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Amyloid Precursor Protein Is Required To Permit And To Limit Cortical Plasticity In Vivo [Meeting Abstract]

William, Christopher; Stern, Matthew; Pei, Xuewei; Saqran, Lubna; Frosch, Matthew; Hyman, Bradley
ISI:000434064400032
ISSN: 0022-3069
CID: 3156202

Vitamin D in the Parkinson Associated Risk Syndrome (PARS) study

Fullard, Michelle E; Xie, Sharon X; Marek, Ken; Stern, Matthew; Jennings, Danna; Siderowf, Andrew; Willis, Allison W; Chen-Plotkin, Alice S
BACKGROUND: Lower vitamin D levels have been associated with manifest Parkinson's disease, prompting the hypothesis that vitamin D insufficiency or deficiency may increase risk for PD. OBJECTIVES: To evaluate vitamin D levels in a population at risk for developing PD. METHODS: Plasma vitamin D levels were measured in the Parkinson Associated Risk Syndrome Study, a cohort of asymptomatic individuals, some of whom are at high risk for PD. Vitamin D levels were compared between subjects at high risk for PD (hyposmia and dopamine transporter scan deficit) versus all others and examined for correlations with dopaminergic system integrity. RESULTS: Mean vitamin D levels did not differ between groups, with a level of 27.8 ng/mL (standard deviation = 12.0) in the high-risk group versus 24.7 ng/mL (standard deviation = 9.0) in all others (P = 0.09). Vitamin D levels did not associate with putaminal dopamine transporter uptake. CONCLUSIONS: Our data from the asymptomatic Parkinson Associated Risk Syndrome cohort do not support the hypothesis that chronic vitamin D insufficiency threatens dopaminergic system integrity, contributing to PD pathogenesis. (c) 2017 International Parkinson and Movement Disorder Society.
PMCID:5721350
PMID: 28906025
ISSN: 1531-8257
CID: 2772372

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial

Warren Olanow, C; Bartus, Raymond T; Baumann, Tiffany L; Factor, Stewart; Boulis, Nicholas; Stacy, Mark; Turner, Dennis A; Marks, William; Larson, Paul; Starr, Phillip A; Jankovic, Joseph; Simpson, Richard; Watts, Ray; Guthrie, Barton; Poston, Kathleen; Henderson, Jaimie M; Stern, Matthew; Baltuch, Gordon; Goetz, Christopher G; Herzog, Christopher; Kordower, Jeffrey H; Alterman, Ron; Lozano, Andres M; Lang, Anthony E
OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 x 1011 vector genomes) and putamen (1.0 x 1012 vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 +/- 9.92; sham, -5.2 +/- 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. Ann Neurol 2015.
PMID: 26061140
ISSN: 1531-8249
CID: 1626462

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial

Marks, William J Jr; Bartus, Raymond T; Siffert, Joao; Davis, Charles S; Lozano, Andres; Boulis, Nicholas; Vitek, Jerrold; Stacy, Mark; Turner, Dennis; Verhagen, Leonard; Bakay, Roy; Watts, Raymond; Guthrie, Barton; Jankovic, Joseph; Simpson, Richard; Tagliati, Michele; Alterman, Ron; Stern, Matthew; Baltuch, Gordon; Starr, Philip A; Larson, Paul S; Ostrem, Jill L; Nutt, John; Kieburtz, Karl; Kordower, Jeffrey H; Olanow, C Warren
BACKGROUND: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS: We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5.4 x 10(1)(1) vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS: Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0.31 [SE 2.63], 95% CI -5.58 to 4.97; p=0.91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION: Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING: Ceregene and Michael J Fox Foundation for Parkinson's Research.
PMID: 20970382
ISSN: 1474-4422
CID: 896442