Faculty Bibliography

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 Parkinson's disease. METHODS: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's 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 Parkinson's disease and shows the promise for gene therapy for neurological disorders. FUNDING: Neurologix.

OBJECTIVES: To identify metabolic brain networks that are associated with Tourette syndrome (TS) and comorbid obsessive-compulsive disorder (OCD). METHODS: We utilized [(18)F]-fluorodeoxyglucose and PET imaging to examine brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls. We utilized a spatial covariance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone). RESULTS: Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial covariance pattern that completely separated patients from controls (p < 0.0001). This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbitofrontal cortex associated with relative increases in premotor cortex and cerebellum. Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients. This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorsolateral prefrontal cortical regions associated with relative increases in primary motor cortex and precuneus. Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005). CONCLUSION: These findings suggest that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks. These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.

Parkinson's disease (PD) is associated with elevated expression of a specific disease-related spatial covariance pattern (PDRP) in radiotracer scans of cerebral blood flow and metabolism. In this study, we scanned nine early-stage patients with PD and nine healthy controls using continuous arterial spin labeling (CASL) perfusion magnetic resonance imaging (pMRI). Parkinson's disease-related metabolic pattern expression in CASL pMRI scans was compared with the corresponding (18)F-fluorodeoxyglucose positron emission tomography values. The PDRP expression was abnormally elevated (P<0.01) in patients scanned with either modality, and the two values were highly intercorrelated (P<0.0001). Perfusion MRI methods can be used for accurate quantification of disease-related covariance patterns

BACKGROUND: Idiopathic Parkinson's disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders. METHODS: Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2.6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis. FINDINGS: 167 patients were assessed. Image-based classification for idiopathic Parkinson's disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV). INTERPRETATION: Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials. FUNDING: National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research

OBJECTIVES: To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Multicenter outpatient trial. PARTICIPANTS: Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008. INTERVENTION: Latrepirdine, 20 mg 3 times daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period. MAIN OUTCOME MEASURES: The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). RESULTS: Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P = .03). No significant treatment effects were seen on the UHDRS or the ADAS-cog. CONCLUSIONS: Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD

Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype

Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in 11 pre-symptomatic HD gene carriers (pHD) and 11 normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQ test). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQ test these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve

We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [15O]-H2O and [18F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor- and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment (p < 0.001). This dissociation was characterized by reductions in network activity in the CMR scans (p < 0.003) occurring concurrently with increases in the CBF scans (p < 0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia