Objective: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). Methods: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. Results: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. Conclusions: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. Classification of Evidence: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Objective: To investigate the incidence of and risk factors for cognitive impairment in a large, well-defined clinical trial cohort of patients with early Parkinson disease (PD).Methods: The Mini-Mental State Examination (MMSE) was administered periodically over a median follow-up period of 6.5 years to participants in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial and its extension studies. Cognitive impairment was defined as scoring 2 standard deviations below age-and education-adjusted MMSE norms.Results: Cumulative incidence of cognitive impairment in the 740 participants with clinically confirmed PD (baseline age 61.0 +/- 9.6 years, Hoehn-Yahr stage 1-2.5) was 2.4% (95% confidence interval: 1.2%-3.5%) at 2 years and 5.8% (3.7%-7.7%) at 5 years. Subjects who developed cognitive impairment (n = 46) showed significant progressive decline on neuropsychological tests measuring verbal learning and memory, visuospatial working memory, visuomotor speed, and attention, while the performance of the nonimpaired subjects (n = 694) stayed stable. Cognitive impairment was associated with older age, hallucinations, male gender, increased symmetry of parkinsonism, increased severity of motor impairment (except for tremor), speech and swallowing impairments, dexterity loss, and presence of gastroenterologic/urologic disorders at baseline.Conclusions: The relatively low incidence of cognitive impairment in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study may reflect recruitment bias inherent to clinical trial volunteers (e.g., younger age) or limitations of the Mini-Mental State Examination-based criterion. Besides confirming known risk factors for cognitive impairment, we identified potentially novel predictors such as bulbar dysfunction and gastroenterologic/urologic disorders (suggestive of autonomic dysfunction) early in the course of the disease. Neurology (R) 2009;73:1469-1477

Organized by the Huntington Study GroupTo be held on Saturday, 1 December 2007, in the Rooftop Ballroom at the Omni Parker House, Boston

Background: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. Methods: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. Results: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). Conclusions: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

BACKGROUND:Tourette syndrome (TS) and related tic disorders are commonly associated with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). It has been argued, however, that any observed association between TS and these and other psychopathologies may be due to ascertainment bias in that individuals with multiple problems are more likely to be referred for medical evaluation.METHODS:In order to overcome the potential confounding by ascertainment bias, the authors conducted a community-based study of school children using direct interviews to determine the prevalence of tic disorders and any comorbid psychopathology. A standard psychiatric interview and standardized rating scales were utilized to diagnose childhood behavioral disorders.RESULTS:Of the 1,596 children interviewed, 339 were identified as having tics. The following psychopathologies were found more commonly (p < 0.05) in the children with tics: OCD, ADHD, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, mania, major depression, and oppositional defiant behavior.CONCLUSION:The behavioral spectrum of tic disorders includes OCD, other anxiety disorders, a mood disorder, and attention-deficit and disruptive behavior disorders.

Objectives: To determine whether chronic treatment with coenzyme Q(10) or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD). Methods: The authors conducted a multicenter, parallel group, double-blind, 2 X 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q(10) 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events. Results: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q(10) showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q(10). Conclusions: Neither remacemide nor coenzyme Q(10), at the dosages studied, produced significant slowing in functional decline in early HD.

Background: Based on the knowledge that Tourette's syndrome (TS) is associated with several clinical features that can impair school function and growing evidence that the disorder is much more common than previously thought, the authors hypothesized that TS and related tic disorders would be associated with school problems in the childhood population at large. Methods: Direct, blinded (to educational placement) interviews of 1,596 schoolchildren in Monroe County, Rochester, NY, were conducted. Results: Twenty-seven percent of 341 students classified as receiving special education (SpEd) had tics compared with 19.7% (p = 0.008) of 1,255 students in regular classroom programs (RegEd). The weighted prevalence estimates for tics were 23.4% in SpEd and 18.5% in RegEd. A higher percentage of students in SpEd (7.0%) met diagnostic criteria for TS than students in RegEd (3.8%; p = 0.01). Conclusions: Although possibly influenced by selection bias, our results indicate that tic disorders are common in children and are highly associated with school dysfunction. Tics may represent an identifiable sign of an underlying brain developmental disorder that contributes to academic difficulties.

The accumulated body of scientific evidence regarding intellectual function, presence of learning disorders, and specific neuropsychological deficits in TS suggests that difficulties in these areas are present in a significant percentage of patients with TS. Despite the numerous methodological shortcomings of past neuropsychological studies of TS, relatively robust and consistent findings have emerged. The literature to date has suggested that intellectual ability is normally distributed in TS. Whether or not individuals with TS have significant discrepancies between their verbal and nonverbal abilities remains unclear. The prevalence of learning disabilities in TS has been reported to be similar to the base rates reported for the general population, although there is evidence to suggest that the prevalence of LDs in children with TS may actually be lower and specific for difficulties in math and written language. Specific cognitive deficits in TS consist of visuomotor integration problems, impaired fine motor skill, and executive dysfunction. The presence of comorbid conditions, notably ADHD and OCD, appears to significantly increase the likelihood that an individual with TS will also have learning problems or some demonstrable cognitive impairment. The presence of a learning disability, specific academic deficiency, or cognitive deficit may pose a greater obstacle for persons with TS than the tic disorder itself. This is particularly salient for children with TS, who may be at a higher risk for poor school performance and academic failure. The psychosocial impact of these problems is also far-reaching. Given the recent emphasis on the early detection of academic and learning problems, it would seem prudent that children with TS who are suspected of having neuropsychological difficulties be evaluated as soon as possible. There are numerous educational interventions and accommodations available to children with LDs and/or specific academic weaknesses that can work equally well in children with TS. The available body of scientific evidence suggests that persons with TS have normally distributed intellectual ability. This would suggest a diminished role for routine IQ testing unless there is compelling clinical evidence to suggest that the IQ score be obtained, such as when the individual is suspected of having an LD. Given that children with TS may be particularly at risk for learning disabilities or academic deficiencies in math and written language, a complete psychoeducational workup should be conducted on any child with TS who is suspected of having such difficulties. This evaluation should be conducted as early as possible, so that educational interventions can be implemented. Traditionally, the psychoeducational evaluation is performed by the school psychologist and should include standardized IQ assessment and academic achievement testing that can objectively identify and quantify the nature and severity of the learning problem. Once the problem has been documented, the school psychologist should recommend appropriate educational and remedial interventions. In addition to psychoeducational testing, neuropsychological testing is indicated to identify specific cognitive deficits that might be present in children with TS, notably problems with visuomotor integration, motor skill, and executive function. The psychoeducational evaluation performed by the school psychologist typically does not assess these cognitive functions. Therefore, referral for neuropsychological testing is indicated if there is a strong clinical suspicion of cognitive deficits. The accumulated neuropsychological literature in TS suggests that a broad-based, comprehensive, and lengthy neuropsychological examination is not necessary, however. At a minimum, the neuropsychological test battery should include assessment of visuomotor integration ability, motor skills, spatial/perceptual abilities, and executive function. This type of assessment would take less time to complete and has greater sensitivity and specificity for identifying neurocognitive deficits that are believed to be unique to TS. Neuropsychological functioning continues to be an important component in understanding the full neurobehavioral spectrum of TS. At present, there is great opportunity to explore neuropsychological functioning in TS with newly emerging technology such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and related techniques that assess cortical metabolic activity, as well as newer electrophysiological techniques. This technology, notably fMRI, allows investigation of neuropsychological functioning in vivo and may reveal important clues to the neuroanatomic substrates of neuropsychological impairment of learning disabilities in TS.

Developmental stuttering (DS) may be related to the extrapyramidal motor system and shares many clinical similarities with Tourette's syndrome (TS), which is widely believed to be associated with extrapyramidal dysfunction. Twenty-two stutterers were examined for neuropsychiatric features commonly seen in TS, including tics, obsessive-compulsive behaviors (OCB), and attention deficit disorders. Eleven stutterers displayed motor tics, and symptoms of OCB were observed at rates similar to those seen in persons with TS. Few stutterers demonstrated significant attentional deficits. Findings are consistent with models suggesting extrapyramidal involvement in DS and raise the possibility that DS and TS are pathogenetically related.

Recent evidence has suggested that the commonly observed comorbid behavioral disorders of Tourette syndrome, including attention deficit hyperactivity disorder and obsessive-compulsive disorder clearly have an impact on cognitive, educational, and psychosocial function. These behavioral features of Tourette syndrome can be more debilitating than the cardinal motor features of the disorder and they require careful clinical assessment so that appropriate treatment intervention can be offered to patients and their families. This article focuses on objective neuropsychological and behavioral assessment of obsessive-compulsive disorder and attention deficit hyperactivity disorder which have proven useful for both the clinical evaluation and treatment of obsessive-compulsive disorder and attention deficit hyperactivity disorder associated with Tourette syndrome and in the research setting. Instruments with proven psychometric reliability and validity for assessing obsessive-compulsive disorder and attention deficit hyperactivity disorder which also have been useful in Tourette syndrome populations are discussed. Objective and quantitative assessment of these comorbid behavioral conditions greatly enhance our ability to treat the full neurobehavioral spectrum of Tourette syndrome.

BACKGROUND A retrospective study of 138 children with Tourette's syndrome for associated school problems revealed that at the time of initial evaluation, 64 subjects (46%) experienced a school-related problem. OBJECTIVE To survey a childhood population with Tourette's syndrome to explore the contributions of neurobehavioral concomitants to academic difficulties. RESULTS A diagnosis of a specific learning disorder had previously been made in 30 (22%) of 138 children. Among the 108 without a diagnosis of learning disorder, 36 (33%) experienced school difficulties defined as grade retention (16 [15%]) and/or special education placement (41 [38%]). Regression analysis of subjects without a diagnosis of learning disability revealed that the presence of attention-deficit hyperactivity disorder served as a significant predictor of school problems. CONCLUSIONS Tics represented the primary reason for referral, but did not emerge as a significant predictor of academic problems. Rather, school-related difficulties appeared to be strongly associated with comorbid attention-deficit hyperactivity disorder.

The authors surveyed 87 adolescent or adult patients with Tourette's syndrome (TS) regarding the presence, characteristics, and functional impact of non-obscene socially inappropriate (SI) behavior. Reported behaviors included insulting others (22%), other SI comments (5%), and SI actions (14%). More often, subjects described having an urge to carry out these behaviors (30%, 26%, 22%, respectively), which they often attempted to suppress. Non-obscene SI behavior was usually directed at a family member or familiar person, at home or in a familiar setting. Social difficulties commonly resulted. Non-obscene SI behavior is a common and potentially disabling feature of TS. It is closely associated with conduct disorder and attention deficit disorder and may represent part of a more general dysfunction of impulse control in TS.

Seventeen adult Tourette's syndrome (TS) patients, 17 adult attention deficit-hyperactivity disorder (ADHD) patients, and 17 adult controls completed a battery of attentional tests and self-report measures of ADHD and obsessive-compulsive disorder (OCD) symptoms. ADHD but not TS participants performed significantly worse than controls on tests of mental flexibility and psychomotor speed. Both the ADHD and TS groups, however, had significantly greater test performance variability as well as several outliers on most of the measures. Among TS patients, those with comorbid ADHD performed significantly worse than TS patients without ADHD on tests of mental flexibility and psychomotor speed, suggesting ADHD-related attentional impairment in TS. In addition, greater amounts of OCD symptomatology were associated with poorer test performance among TS patients.

A substantial body of scientific evidence suggests that obsessive-compulsive behavior occurs in a large percentage of patients with TS. Reliable estimates suggest that nearly 50% of patients with TS have some degree of obsessive-compulsive features. Most patients with TS have only mild OCB and thus would not meet the DSM-IV diagnostic criteria for OCD. Therefore, OCB is perhaps a more appropriate characterization of this behavioral phenomenon that occurs in TS. OCB in TS appears similar to the spectrum of the tic disorder in terms of its onset, severity, and course. As with tics, OCB is typically mild and not always substantially disabling. Although clinical features between TS + OCB and primary OCD overlap considerably, patients with TS + OCB appear to experience different types of obsessive thoughts and compulsive rituals. Compelling genetic evidence suggests that OCB may be an alternative expression of the TS phenotype, which may selectively affect female gene carriers. Identifying the TS gene in the future will substantially broaden our knowledge of this intriguing neurobehavioral disorder. Finally, neurobiologic evidence points to similar anatomic and chemical substrates in the pathogenesis of TS and OCD, suggesting that these two disorders share a common pathophysiology. The clinical evaluation of patients with TS and their families should always include an assessment for OCB. Self-rated inventories of OCD such as the LOI, LOI-CV, and MOCI are useful screening scales. A more structured interview using the Y-BOCS (CY-BOCS) is useful for determining the degree and severity of OCB in TS as well as the response to therapy. Clinicians should keep in mind that OCB may be the most disabling feature of TS and may require treatment. Pharmacologic agents, such as SSRIs, and traditional behavioral therapy are proven effective treatments for OCB, which can substantially reduce the full effect of TS on patients and their families.

To determine whether children requiring special education represent a high-risk group for identifying Tourette's syndrome (TS), we performed direct examinations for the presence of tics in 35 special education and 35 regular classroom students from a single school district. Of the special education students, nine (26%) had definite or probable tics as compared with only two (6%) of the regular classroom students. About one-third of the students with tics currently meet diagnostic criteria for TS and probably more will do so in the future. About one-half of the subjects with tics have evidence of obsessive-compulsive behavior (OCB) or an attention-deficit hyperactivity disorder (ADHD). For three randomly selected students with definite tics, direct examinations of first-degree relatives revealed the presence of tics in all families. Subjects to the limitations of this pilot study, we conclude that TS and related tic disorders are commonly associated with the need for special education in this single school district. TS might also be an important contributor to school problems in the childhood population at large and may be a highly prevalent condition. In addition, we conclude that childhood tics are associated with OCB and ADHD, are genetically determined, and are part of the TS clinical spectrum.