Karen Blindauer

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families

Objective: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreichs ataxia (FA) among a large panel of ataxia families. Background: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. Methods: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. Results: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. Conclusions: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Test–Retest reliability of the Unified Parkinson's Disease Rating Scale in patients with early Parkinson's disease: Results from a multicenter clinical trial

Our objective was to assess the test–retest reliability of the Unified Parkinsons Disease Rating Scale (UPDRS). The UPDRS is the most widely used instrument for measuring severity of parkinsonian symptoms in clinical research and in practice. The validity and inter‐rater reliability of this scale have been previously studied. We examined the test–retest (intrarater) reliability of the UPDRS and derived subscales. Four hundred patients with early‐stage Parkinsons disease (PD) who were participating in a multicenter clinical trial were evaluated using the UPDRS on two separate occasions (screening and baseline visits) prior to receiving treatment. The same neurologist at each center rated the subjects at both examinations that were, on average, 14.6 ± 7.6 days apart (range 3–36 days). Test–retest reliability was estimated using the intraclass correlation coefficient (ICC) for the total UPDRS score, the mental, ADL, and motor subscale scores, and other derived subscale scores. Weighted kappa statistics were calculated for individual UPDRS items. The ICCs for the UPDRS scores were as follows: total score, 0.92; mental, 0.74; ADL, 0.85; motor, 0.90. ICCs for derived symptom‐based scales ranged from 0.69–0.88. Reliability of specific items was generally lower than for summary scales. Reliability was slightly better in patients for whom the testing interval was within 14 days. Based on conventional standards, the UPDRS scores were found to have excellent test–retest reliability in this sample of patients with early PD rated by academic movement disorder specialists. The findings are in agreement with previous reports on interrater reliability.

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.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

IMPORTANCE Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01795859.

Rasagiline improves quality of life in patients with early Parkinson's disease

The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinsons disease (PD). Rasagiline, a potent, second‐generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once‐daily rasagiline 1 mg/day, rasagiline 2 mg/day, or placebo in a 6‐month, double‐blind trial (n = 404). At the end of 6 months, patients entered the preplanned, active‐treatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinsons Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of −2.91 units (−5.19, −0.64, P = 0.01) for the 1 mg/day group and −2.74 units (−5.02, −0.45, P = 0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit to the self‐image/sexuality domain. At 12 months (n = 266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline.

Effects of tyramine administration in Parkinson's disease patients treated with selective MAO-B inhibitor rasagiline

Rasagiline is a novel, potent, and selective MAO‐B inhibitor shown to be effective for Parkinsons disease. Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. To test safety, tyramine challenges (50–75 mg) were performed in 72 rasagiline‐treated and 38 placebo‐treated Parkinsons disease (PD) patients at the end of two double‐blind placebo‐controlled trials of rasagiline. An abnormal pressor response was prespecified as three consecutive measurements of systolic blood pressure (BP) increases of ≥ 30 mm Hg and/or bradycardia of < 40 beats/min. In the first study involving 55 patients with early PD on rasagiline monotherapy, no patients randomized to rasagiline (1 mg/2 mg; n = 38) or placebo (n = 17) developed systolic BP (SBP) or heart rate changes indicative of a tyramine reaction. In the second trial involving 55 levodopa‐treated patients, 3 of 22 subjects on rasagiline 0.5 mg/day and 1 of 21 subjects on placebo developed asymptomatic, self‐limiting SBP elevations ≥ 30 mm Hg on three measurements. No subject on 1 mg/day rasagiline (0/12) experienced significant BP or heart rate changes following tyramine ingestion. These data demonstrate that rasagiline 0.5 to 2 mg daily is not associated with clinically significant tyramine reactions and can be used as monotherapy or adjunct to levodopa in PD patients without specific dietary tyramine restriction.

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.

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinsons disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinsons disease in our large sample of familial PD patients.

Where is the action? Action sentence processing in Parkinson's disease

According to an influential view of conceptual representation, action concepts are understood through motoric simulations, involving motor networks of the brain. A stronger version of this embodied account suggests that even figurative uses of action words (e.g., grasping the concept) are understood through motoric simulations. We investigated these claims by assessing whether Parkinsons disease (PD), a disorder affecting the motor system, is associated with selective deficits in comprehending action-related sentences. Twenty PD patients and 21 age-matched controls performed a sentence comprehension task, where sentences belonged to one of four conditions: literal action, non-idiomatic metaphoric action, idiomatic action, and abstract. The same verbs (referring to hand/arm actions) were used in the three action-related conditions. Patients, but not controls, were slower to respond to literal and idiomatic action than to abstract sentences. These results indicate that sensory-motor systems play a functional role in semantic processing, including processing of figurative action language.

Fulminant progression of demyelinating disease after valproate-induced encephalopathy

We report the clinical, radiologic, and pathologic features of a patient who had fulminant demyelinating disease and who experienced acute progression of his disease after an episode of valproate-induced hyperammonemic encephalopathy. The role hyperammonemia played in the progression of the demyelination is uncertain. This case raises concern of a possible risk with the use of valproic acid in the subset of patients with fulminant demyelinating disease.