Christopher O'Brien

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.

Ropinirole for the treatment of early Parkinson's disease

A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist, in patients with early Parkinsons disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n= 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinsons Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinsons disease.

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.

Intensive speech treatment for patients with Parkinson's disease Short- and long-term comparison of two techniques

The purpose of this study was to evaluate the long-term (12 months) effects of two forms of speech treatment on the speech and voice deficits that occur in Parkinsons disease. Thirty-five patients with idiopathic Parkinsons disease were assigned to one of two speech treatment groups: voice and respiration (The Lee Silverman Voice Treatment [LSVT]) or placebo (respiration) treatment. Vocal intensity data from before, immediately after, and at 6 and 12 months after speech treatment revealed statistically significant differences between the treatment groups. Only subjects in the LSVT group improved or maintained vocal intensity above pretreatment levels by 12 months after treatment. The placebo group had statistically significant deterioration of vocal intensity levels from before to 12 months after treatment during conversational monologue. The LSVT group did not deteriorate to levels below pretreatment in vocal intensity over the 12-month period. This study is the first to document the short- and long-term effects of intensive speech treatment (LSVT), which focuses on the voice, for patients with Parkinsons disease compared with a placebo speech treatment group. NEUROLOGY 1996;47: 1496-1504

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.

The efficacy of cognitive-behavioral therapy for insomnia in patients with chronic pain

STUDY OBJECTIVES To assess the efficacy of cognitive-behavioral therapy for insomnia (CBT-I) in patients with non-malignant chronic pain. METHODS Twenty-eight subjects with chronic neck and back pain were stratified according to gender, age, and ethnicity, then assigned to one of the two treatment groups: CBT-I or a contact control condition. INTERVENTION Eight weeks of CBT-I including sleep restriction, stimulus control, sleep hygiene, and one session of cognitive therapy devoted to catastrophic thoughts about the consequences of insomnia. MEASUREMENTS AND RESULTS Outcomes included sleep diary assessments of sleep continuity, pre-post measures of insomnia severity (ISI), pain (Multidimensional Pain Inventory), and mood (BDI and POMS). Subjects receiving CBT-I (n=19), as compared to control subjects (n=9), exhibited significant decreases in sleep latency, wake after sleep onset, number of awakenings, and significant increase in sleep efficiency. The diary findings were paralleled by significant changes in the ISI (p=0.05). Significant improvement (p=0.03) was found on the Interference Scale of the Multidimensional Pain Inventory. The groups did not significantly differ on mood measures or measures of pain severity. CONCLUSIONS CBT-I was successfully applied to patients experiencing chronic pain. Significant improvements were found in sleep as well as in the extent to which pain interfered with daily functioning. The observed effect sizes for the sleep outcomes appear comparable to or better than meta-analytic norms for subjects with Primary Insomnia.

The natural history of embouchure dystonia

Focal task‐specific dystonias are unusual disorders of motor control, often affecting individuals who perform complex repetitive movements. Musicians are especially prone to develop these disorders because of their training regimens and intense practice schedules. Task‐specific dystonia occurring in keyboard or string instrumentalists usually affects the hand. In contrast, there have been few descriptions of musicians with task‐specific dystonia affecting the muscles of the face and jaw. We report detailed clinical observations of 26 professional brass and woodwind players afflicted with focal task‐specific dystonia of the embouchure (the pattern of lip, jaw, and tongue muscles used to control the flow of air into a mouthpiece). This is the largest and most comprehensively studied series of such patients. Patients developed embouchure dystonia in the fourth decade, and initial symptoms were usually limited to one range of notes or style of playing. Once present, dystonia progressed without remission and responded poorly to oral medications and botulinum toxin injection. Patients with embouchure dystonia could be separated by the pattern of their abnormal movements into several groups, including embouchure tremor, involuntary lip movements, and jaw closure. Dystonia not infrequently spread to other oral tasks, often producing significant disability. Effective treatments are needed for this challenging and unusual disorder.

Heterogeneous dopamine receptor changes in early and late Huntington's disease

Quantitative receptor autoradiography was used to study dopamine (DA) receptors in dorsal striatum and its projection regions in brains from individuals dying with Huntingtons disease (HD) and controls. Heterogeneous loss of both D1 and D2 receptors was present in the striatum of early and late stage HD brains. The degree of receptor loss was greater for the D1 receptor than for the D2 receptor in early stage HD. The pattern of receptor loss did not correspond to heterogeneities identified with acetylcholinesterase staining. Progressive loss of D1 receptors in the internal globus pallidus and substantia nigra pars reticulata and D2 receptors in the external globus pallidus corresponded to advancing pathologic grade.

Striatonigral degeneration Clinical, MRI, and pathologic correlation

We report a patient with striatonigral degeneration in whom T2-weighted MRI imaging revealed low signal and atrophy in the putamen. Neuropathologic studies confirmed putaminal atrophy and iron deposition in the MRI low signal regions.

Interrater agreement in the assessment of motor manifestations of Huntington's disease

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntingtons disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy‐five clinicians experienced in the evaluation of patients with early HD and six non‐clinicians were shown a videotape compiled from the film archives of the United States–Venezuela Collaborative HD Research Project. Observers were asked to rate a 2–3‐minute segment of the motor examination for each of 17 at‐risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted κ statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted κ = 0.67; standard error (SE) = 0.09). Agreement among the non‐clinicians was only fair (weighted κ = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.