Dance Revolution) as a potential exercise therapy in Huntington’s disease: a controlled clinical trial

Objective: To investigate the feasibility, acceptability, and safety of a supervised video game exercise program administered via Dance Dance Revolution in individuals with Huntington’s disease. Design: A cross-over, controlled, single-blinded, six-week trial. Setting: Home-based. Participants: Eighteen ambulatory individuals with Huntington’s disease (seven male, mean age 50.7 SD 14.7). Interventions: Participants played the Dance Dance Revolution game with supervision and the handheld game without supervision for 45 minutes, two days per week for six weeks. Outcome measures: Game play performance and adherence, participant perceptions of the game, safety (vital signs, adverse health changes), spatiotemporal gait measures, Four-Square Step Test, Tinetti Mobility Test, Activities-Specific Balance Confidence Scale, and World Health Organization Quality of Life – Bref, before and after each intervention. Results: Most participants improved on game play, enjoyed playing the game, and wanted to continue playing after study completion. After playing Dance Dance Revolution, participants showed significant reductions in double support percentage (adjusted mean difference (95% confidence intervals): –2.54% (–4.75, –0.34) for forward walking and −4.18 (–6.89, –0.48) for backward walking) and those with less severe motor symptoms had reductions in heel-to-heel base of support during forward walking. The remaining measures were not significantly impacted by the intervention. Conclusion: Dance Dance Revolution appears to be a feasible, motivating, and safe exercise intervention for individuals with Huntington’s disease.

The Impact of Different Types of Assistive Devices on Gait Measures and Safety in Huntington's Disease

Background Gait and balance impairments lead to frequent falls and injuries in individuals with Huntingtons disease (HD). Assistive devices (ADs) such as canes and walkers are often prescribed to prevent falls, but their efficacy is unknown. We systematically examined the effects of different types of ADs on quantitative gait measures during walking in a straight path and around obstacles. Methods Spatial and temporal gait parameters were measured in 21 subjects with HD as they walked across a GAITRite walkway under 7 conditions (i.e., using no AD and 6 commonly prescribed ADs: a cane, a weighted cane, a standard walker, and a 2, 3 or 4 wheeled walker). Subjects also were timed and observed for number of stumbles and falls while walking around two obstacles in a figure-of-eight pattern. Results Gait measure variability (i.e., coefficient of variation), an indicator of fall risk, was consistently better when using the 4WW compared to other ADs. Subjects also walked the fastest and had the fewest number of stumbles and falls when using the 4WW in the figure-of-eight course. Subjects walked significantly slower using ADs compared to no AD both across the GAITRite and in the figure-of-eight. Measures reflecting gait stability and safety improved with the 4WW but were made worse by some other ADs.

Assistive devices alter gait patterns in Parkinson disease: Advantages of the four-wheeled walker

Gait abnormalities are a hallmark of Parkinsons disease (PD) and contribute to fall risk. Therapy and exercise are often encouraged to increase mobility and decrease falls. As disease symptoms progress, assistive devices are often prescribed. There are no guidelines for choosing appropriate ambulatory devices. This unique study systematically examined the impact of a broad range of assistive devices on gait measures during walking in both a straight path and around obstacles in individuals with PD. Quantitative gait measures, including velocity, stride length, percent swing and double support time, and coefficients of variation were assessed in 27 individuals with PD with or without one of six different devices including canes, standard and wheeled walkers (two, four or U-Step). Data were collected using the GAITRite and on a figure-of-eight course. All devices, with the exception of four-wheeled and U-Step walkers significantly decreased gait velocity. The four-wheeled walker resulted in less variability in gait measures and had less impact on spontaneous unassisted gait patterns. The U-Step walker exhibited the highest variability across all parameters followed by the two-wheeled and standard walkers. Higher variability has been correlated with increased falls. Though subjects performed better on a figure-of-eight course using either the four-wheeled or the U-Step walker, the four-wheeled walker resulted in the most consistent improvement in overall gait variables. Laser light use on a U-Step walker did not improve gait measures or safety in figure-of-eight compared to other devices. Of the devices tested, the four-wheeled-walker offered the most consistent advantages for improving mobility and safety.

ROBUST AXONAL GROWTH AND A BLUNTED MACROPHAGE RESPONSE ARE ASSOCIATED WITH IMPAIRED FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY IN THE MRL/MpJ MOUSE

Spinal cord injury (SCI) in mammals leads to a robust inflammatory response followed by the formation of a glial and connective tissue scar that comprises a barrier to axonal regeneration. The inbred MRL/MpJ mouse strain exhibits reduced inflammation after peripheral injury and shows true regeneration without tissue scar formation following an ear punch wound. We hypothesized that following SCI, the unique genetic wound healing traits of this strain would result in reduced glial and connective tissue scar formation, increased axonal growth, and improved functional recovery. Adult MRL/MpJ and C57BL/6J mice were subjected to a mid-thoracic spinal contusion and the distribution of axon profiles and selected cellular and extracellular matrix components was compared at 1, 2, 4 and 6 weeks post-injury. Recovery of hind-limb locomotor function was assessed over the same time period. The MRL/MpJ mice exhibited robust axon growth within the lesion, beginning at 4 weeks post-injury. This growth was accompanied by reduced macrophage staining at 1, 2, 4 and 6 weeks post-injury, decreased chondroitin sulfate proteoglycan staining at 1-2 weeks and increased laminin staining throughout the lesion at 2-6 weeks post-injury. Paradoxically, the extent of locomotor recovery was impaired in the MRL/MpJ mice. Close examination of the chronic lesion site revealed evidence of ongoing degeneration both within and surrounding the lesion site. Thus, the regenerative genetic wound healing traits of the MRL/MpJ mice contribute to the evolution of a lesion environment that supports enhanced axon growth after SCI. However, this response occurs at the expense of meaningful functional recovery.

Clinimetric properties of the Tinetti Mobility Test, Four Square Step Test, Activities-specific Balance Confidence Scale, and spatiotemporal gait measures in individuals with Huntington's disease

BACKGROUND AND PURPOSE Individuals with Huntingtons disease (HD) experience balance and gait problems that lead to falls. Clinicians currently have very little information about the reliability and validity of outcome measures to determine the efficacy of interventions that aim to reduce balance and gait impairments in HD. This study examined the reliability and concurrent validity of spatiotemporal gait measures, the Tinetti Mobility Test (TMT), Four Square Step Test (FSST), and Activities-specific Balance Confidence (ABC) Scale in individuals with HD. METHODS Participants with HD [n = 20; mean age ± SD=50.9 ± 13.7; 7 male] were tested on spatiotemporal gait measures and the TMT, FSST, and ABC Scale before and after a six week period to determine test-retest reliability and minimal detectable change (MDC) values. Linear relationships between gait and clinical measures were estimated using Pearsons correlation coefficients. RESULTS Spatiotemporal gait measures, the TMT total and the FSST showed good to excellent test-retest reliability (ICC > 0.75). MDC values were 0.30 m/s and 0.17 m/s for velocity in forward and backward walking respectively, four points for the TMT, and 3s for the FSST. The TMT and FSST were highly correlated with most spatiotemporal measures. The ABC Scale demonstrated lower reliability and less concurrent validity than other measures. CONCLUSIONS The high test-retest reliability over a six week period and concurrent validity between the TMT, FSST, and spatiotemporal gait measures suggest that the TMT and FSST may be useful outcome measures for future intervention studies in ambulatory individuals with HD.

Dopaminergic modulation of semantic priming in Parkinson disease.

ObjectiveOur purpose is to examine the effect of D2/D3 agonists on semantic priming. BackgroundDopamine seems to restrict the semantic network in semantic priming. However, which dopamine receptor mediates this effect is unknown. MethodsTo better understand the receptors involved, 15 nondemented Parkinson disease patients performed a lexical decision task before and 1 hour after they received their first morning medication dose, 8 after D2 and D3 agonists pramipexole or ropinirole, and 7 after L-dopa. Semantic priming was measured for closely, distantly, and unrelated word pairs across a stimulus onset asynchrony of 700 ms. ResultsClosely related pairs were recognized significantly faster than unrelated and distantly related pairs before the drugs, as well as after D2/D3 agents. After L-dopa, closely related pairs remained faster than unrelated, but not faster than distantly related pairs. ConclusionsThis suggests that D1 receptors may mediate the dopaminergic modulation of semantic priming.