Search

The University of Alabama at Birmingham academic medical center (UAB AMC) had achieved great success and growth during the 50 years since its founding. However, the challenging and more competitive environment of the 2000s left the UAB AMC on a downward trajectory. The UAB AMC had to overcome difficult internal cultural and structural barriers that stood in the way of the transformational change needed to remain competitive. Competition rather than collaborative and strategic financial investment were the primary cultural barriers for the UAB AMC, while people were the primary structural barrier. Leadership identified 5 steps that were critical for the transformation that occurred between 2013 and 2018: alignment of leadership; creating a compelling and credible shared vision; identifying cultural and structural barriers; creating a thoughtful, data-driven intervention; and improved communication and accountability. Following these steps enabled the UAB AMC to transform its institutional structure and culture. As a result, the UAB AMC thrived, returning to substantial growth in research and clinical care. UAB AMC School of Medicine grew by $100 million in National Institutes of Health funding and moved up 10 spots in ranking. In 2018, UAB Hospital had 10 specialties ranked by U.S. News & World Report, 7 more than in 2013. This article outlines the approach taken and provides a conceptual framework for other AMCs eager to transform their structure and culture and position themselves for growth.

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 × 1011 vector genomes) and putamen (1.0 × 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;78:248–257

Subthalamic nucleus (STN) deep brain stimulation is a successful intervention for medically refractory Parkinson disease, although its efficacy depends on optimal electrode placement. Even though the predominant effect is observed contralaterally, modest improvements in ipsilateral and midline symptoms are also observed.To elucidate the role of contact location of unilateral deep brain stimulation on contralateral, ipsilateral, and axial subscores of Parkinson disease motor symptoms.Eighty-six patients receiving first deep brain stimulation STN electrode placements were identified, yielding 73 patients with 3-month follow-up. Total preoperative and postoperative Unified Parkinson Disease Rating Scale Part III scores were obtained and divided into contralateral, ipsilateral, and midline subscores. Contact location was determined on immediate postoperative magnetic resonance imaging. A 3-dimensional ordinary "kriging" algorithm generated spatial interpolations for total, ipsilateral, contralateral, and midline symptom categories. Interpolative reconstructions were performed in the axial planes (z = -0.5, -1.0, -1.5, -3.5, -4.5, -6.0) and a sagittal plane (x = 12.0). Interpolation error and significance were quantified by use of a cross-validation technique and quantile-quantile analysis.There was an overall reduction in Unified Parkinson Disease Rating Scale Part III symptoms: total = 37.0 ± 24.11% (P.05), ipsilateral = 15.9 ± 51.8%, contralateral = 56.2 ± 26.8% (P.05), and midline = 26.5 ± 34.7%. Kriging interpolation was performed and cross-validated with quantile-quantile analysis with high correlation (R20.92) and demonstrated regions of efficacy for each symptom category. Contralateral symptoms demonstrated broad regions of efficacy across the peri-STN area. The ipsilateral and midline regions of efficacy were constrained and located along the dorsal STN and caudal zona incerta.We provide evidence for a unique functional topographic window in which contralateral, ipsilateral, and midline structures may achieve the best efficacy. Although there are overlapping regions, laterality demonstrates distinct topographies. Surgical optimization should target the intersection of optimal regions for these symptom categories.

Deep brain stimulation (DBS) in Parkinson's disease (PD) is frequency-dependent. Past studies of the effect of DBS frequency, however, involved scrutiny of too few frequencies to eliminate risk of undersampling. Also, these studies presented averaged measures across subjects; high intersubject variability makes these measures problematic. In this study, 6 subjects with PD were tested in a drug-minimal state. Following 10 minutes of stimulation at the new frequency, all available frequencies were tested. Hand-opening and hand-closing amplitude and frequency were measured in 3 epochs of 15 seconds each. Multiple frequencies (low and high) resulted in peaks of increased movement amplitudes. Peaks were specific and varied among individuals. No clear relationship between stimulation frequency and movement frequency was discovered. In light of the findings, a wider range of stimulation frequencies should be examined, particularly lower frequencies. Most current theories of PD pathophysiology and DBS mechanisms of action fail to explain results of the kind demonstrated herein.

Object While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD). Methods Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. Results At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2-year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8–64.9), high tremor subscore (OR 7.2, CI 1.5–35.0), and low body weight (OR 5.5, 95% CI 1.4–22.3). Conclusions This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS.

Background: Depression is common in Parkinson's disease (PD) and adversely affects quality of life. Both unilateral and bilateral subthalamic (STN) deep brain stimulation (DBS) effectively treat the motor symptoms of PD, but questions remain regarding the impact of unilateral STN DBS on non-motor symptoms, such as depression. Methods: We report changes in depression, as measured by the Hamilton Depression Rating Scale (HAMD-17), in 50 consecutive PD patients who underwent unilateral STN DBS. Participants were also evaluated with UPDRS part III, Parkinson's Disease Questionnaire-39, and Pittsburgh Sleep Quality Index. The primary outcome was change in HAMD-17 at 6 months versus pre-operative baseline, using repeated measures analysis of variance (ANOVA). Secondary outcomes included the change in HAMD-17 at 3, 12, 18, and 24 months post-operatively and correlations amongst outcome variables using Pearson correlation coefficients. As a control, we also evaluated changes in HAMD-17 in 25 advanced PD patients who did not undergo DBS. Results: Participants with unilateral STN DBS experienced significant improvement in depression 6 months post-operatively (4.94 ± 4.02) compared to preoperative baseline (7.90 ± 4.44) (mean ± SD) (p =

Deep brain stimulation relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate nucleus stimulation for essential tremor activates cortex at short latencies and that this potential is related to suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (7 brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event related potential in ipsilateral sensorimotor cortex with peaks at discrete latencies beginning less than one millisecond after stimulus onset (mean latencies 0.9±0.2, 5.6±0.7, and 13.9±1.4 milliseconds, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (p

Subthalamic deep brain stimulation (DBS) is superior to medical therapy for the motor symptoms of advanced Parkinson's disease (PD), and additional evidence suggests that it improves refractory symptoms of essential tremor, primary generalized dystonia, and obsessive-compulsive disorder. Despite this, its therapeutic mechanism is unknown. We hypothesized that subthalamic stimulation activates the cerebral cortex at short latencies after stimulus onset during clinically effective stimulation for PD. In 5 subjects (six hemispheres), EEG measured the response of cortex to subthalamic stimulation across a range of stimulation voltages and frequencies. Novel analytical techniques reversed the anode and cathode electrode contacts and summed the resulting pair of event-related potentials to suppress the stimulation artifact. We found that subthalamic brain stimulation at 20 Hz activates the somatosensory cortex at discrete latencies (mean latencies: 1.0 ± 0.4, 5.7 ± 1.1, and 22.2 ± 1.8 ms, denoted as R1, R2, and R3, respectively). The amplitude of the short latency peak (R1) during clinically effective high-frequency stimulation is nonlinearly dependent on stimulation voltage (P < 0.001; repeated-measures analysis of variance), and its latency is less variable than that of R3 (1.02 versus 19.46 ms; P < 0.001, Levene's test). We conclude that clinically effective subthalamic brain stimulation in humans with PD activates the cerebral cortex at 1 ms after stimulus onset, most likely by antidromic activation. These findings suggest that alteration of the precise timing of action potentials in cortical neurons with axonal projections to the subthalamic region may be an important component of the therapeutic mechanism of subthalamic brain stimulation.

Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson's disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson's disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the am- plitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimula- tion condition. There were no statistically significant dif- ferences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson's disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific. V C 2011 Movement Disorder Society

Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case–control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.

Summary Background Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. Methods In this randomised, double-blind study eligible patients were aged 36–70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3–4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38–70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325 000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687. Findings Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (−10·5 [SD 10·26] for transplantation vs −10·1 [SD 12·26] for sham surgery, p=0·9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. Interpretation Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. Funding Bayer HealthCare AG.

Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.

Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor DeltaFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of DeltaFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of DeltaFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic DeltaFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of DeltaFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high DeltaFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal DeltaFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.

Objective: To examine changes in quality of life (QOL) and global clinical status after 30 days of adjunctive treatment with tolcapone, a reversible inhibitor of catechol-O-methyltransferase, in patients with fluctuating Parkinson's disease.Methods: This 30-day, multicenter, open-label, community-based study enrolled fluctuating Parkinson's disease patients to receive tolcapone 100 mg TID as an adjunct to levodopa/carbidopa. The primary end point was QOL change assessed using the Parkinson's Disease Questionnaire (PDQ)-8. Clinical change was assessed using the investigator-rated Clinical Global Impression of Improvement Scale (CGI-I).Results: Fifty-six physicians enrolled 202 patients; 138 (68%) were ≥65 years of age and 116 (57%) had Parkinson's disease for ≥5 years. The mean PDQ-8 total score improved from 42.1 to 34.8 after 30 days of tolcapone (PConclusions: Adjunctive tolcapone treatment was associated with statistically significant improvement in QOL in fluctuating Parkinson's disease patients. A majority of patients experienced clinical benefits and continued treatment beyond the end of this study. No liver-related adverse events were reported.

Purpose In this article, the authors report a case of acquired stuttering associated with Parkinson’s disease (PD) that was responsive to unilateral subthalamic nucleus deep-brain stimulation (STN DBS) in the language-dominant hemisphere. Method A single-subject, masked, multiple baseline design was used to evaluate the effects of unilateral left STN DBS on stuttering associated with PD. The patient underwent 3 formal speech assessments of spontaneous speech and the reading of passages with DBS off and on. Speech samples were videotaped and placed in random order, and 2 independent speech-language pathologists calculated the percentage of stuttered syllables and classified individual stuttering events. Results Stuttering improved significantly in the DBS-on condition. In total, 10% of syllables were affected by stuttering events with DBS off, and less than 1% of syllables were affected by stuttering events with DBS on ( n = 2,281 syllables, p < .00001, in a χ 2 test). The effect of unilateral STN DBS on stuttering was relatively independent of whether the patient was on or off dopaminergic medications. Conclusion This article emphasizes the important role of the subthalamic region in the motor control of speech and language.

The delivery of stimulus by a deep brain stimulation (DBS) contact electrode at a particular location may lead to a quantifiable physiologic effect, both intraoperatively and postoperatively. Consequently, measured data values can be attributed to discrete scattered points in neuroanatomic space, allowing for interpolative techniques to generate a topographic map of spatial patterns. Ultimately, by relating the topographies of various intraoperative measurements to the postoperative counterparts and neuroanatomic atlases, outcome-guided adjustments to electrode position can be pursued intraoperatively. In this study, 52 Parkinson’s disease patients were tested with a postoperative trial of stimulation and thresholds were recorded for motor adverse effects. A ‘roving window’ interpolation algorithm was adapted to generate a topographic map of voltage threshold along selected axial, coronal and sagittal planes. By developing these relational topographies for a variety of intraoperative and postoperative effects, a multivariable approach towards DBS optimization emerges.

OBJECTIVE: To quantify the benefit of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on contralateral, ipsilateral, and axial symptoms of advanced Parkinson's disease. METHODS: Thirty-seven patients received unilateral STN DBS and were rated on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed tests of motor function in the "practically defined off" state at baseline and at 3, 6, and 12 months postoperatively. RESULTS: UPDRS motor scores improved significantly at 3, 6, and 12 months relative to the preoperative baseline (P < 0.001, 37.1 % at 1 year). There was improvement in the contralateral UPDRS subscores (P < 0.001, 54.6% at 1 year), and although contralateral benefit was larger on all outcome measures, ipsilateral benefit was present at 3 and 6 months on the UPDRS subscore (P = 0.013 and 23.5%, P = 0.005 and 27.7%, respectively). A trend toward ipsilateral benefit was present on the UPDRS subscore at 12 months; however, the effect was not statistically significant. Two timed tests of motor function in the upper extremities showed significant ipsilateral benefit in bradykinesia at 12 months (P < 0.001 and P = 0.014, respectively). Significant benefit was also observed in the UPDRS part 2 "off" medications and the UPDRS part 4 after unilateral STN DBS at 12 months (both P < 0.001 ). CONCLUSION: Considering the bilateral effects and tolerability of unilateral STN DBS, unilateral stimulation followed by a contralateral procedure later, if necessary, is a reasonable option for patients with advanced Parkinson's disease, especially with prominent asymmetry.

Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimer's disease (AD) and in Parkinson's disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS).Twelve patients with idiopathic PDD, 22 patients with probable mild AD, and 61 healthy older controls underwent posterior cingulate MRS.Patients with AD exhibited reduced N-acetyl aspartate (NAA)/creatine (Cr) (P.05) and increased choline (Cho)/Cr (P.05) and myo-inositol (mI)/Cr (P.01) compared with controls. Patients with PDD exhibited reduced NAA/Cr (P.05) and glutamate (Glu)/Cr (P.01) compared with controls. There was reduced Glu/Cr in PDD compared with AD (P.01).Patients with AD and patients with PDD exhibited distinct brain metabolic MRS profiles. Findings suggest that comparison of brain MRS profiles across dementias provides useful direction for future study.

Little is currently known about the higher order functional skills of patients with Parkinson disease and cognitive impairment. Medical decision-making capacity (MDC) was assessed in patients with Parkinson's disease (PD) with cognitive impairment and dementia. Participants were 16 patients with PD and cognitive impairment without dementia (PD-CIND), 16 patients with PD dementia (PDD), and 22 healthy older adults. All participants were administered the Capacity to Consent to Treatment Instrument (CCTI), a standardized capacity instrument assessing MDC under five different consent standards. Parametric and non-parametric statistical analyses were utilized to examine capacity performance on the consent standards. In addition, capacity outcomes (capable, marginally capable, or incapable outcomes) on the standards were identified for the two patient groups. Relative to controls, PD-CIND patients demonstrated significant impairment on the understanding treatment consent standard, clinically the most stringent CCTI standard. Relative to controls and PD-CIND patients, patients with PDD patients were impaired on the three clinical standards of understanding, reasoning, and appreciation. The findings suggest that impairment in decisional capacity is already present in cognitively impaired PD patients without dementia, and increases as these patients develop dementia. Clinicians and researchers should carefully assess decisional capacity in all PD patients with cognitive impairment.

Persons with Parkinson disease (PD) are at risk of developing dementia. Of the dementias affecting patients with PD, PD with dementia (PDD) is not well understood, although brain imaging studies to date have observed characteristic patterns of brain atrophy. Metabolic differences have been observed in magnetic resonance spectroscopy (MRS) studies comparing patients with PDD to nondemented PD patients, although it is unclear whether PDD patients have abnormally low MRS ratios compared with healthy age-matched adults. In this study, 12 patients with PDD, 12 patients with PD and no dementia, and 12 age-matched healthy older adults underwent MRS of the posterior cingulate gyrus. Patients with PDD showed lower N-acetylaspartate/creatine (NAA/Cr) compared with controls (P = 0.004) and compared with nondemented PD patients (P = 0.003). No abnormalities were observed in choline/Cr or myo-Inositol/Cr. NAA/Cr was correlated with mental status in patients with PD and in patients with PDD (r = 0.56; P = 0.029). The findings suggest that reduced NAA/Cr of the posterior cingulate could be used as a marker for dementia in patients with PD. Future studies investigating the utility of brain MRS as a predictor of dementia in PD and comparing brain metabolism in PDD with other dementias seem warranted.

In a 5-year, double-blind study, subjects with Parkinson's disease (PD) who were randomized to initial treatment with ropinirole had a significantly lower incidence of dyskinesia compared with subjects randomized to levodopa, although Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were significantly more improved in the levodopa group. Subjects who completed the original study were eligible to participate in a long-term extension study conducted according to an open, naturalistic design and were evaluated approximately every 6 months until they had been followed for a total of 10 years. Comparing subjects randomized to initial treatment with ropinirole (n = 42) and levodopa (n = 27), the incidence of dyskinesia was significantly lower in the ropinirole group (adjusted odds ratio [OR] = 0.3; 95% confidence interval [CI]: 0.1, 1.0; P = 0.046) and the median time to dyskinesia was significantly longer (adjusted hazard ratio = 0.4; 95% CI: 0.2, 0.8; P = 0.007). The incidence of at least moderate wearing off ("off" time >/=26% of the awake day) was also significantly lower in the ropinirole group (adjusted OR = 0.3; 95% CI: 0.09, 0.03; P = 0.03). There were no significant differences in change in UPDRS activities of daily living or motor scores, or scores for the 39-item PD questionnaire, Clinical Global Impression, or the Epworth Sleepiness Scale. Early treatment decisions for individual patients depend largely on the anticipated risk of side effects and long-term complications. Both ropinirole and levodopa are viable treatment options in early PD.

This multicenter, randomized, double-blind study was performed to compare the safety and efficacy of the once-daily dopamine agonist rotigotine, in a continuous-dosing transdermal-patch formulation, vs placebo in patients with early-stage Parkinson disease (PD).Patients were randomized to receive placebo (n = 96) or rotigotine (n = 181), starting at 2 mg/24 h (10-cm(2) patch size; 4.5-mg total drug content), titrated weekly up to 6 mg/24 h (30-cm(2) patch size; 13.5-mg total drug content), and then maintained for 6 months. The primary efficacy measures were 1) the change in the Unified Parkinson's Disease Rating Scale (UPDRS) scores (parts II and III) from baseline to end of treatment and 2) responder rates (patients withor =20% improvement).Patients receiving rotigotine had a mean absolute difference of 5.28 (+/-1.18) points lower in UPDRS subtotal scores compared with those receiving placebo (p0.0001). The mean change in part III motor scores was -3.50 (+/-7.26) (n = 177) and was the greatest contributor to UPDRS improvement. The rotigotine group had more responders (48 vs 19%; p0.0001). The most commonly reported adverse events were application site reactions (44% rotigotine vs 12% placebo), nausea (41 vs17%), somnolence (33 vs 20%), and dizziness (19 vs 13%), and most were mild or moderate in intensity.Transdermal rotigotine, when titrated to a dosage of 6 mg/24 h, was effective for the treatment of early-stage Parkinson disease in this trial. Adverse events were similar to those found with other transdermal systems and dopamine agonists.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Background: Polymorphisms in the glutathione S-transferase pi gene ( GSTP1 ), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the Gene PD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. Methods: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. Results: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. Conclusions: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Background: Few occupational risk factors for Parkinson disease (PD) have been identified. Healthcare, teaching, and farming have been associated with increased risk, while welding has been proposed to accelerate age at PD onset. The aim of the present study was to investigate occupational associations with PD or parkinsonism drawing from three different movement disorders clinics. Methods: Medical records of 2,249 consecutive patients with PD or parkinsonism from specialty clinics in Sunnyvale, CA, New York, NY, and Atlanta, GA, were reviewed for primary lifetime occupation. Job frequencies were compared with Department of Labor regional statistics. PD diagnosis age and risk of diagnosis ≤50 were determined for each job. Results: Physicians/dentists, farmers, and teachers were significantly more common than expected among PD patients, as were lawyers, scientists, and religion-related jobs. Computer programmers had a younger age at PD diagnosis, and risk of diagnosis ≤50 was greater in computer programmers and technicians. Conclusions: Consistent with prior studies, healthcare, teaching, and farming were common occupations in Parkinson disease (PD) patients, but welders were not over-represented. Even though several occupations were associated with younger age at PD diagnosis, these results may reflect biases inherent in specialty clinic surveys, including over-representation of younger, employed, and insured patients. Carefully designed analytic studies utilizing appropriate control populations will be required to test hypotheses regarding occupation and PD risk.

Background and purpose Restless legs syndrome (RLS) is a condition characterized by an urge to move the legs, usually accompanied by lower limb paresthesias. These symptoms worsen at rest, are relieved by activity, and are worse at night. Previous studies have suggested that dopaminergic drugs such as L-dopa and dopamine agonists, as well as benzodiazepines and opioids, can treat RLS successfully. The purpose of this study was to test the clinical efficacy of ropinirole, a D2/D3 agonist, in the treatment of RLS in a double-blind, short-term, placebo-controlled clinical trial. Patients and methods After undergoing successful open-label titration and dose adjustments with ropinirole for RLS symptoms over a period of 4 weeks, 22 RLS patients (mean age=50.8; mean duration of symptoms=26.1 years) were randomized to receive either placebo (n=13) or ropinirole (n=9) for 2 additional weeks. Outcome measures included assessment of periodic leg movements in sleep (PLMS) recorded with nocturnal polysomnography and RLS symptoms as assessed with the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. Secondary outcomes included sleep macroarchitecture. Results Results indicated that relative to placebo, ropinirole, at a mean dose of 1.4 mg HS significantly decreased PLMS and RLS symptoms. Sleep macroarchitecture did not change. Side effects were typical of all dopamine agonists and were dose related. The majority of patients elected to continue treatment with ropinirole upon study completion. Conclusions Ropinirole successfully treated long-standing RLS and can be considered a viable short-term treatment for this condition.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Depression is an important and common nonmotor feature of Parkinson's disease (PD) that is associated with significant disability and a negative impact on quality of life. The physician should remain vigilant for symptoms of depression as they may be mistaken for the progression of Parkinson's disease itself. Transient dysphoria that occurs during 'off' periods in fluctuating PD patients must be distinguished from true depression. Antidepressant therapy should be instituted if depression is interfering with the patient's daily function. The use of serotonin reuptake inhibitors and tricyclic antidepressants in the treatment of depression in PD is widespread in clinical practice. Dopamine agonists may be effective in the treatment of milder depression as well. Individual or family counseling may be helpful. In patients with severe depression who are refractory to antidepressant medications, a series of electroconvulsive treatments can be lifesaving. Nonconventional therapies such as transcranial magnetic stimulation are being investigated.

Patients with Parkinson's disease (PD) commonly complain of impaired visual function and difficulty reading, despite normal visual acuity. Although previous studies have evaluated contrast sensitivity, color vision, visuospatial processing, visual hallucinations, and ocular movements, none has systematically evaluated the ocular complaints and ocular findings of PD patients. Thirty patients with early untreated PD and 31 control subjects without neurologic or known ocular diseases were ophthalmologically evaluated for the frequency of visual complaints, dry eyes, blepharitis, visual hallucinations, reduced blink rate, blepharospasm, and convergence insufficiency. Ocular complaints suggesting ocular surface irritation, altered tear film, visual hallucinations, blepharospasm, decreased blink rate, and decreased convergence amplitudes were more common in PD patients than in control subjects. These findings likely account for many of the visual difficulties commonly encountered by PD patients. These ocular abnormalities frequently respond to treatment.

The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.Videos of 44 patients and 6 controls were rated by 10 specialists on 2 occasions 1-2 months apart. Inter- and intrarater reliability was assessed with a 2-way random-effects intraclass correlation, using an absolute agreement definition.Inter- and intrarater intraclass correlations for head and upper-limb tremor ranged from 0.86 to 0.96, and intraclass correlations for total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk, and leg were less robust.This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.

Objective: To identify a haplotype influencing onset age for Parkinson’s disease (PD) in the PARK3 region on chromosome 2p13. Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset ( p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) ( SPR ) gene, rs1876487 ( p = 0.02) and rs1150500 ( p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394 . The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP—rs2421095, rs1876487, rs1561244—revealed an association with onset age ( p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD ( p = 0.005). Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.

Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2–3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations ( P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45–56%, IV: +39–54%). These adaptations were accompanied by a host of functional and clinical improvements ( P < 0.05): total body strength (+30–56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (−30%); 6-min walk (+43 m), Parkinson's Disease Quality of Life Scale (PDQ-39, −7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (−5.7 pts) and motor (−2.7 pts); and fatigue severity (−17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON ( P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.

Parkinson’s disease (PD) is named in honor of James Parkinson, whose classic monograph, “An Essay on the Shaking Palsy,” written in 1817, has provided an enduring description of the clinical features of this disorder.1 PD is an age-related neurodegenerative disorder with an average age at onset of 60 years. An estimated 1 million persons in the United States suffer from PD,2 and there are approximately 60,000 new cases each year. United States Census Bureau projections indicate that there will be a substantial increase in the number of at-risk individuals 60 years of age and older, and therefore the prevalence of PD is likely to increase in the coming decades. The introduction of levodopa in the late 1960s represented a major therapeutic advance in the management of PD,3 providing clinical benefit to virtually all patients and reduced mortality. However, it soon became apparent that long-term treatment with levodopa is complicated by the development of adverse events that include motor fluctuations, dyskinesias, and neuropsychiatric complications.4-6⇓⇓ In addition, with disease progression, patients develop features that do not respond well to levodopa therapy, such as freezing episodes, autonomic dysfunction, falling, and dementia. As a consequence, despite levodopa treatment, most PD patients eventually suffer disabilities that cannot be satisfactorily controlled with existing medical therapies. Therefore, there has been an intensive effort to develop new treatments that reverse disabilities in patients with advanced disease, that provide enhanced clinical benefits with a reduced risk for adverse events, and that slow the rate of disease progression. This has led to an explosion of new laboratory and clinical information and to a variety of new treatment strategies for the management of PD. Physicians who treat PD patients must now assimilate a considerable body of data to optimally manage patients with this complex disorder. …

Corticobasal degeneration (CBG) is an increasingly recognized neurodegenerative disease with both motor and cognitive dysfunction. The diagnosis is probably underestimated because of the heterogeneity of clinical features, overlap with symptoms, and pathologic findings of other neurodegenerative diseases. The most characteristic initial motor symptoms are akinesia, rigidity, and apraxia. Dystonia and alien limb phenomena are frequently observed. There is often a parkinsonian picture with failure or lack of efficacy of dopaminergic medical therapy. Cognitive decline, prompting the diagnosis of dementia, may be the most common presentation of CBD that is misdiagnosed. Pathology is characterized by an asymmetric frontoparietal neuronal loss and gliosis with ballooned, achromatic cortical neurons, nigral degeneration, and variable subcortical involvement. Neuroimaging and electrophysiologic studies may help with the diagnosis but are not specific. Treatment is primarily symptomatic and minimally effective, especially after the first several years of symptoms. CBD should be considered in the differential diagnosis of patients with motor and cognitive dysfunction presenting with cortical and subcortical features. Further studies to elucidate molecular abnormalities and biological markers associated with CBD are needed to improve clinical diagnosis and treatment of patients with this disorder.

Deep brain stimulation (DBS) in Parkinson's disease (PD) is frequency-dependent. Past studies of the effect of DBS frequency, however, involved scrutiny of too few frequencies to eliminate risk of undersampling. Also, these studies presented averaged measures across subjects; high intersubject variability makes these measures problematic. In this study, 6 subjects with PD were tested in a drug-minimal state. Following 10 minutes of stimulation at the new frequency, all available frequencies were tested. Hand-opening and hand-closing amplitude and frequency were measured in 3 epochs of 15 seconds each. Multiple frequencies (low and high) resulted in peaks of increased movement amplitudes. Peaks were specific and varied among individuals. No clear relationship between stimulation frequency and movement frequency was discovered. In light of the findings, a wider range of stimulation frequencies should be examined, particularly lower frequencies. Most current theories of PD pathophysiology and DBS mechanisms of action fail to explain results of the kind demonstrated herein.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Weight gain following bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson disease (PD) has been characterized previously, but little is known about changes in weight following unilateral STN DBS. Weight gain of approximately 10 kg at one year after bilateral STN DBS for PD has been noted in previous studies, and PD in the absence of DBS has been associated with weight loss. A case-control comparison evaluated the change in weight following unilateral STN DBS in PD. In 39 patients who underwent unilateral STN DBS for PD, we measured the weight change over 1 year versus both preoperative weight change and the weight change in 40 age- and disease severity-matched PD controls without DBS. Regression analyses incorporating age, gender, baseline weight in case or control were conducted to assess weight changes. At 12 months following surgery, the mean weight of unilateral STN DBS patients increased by 4.3+/-7.2 kg versus the preoperative baseline weight (p0.001) and this increase was 4.8 kg compared with the controls (p=0.015). Over a 1 year time interval, weight gain occurred in 41% of the preoperative unilateral STN DBS patients and 45% of the PD controls, while 85% of the unilateral STN DBS patients had gained weight at 12 months after surgery (p0.0001, respectively, chi square test). We conclude that unilateral STN DBS in PD is associated with weight gain, which offsets weight loss associated with advanced PD.

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 10(8) fmol/min x 10(6) cells, and that this uptake can be specifically blocked 88% by the addition of 10nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP-treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18-F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5-13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer-encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

Recent evidence from clinical studies suggests an expanded role for dopamine agonists as initial dopaminergic monotherapy in the treatment of Parkinson's disease (PD). The rationale for the use of dopamine agonist monotherapy in early disease is to delay the initiation of levodopa or to decrease the total exposure to levodopa, thereby reducing the motor complications of long-term levodopa therapy. Dopamine agonists, when used alone, rarely promote the development of dyskinesias and motor fluctuations that complicate levodopa treatment. Theoretically, there is potential for a neuroprotective effect by decreasing the oxidative breakdown of dopamine and free radical generation. Because they act on postsynaptic dopamine receptors of the striatum, dopamine agonists act independent of the synthetic dopaminergic enzyme system and are not dependent on degenerating presynaptic neurons in the substantia nigra. This article will review the traditional role of dopamine agonists and will focus on emerging strategies for the treatment of PD, including early monotherapy with dopamine agonists and early combination therapy with dopamine agonists and levodopa.

We investigated clinical and neuropathologic heterogeneity and apolipoprotein E (apoE) genotype in 11 cases of neuropathologically diagnosed corticobasal degeneration (CBD). Although seven of the 11 patients presented with unilateral limb dysfunction, the remaining four patients had less typical presentations including memory loss, behavioral changes, and difficulties with speech or gait. All 11 patients eventually developed extrapyramidal signs as well as cortical features, most commonly apraxia. At autopsy, the brains of seven of the 11 patients exhibited predominant neuronal loss and gliosis of perirolandic cortex; degeneration of more rostral frontal cortex was observed in three of the four patients with atypical clinical presentations. All cases displayed ballooned neurons, tau-positive neuronal and glial inclusions, threads and grains, and nigral degeneration. Six of the 11 cases manifested overlapping neuropathologic features of one or more disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Parkinson's disease (PD), and hippocampal sclerosis. Interestingly, these six patients all exhibited memory loss early in the course of their illness. The 11 CBD cases exhibited increased frequency (0.32) of the epsilon 4 allele of apoE, relative to control populations; the frequency remained elevated (0.25) even when the three cases with concomitant AD were excluded. Beta-amyloid (A beta) deposition in hippocampus or cortex was present in five of the seven cases with an epsilon 4 genotype. These observations indicate that CBD is a pathologically and clinically heterogeneous disorder with substantial overlap with other neurodegenerative disorders.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Purpose Financial capacity (FC) is an instrumental activity of daily living (IADL) critical to independent functioning and sensitive to cognitive impairment in dementia. Little is known about FC in cognitively impaired patients with Parkinson's disease (PD). The present study investigated FC in PD patients with prodromal and clinical dementia. Methods Participants were 20 older controls and 35 PD patients who met consensus criteria for either mild cognitive impairment (PD-MCI, n = 18) or PD dementia (PDD, n = 17). FC was assessed using a standardized performance based measure consisting of 9 domain and two global scores (Financial Capacity Instrument; FCI) (1). FCI domain and global performance scores were compared across groups. Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) were calculated for each PD patient's domain and global scores. Results Relative to controls, PD-MCI patients were impaired on both FCI global scores and domains of basic monetary skills, financial concepts, and investment decision-making. Relative to both controls and PD-MCI patients, PDD patients were impaired on virtually all FCI variables. With respect to impairment ratings, greater than 50% of PD-MCI patients and greater than 90% of PDD patients were classified as either mild/moderate or severely impaired on the two FCI global scores. Conclusions Impairment of financial capacity is already present in PD-MCI and is advanced in PDD. Complex cognitively-mediated IADLs such as financial capacity appear to be impaired early in the course of PD dementia.