Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease.

BACKGROUND AND PURPOSE: Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison. MATERIALS AND METHODS: Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years. RESULTS: Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline (P < .001 and P = .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group × time interaction increases (P = .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group × time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra. CONCLUSIONS: Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared with previously studied cohorts and the known posterior-to-anterior substantia nigra degeneration that occurs over time in idiopathic Parkinson disease.

Influence of gender on Tourette syndrome beyond adolescence.

Although boys are disproportionately affected by tics in Tourette syndrome (TS), this gender bias is attenuated in adulthood and a recent study has suggested that women may experience greater functional interference from tics than men. The authors assessed the gender distribution of adults in a tertiary University-based TS clinic population and the relative influence of gender and other variables on adult tic severity (YGTSS score) and psychosocial functioning (GAF score). We also determined retrospectively the influence of gender on change in global tic severity and overall TS impairment (YGTSS) since adolescence. Females were over-represented in relation to previously published epidemiologic surveys of both TS children and adults. Female gender was associated with a greater likelihood of tic worsening as opposed to tic improvement in adulthood; a greater likelihood of expansion as opposed to contraction of motor tic distribution; and with increased current motor tic severity and tic-related impairment. However, gender explained only a small percentage of the variance of the YGTSS global severity score and none of the variance of the GAF scale score. Psychosocial functioning was influenced most strongly by tic severity but also by a variety of comorbid neuropsychiatric disorders.

Influence of family history on clinical expression of Tourette's syndrome.

OBJECTIVE: To determine the influence of family history on clinical expression of Tourette's syndrome (TS). BACKGROUND: Recent studies have suggested that clinical expression of TS is similar among sporadic (SP) and familial patients but may be influenced by bilineal (BIL) transmission of tics or obsessive-compulsive behavior (OCB) in high-density pedigrees. METHODS: The authors used family history methodology, supported by direct examination of affected relatives in 73% of familial patients, to determine the frequency of SP TS, and of unilineal (UNL) and BIL transmission of tics or OCB in 111 consecutively ascertained juvenile TS patients. For individuals in each group, severity of tics, attention deficit hyperactivity disorder (ADHD), and OCB were assessed at presentation and after a mean follow-up interval of 2.6 years, using the Tourette's Syndrome Global Scale and the Clinical Global Impression scales. The phenomenology of OCB was evaluated using the symptom checklist of the Children's Yale-Brown Obsessive Compulsive Scale. RESULTS: The authors documented BIL transmission of tics in seven patients (6%). Patient age and sex were similar for the SP (n = 21; 19%), UNL (n = 66; 59%), and BIL (n = 24; 22%) groups, as was ADHD and tic severity at presentation and follow-up. Severity of OCB differed significantly between groups, with moderate to severe OCB affecting 5% of SP, 12% of UNL, and 37% of BIL patients at presentation (p = 0.007), and 5% of SP, 17% of UNL, and 54% of BIL patients at follow-up (p = 0.0001). Relative to UNL or SP patients, BIL patients were more likely to exhibit self-injurious behaviors (p = 0.0005). CONCLUSIONS: OCB is less prominent in SP than in familial TS, perhaps reflecting a more restricted pathophysiology in this subgroup. Although BIL transmission of tics is relatively infrequent in consecutive TS pedigrees, cotransmission of OCB from an otherwise unaffected parent is common and significantly influences development of OCB and self-injurious behaviors, but not tics, in offspring. Genetic heterogeneity, epigenetic factors, and gene-environment interactions may play a more important role than genetic dosage effects in determining tic severity in TS.

Slowed reaction time during a continuous performance test in children with Tourette's syndrome.

The phenomonology of Tourette's syndrome (TS) not only includes tics but also apparent deficits in attention. These attentional deficits in TS likely involve anomalies in frontal-striatal circuits. In this study, performance of 22 boys with TS and 22 age-matched boys without TS was compared on a continuous performance test (CPT) of attention. TS children demonstrated a normal capacity for discriminating targets from nontargets during the task, but showed significantly slower reaction times than controls. Severity of complex vocal tics was predictive of reaction time performance. Possible explanations for these findings are discussed and include the presence of attentional difficulties in TS, interference associated with tic suppression, a conservative strategy taken by TS children, and a general impairment of motor performance.

Predictors of clonidine response in Tourette syndrome: implications and inferences.

Clonidine is an alpha-adrenergic agonist which may alleviate emerging symptoms in Tourette syndrome, an observation that has fueled speculation regarding involvement of stress-sensitive central noradrenergic systems in this disorder. We conducted a retrospective study of 53 juvenile patients with Tourette syndrome to assess predictors of short-term behavioral and tic response to oral clonidine and to examine the relationship, if any, among pretreatment blood pressure, tic severity, and clonidine response. When adverse effects were considered, older subjects experienced a better therapeutic response to clonidine, independent of dose. Improvement in symptoms of attention-deficit hyperactivity disorder was associated with a longer duration of vocal tics before treatment. Baseline sitting diastolic blood pressure was directly correlated with measures of tic severity but not with tic response to clonidine. The findings (1) provide indirect support for involvement of central noradrenergic systems in tic expression; (2) suggest that emergence of a tic-related neurophysiologic dysfunction may be necessary for optimal behavioral response to clonidine in Tourette syndrome; and (3) provide broad guidelines for the clinician considering clonidine therapy for pediatric patients with Tourette syndrome, particularly those with comorbid attention-deficit hyperactivity disorder.

Parkinsonism associated with fluoxetine and cimetidine: a case report.

Fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of depression in the elderly and offer a safer side-effect profile as compared to tricyclics and monoamine oxidase inhibitors. We report a case in which a patient treated with fluoxetine developed parkinsonism following the introduction of cimetidine. Inhibition of hepatic P450 cytochrome enzymes by cimetidine with an increase in serum levels of norfluoxetine may have precipitated this extrapyramidal syndrome, which has been related to agonism of the serotonergic input to nigrostriatal tracts and basal ganglia. Parkinsonism as a side effect of SSRIs occurs infrequently, suggesting an idiosyncratic response resulting from a functional imbalance of serotonergic and dopaminergic activity in susceptible individuals. Careful monitoring of geriatric patients treated with fluoxetine is indicated, particularly for those on high doses, those with impaired hepatic functioning, or those treated with concurrent medications that slow the metabolism of fluoxetine.

Clinical evidence of genomic imprinting in Tourette's syndrome.

Recent genetic studies of Tourette's syndrome (TS) have suggested a sex-specific expression of TS behaviors but not a sex-associated difference in their transmission. In a retrospective study designed to assess the influence of gender of the affected parent on childhood TS phenotype, we compared unmedicated TS subjects with patrilineal (n = 25) or matrilineal (n = 25) inheritance of TS, as determined by family history methodology, with respect to demographic variables, temporal profile of tic evolution, and clinical ratings of tics and associated behaviors, particularly obsessive-compulsive symptoms and attention deficit hyperactivity disorder (ADHD). Maternal transmission of TS was characterized by trends toward greater motor tic complexity and more frequent noninterfering rituals (p < 0.05); paternal transmission was associated with increased vocal tic frequency (p = 0.01), an earlier onset of vocal tics relative to motor tics (p < 0.01), and more prominent ADHD behaviors, including motor restlessness (p < 0.01). These findings are consistent with genomic imprinting in TS. Confirmation of this phenomenon promises not only to advance understanding concerning the genetic link between TS and ADHD but may also help to explain the apparent fit of competing models of genetic transmission in TS.

Tremor at onset. Predictor of cognitive and motor outcome in Parkinson's disease?

We examined 46 male patients with idiopathic Parkinson's disease to see whether tremor at onset was as useful a predictor of benign clinical outcome as tremor predominance after several years. When we compared patients with tremor at onset (n = 27) with those whose disease began with brady-kinesia/rigidity (n = 9), or gait disorder (n = 10), we found no significant differences after a mean of 7 years in motor, cognitive, or affective status. Sixteen of the tremor-onset patients continued to have tremor predominance with minimal gait disorder after about 7 years. These tremor-predominant patients had significantly better motor outcome and somewhat better cognitive outcome than either tremor-onset patients who subsequently developed gait disorder (n = 11) or patients without tremor at onset (n = 19). Tremor predominance after several years appears to be a better predictor of a benign clinical course of Parkinson's disease than tremor at onset.

Cognitive and motor dysfunction in Parkinson's disease. Clinical, performance, and computed tomographic correlations.

The neuropathologic and pathophysiological relationship of specific to more generalized cognitive dysfunction in Parkinson's disease (PD) remains incompletely understood. This issue was examined in a study of 39 patients with PD, utilizing standardized clinical measures, computerized neuropsychological tests, and quantitative computed tomography. Disorders of visuospatial discrimination and perceptual-motor function closely paralleled motor scores, suggesting a common neuropathologic basis. Caudate nuclear and mesocortical dopamine depletion play a role in this context. More generalized cognitive dysfunction occurred in older patients with a somewhat longer disease duration, more advanced parkinsonism, and computed tomographic evidence of subcortical and frontal cortical atrophy but without significant cerebral atrophy when compared with age-matched controls. Further prospective clinicopathologic studies will be required to clarify the relative contribution of the primary dopaminergic dysfunction, age-related changes, Alzheimer-type pathologic condition, and other coexisting neurotransmitter deficits to the dementia seen in PD.