Paul Tuite

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson's disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)

Based on new understanding of nondopaminergic pathways involved in Parkinsons disease (PD) pathophysiology, a selective adenosine A2A receptor antagonist, istradefylline, shows promise for the treatment of PD.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Proprioception and Motor Control in Parkinson's Disease

ABSTRACT Parkinsons disease (PD) is a neurodegenerative disorder that leads to a progressive decline in motor function. Growing evidence indicates that PD patients also experience an array of sensory problems that negatively impact motor function. This is especially true for proprioceptive deficits, which profoundly degrade motor performance. This review specifically address the relation between proprioception and motor impairments in PD. It is structured around 4 themes: (a) It examines whether the sensitivity of kinaesthetic perception, which is based on proprioceptive inputs, is actually altered in PD. (b) It discusses whether failed processes of proprioceptive-motor integration are central to the motor problems in PD. (c) It presents recent findings focusing on the link between the proprioception and the balance problems in PD. And (d) it discusses the current state of knowledge of how levodopa medication and deep brain stimulation affect proprioceptive and motor function in PD. The authors conclude that a failure to evaluate and to map proprioceptive information onto voluntary and reflexive motor commands is an integral part of the observed motor symptoms in PD.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Altered Diffusion in the Frontal Lobe in Parkinson Disease

BACKGROUND AND PURPOSE: Parkinson disease (PD) is characterized by basal ganglia abnormalities. However, there are neurodegenerative changes in PD that extend beyond the basal ganglia and that are not sufficiently evaluated with standard MR imaging. The aim of this study was to characterize whole-brain gray matter (GM) and white matter (WM) changes in PD by using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Thirteen control and 12 subjects with nondemented PD were examined by using DTI and 3D anatomic T1-weighted images. Statistical parametric mapping analyses of DTI and anatomic images were performed. Patients were evaluated with a variety of neurocognitive measures and the Unified Parkinsons Disease Rating Scale (UPDRS) OFF (cessation of medication) and ON (taking medications as normal) their antiparkinsonian medications. RESULTS: The PD participants had dopa-responsive features as ascertained by the UPDRS OFF versus ON medications and had no cognitive impairment. Decreased fractional anisotropy (FA) was observed in subjects with PD bilaterally in the frontal lobes, including the supplementary motor area, the presupplementary motor area, and the cingulum. There were no significant differences in mean diffusivity or GM/WM attenuation between PD subjects and controls. CONCLUSION: Statistical parametric mapping analysis of DTI showed changes in FA in frontal areas without volume loss. These results confirm that the neurodegenerative process extends beyond the basal ganglia in PD.

Paraneoplastic chorea associated with CRMP‐5 neuronal antibody and lung carcinoma

Paraneoplastic chorea is described in 16 patients: 11 with limited small‐cell carcinoma, 2 with lung cancer revealed by imaging, 1 with renal cell carcinoma, and 1 with lymphoma. All had CRMP‐5‐IgG; 6 also had ANNA‐1 (anti‐Hu), including 1 without evident cancer. Chorea was the initial and most prominent symptom in 11 patients, asymmetric or unilateral in 5 patients, and part of a multifocal syndrome in 14 patients. Basal ganglia abnormalities were revealed by magnetic resonance imaging and at autopsy (as perivascular inflammation and microglial activation). Four patients improved with chemotherapy, and 2 improved with intravenous methylprednisolone.

Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts

Postmortem demonstration of increased iron in the substantia nigra (SN) is a well‐appreciated finding in Parkinsons disease (PD). Iron facilitates generation of free radicals, which are thought to play a role in dopamine neuronal loss. To date, however, magnetic resonance imaging (MRI) has failed to show significant in vivo differences in SN iron levels in subjects with PD versus control subjects. This finding may be due to the limitations in tissue contrasts achievable with conventional T1‐ and T2‐weighted MRI sequences that have been used. With the recent development of novel rotating frame transverse (T2ρ) and longitudinal (T1ρ) relaxation MRI methods that appear to be sensitive to iron and neuronal loss, respectively, we embarked on a study of 8 individuals with PD (Hoehn & Yahr, Stage II) and 8 age‐matched control subjects. Using these techniques with a 4T MRI magnet, we assessed iron deposits and neuronal integrity in the SN. First, T2ρ MRI, which is reflective of iron‐related dynamic dephasing mechanisms (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities), demonstrated a statistically significant difference between the PD and control group, while routine T2 MRI did not. Second, T1ρ measurements, which appear to reflect upon neuronal count, indicated neuronal loss in the SN in PD. We show here that sub‐millimeter resolution T1ρ and T2ρ MRI relaxation methods can provide a noninvasive measure of iron content as well as evidence of neuronal loss in the midbrain of patients with PD.

Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS.

Background Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. γ-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p<0.001 for pons and p<0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of the lower brainstem. This study provides in vivo evidence for an alteration in the GABAergic tone in the lower brainstem and striatum in early-moderate PD, which may underlie disease pathogenesis and may provide a biomarker for disease staging.

Interval timing and Parkinson's disease: heterogeneity in temporal performance.

Interval timing deficiencies in Parkinson’s disease (PD) patients have been a matter of debate. Here we test the possibility of PD heterogeneity as a source for this discrepancy. Temporal performance of PD patients and control subjects was assessed during two interval tapping tasks and during a categorization task of time intervals. These tasks involved temporal processing of intervals in the hundreds of milliseconds range; however, they also covered a wide range of behavioral contexts, differing in their perceptual, decision-making, memory, and execution requirements. The results showed the following significant findings. First, there were two clearly segregated subgroups of PD patients: one with high temporal variability in the three timing tasks, and another with a temporal variability that did not differ substantially from control subjects. In contrast, PD patients with high and low temporal variability showed similar perceptual, decision-making, memory, and execution performance in a set of control tasks. Second, a slope analysis, designed to dissociate time-dependent from time-independent sources of variation, revealed that the increase in variability in this group of PD patients was mainly due to an increment in the variability associated with the timing mechanism. Third, while the control subjects showed significant correlations in performance variability across tasks, PD patients, and particularly those with high temporal variability, did not show such task correlations. Finally, the results showed that dopaminergic treatment restored the correlation effect in PD patients, producing a highly significant correlation between the inter-task variability. Altogether, these results indicate that a subpopulation of PD patients shows a strong disruption in temporal processing in the hundreds of milliseconds range. These findings are discussed in terms of the role of dopamine as a tuning element for the synchronization of temporal processing across different behavioral contexts in PD patients.