Kelly D. Foote

Genome-wide association study reveals genetic risk underlying Parkinson's disease

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinsons disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues

OBJECTIVE To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). DATA SOURCES AND STUDY SELECTION An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. DATA EXTRACTION AND SYNTHESIS A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. CONCLUSIONS (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson’s disease

Background: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown. Objective: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson’s disease (PD) followed up for three years. Methods: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson’s disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up. Results: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent). Conclusions: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.

Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data

BACKGROUND Several genes underlying rare monogenic forms of Parkinsons disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinsons disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinsons disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinsons disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION We generated publicly available genotype data for Parkinsons disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

Cognition and Mood in Parkinson's Disease in Subthalamic Nucleus versus Globus Pallidus Interna Deep Brain Stimulation: The COMPARE Trial

Our aim was to compare in a prospective blinded study the cognitive and mood effects of subthalamic nucleus (STN) vs. globus pallidus interna (GPi) deep brain stimulation (DBS) in Parkinson disease.

Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming

Background: Recently, anterior limb of the internal capsule and nucleus accumbens deep brain stimulation (DBS) has been used in the treatment of medication-refractory obsessive–compulsive disorder (OCD). This region has been previously explored with lesion therapy, but with the advent of DBS there exists the possibility of monitoring the acute and chronic effects of electrical stimulation. The stimulation-induced benefits and side effects can be reversibly and blindly applied to a variety of locations in this region. Objective: To explore the acute effects of DBS in the anterior limb of the internal capsule and nucleus accumbens region. Methods: Ten total DBS leads in five patients with chronic and severe treatment-refractory OCD were tested. Patients were examined 30 days after DBS placement and received either “sham” testing or actual testing of the acute effects of DBS (the alternative condition tested 30 days later). Results: Pooled responses were reviewed for comparability of distribution using standard descriptive methods, and relationships between the variables of interest were sought using χ2 analysis. A total of 845 stimulation trials across the five patients were recorded and pooled. Of these 16% were elicited from sham stimulation and 17% from placebo (0 V stimulation). A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Non-mood-related responses were found to be significantly associated with the ventral lead contacts (0 and 1) (p = 0.001). Responses such as taste, smell and smile were strongly associated with the most ventral lead positions. Similarly, physiological responses—for example, autonomic changes, increased breathing rate, sweating, nausea, cold sensation, heat sensation, fear, panic and panic episodes—were significantly associated with ventral stimulation (p = 0.001). Fear and panic responses appeared clustered around the most ventral electrode (0). Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule. Conclusion: The acute effects of DBS in the region of the anterior limb of the internal capsule and nucleus accumbens, particularly when obtained in a blinded fashion, provide a unique opportunity to localise brain regions and explore circuitry.

Tourette syndrome deep brain stimulation: A review and updated recommendations

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25‐year‐old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post‐DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Mood changes with deep brain stimulation of STN and GPi: results of a pilot study

The results of this study suggest that there are mood changes associated with deep brain stimulation of the subthalamic nucleus (STN) and the globus pallidus interna (GPi). Further, optimal placement of electrodes in both STN and GPi seems to result in overall improvement in mood and is associated with a lower incidence of adverse mood effects than stimulation outside the optimal site. Preliminary data from this study, however, suggest that slight movement dorsal or ventral to the site of optimal motor performance may be associated with more adverse changes in mood with STN stimulation than with GPi stimulation.

Image localization for frameless stereotactic radiotherapy

PURPOSE Infrared light-emitting diodes (IRLEDs) have been used for optic-guided stereotactic radiotherapy localization at the University of Florida since 1995. The current paradigm requires stereotactic head ring placement for the patients first fraction. The stereotactic coordinates and treatment plan are determined relative to this head ring. The IRLEDs are attached to the patient via a maxillary bite plate, and the position of the IRLEDs relative to linac isocenter is saved to file. These positions are then recalled for each subsequent treatment to position the patient for fractionated therapy. The purpose of this article was to report a method of predicting the desired IRLED locations without need for the invasive head ring. METHODS AND MATERIALS To achieve the goal of frameless optic-guided radiotherapy, a method is required for direct localization of the IRLED positions from a CT scan. Because it is difficult to localize the exact point of light emission from a CT scan of an IRLED, a new bite plate was designed that contains eight aluminum fiducial markers along with the six IRLEDs. After a calibration procedure to establish the spatial relationship of the IRLEDs to the aluminum fiducial markers, the stereotactic coordinates of the IRLED light emission points are determined by localizing the aluminum fiducial markers in a stereotactic CT scan. RESULTS To test the accuracy of direct CT determination of the IRLED positions, phantom tests were performed. The average accuracy of isocenter localization using the IRLED bite plate was 0.65 +/- 0. 17 mm for these phantom tests. In addition, the optic-guided system has a unique compatibility with the stereotactic head ring. Therefore, the isocentric localization capability was clinically tested using the stereotactic head ring as the absolute standard. The ongoing clinical trial has shown the frameless system to provide a patient localization accuracy of 1.11 +/- 0.3 mm compared with the head ring. CONCLUSION Optic-guided radiotherapy using IRLEDs provides a mechanism through which setup accuracy may be improved over conventional techniques. To date, this optic-guided therapy has been used only as a hybrid system that requires use of the stereotactic head ring for the first fraction. This has limited its use in the routine clinical setting. Computation of the desired IRLED positions eliminates the need for the invasive head ring for the first fraction. This allows application of optic-guided therapy to a larger cohort of patients, and also facilitates the initiation of extracranial optic-guided radiotherapy.