Principal component analysis of PiB distribution in Parkinson and Alzheimer diseases.

OBJECTIVE: To use principal component analyses (PCA) of Pittsburgh compound B (PiB) PET imaging to determine whether the pattern of in vivo ß-amyloid (Aß) in Parkinson disease (PD) with cognitive impairment is similar to the pattern found in symptomatic Alzheimer disease (AD). METHODS: PiB PET scans were obtained from participants with PD with cognitive impairment (n = 53), participants with symptomatic AD (n = 35), and age-matched controls (n = 67). All were assessed using the Clinical Dementia Rating and APOE genotype was determined in 137 participants. PCA was used to (1) determine the PiB binding pattern in AD, (2) determine a possible unique PD pattern, and (3) directly compare the PiB binding patterns in PD and AD groups. RESULTS: The first 2 principal components (PC1 and PC2) significantly separated the AD and control participants (p < 0.001). Participants with PD with cognitive impairment also were significantly different from participants with symptomatic AD on both components (p < 0.001). However, there was no difference between PD and controls on either component. Even those participants with PD with elevated mean cortical binding potentials were significantly different from participants with AD on both components. CONCLUSION: Using PCA, we demonstrated that participants with PD with cognitive impairment do not exhibit the same PiB binding pattern as participants with AD. These data suggest that Aß deposition may play a different pathophysiologic role in the cognitive impairment of PD compared to that in AD.

A pilot study of basal ganglia and thalamus structure by high dimensional mapping in children with Tourette syndrome.

BACKGROUND: Prior brain imaging and autopsy studies have suggested that structural abnormalities of the basal ganglia (BG) nuclei may be present in Tourette Syndrome (TS). These studies have focused mainly on the volume differences of the BG structures and not their anatomical shapes.  Shape differences of various brain structures have been demonstrated in other neuropsychiatric disorders using large-deformation, high dimensional brain mapping (HDBM-LD).  A previous study of a small sample of adult TS patients demonstrated the validity of the method, but did not find significant differences compared to controls. Since TS usually begins in childhood and adult studies may show structure differences due to adaptations, we hypothesized that differences in BG and thalamus structure geometry and volume due to etiological changes in TS might be better characterized in children. OBJECTIVE: Pilot the HDBM-LD method in children and estimate effect sizes. METHODS: In this pilot study, T1-weighted MRIs were collected in 13 children with TS and 16 healthy, tic-free, control children. The groups were well matched for age.  The primary outcome measures were the first 10 eigenvectors which are derived using HDBM-LD methods and represent the majority of the geometric shape of each structure, and the volumes of each structure adjusted for whole brain volume. We also compared hemispheric right/left asymmetry and estimated effect sizes for both volume and shape differences between groups. RESULTS: We found no statistically significant differences between the TS subjects and controls in volume, shape, or right/left asymmetry.  Effect sizes were greater for shape analysis than for volume. CONCLUSION: This study represents one of the first efforts to study the shape as opposed to the volume of the BG in TS, but power was limited by sample size. Shape analysis by the HDBM-LD method may prove more sensitive to group differences.

A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease.

BACKGROUND: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use.  OBJECTIVE: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable. METHODS: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson's Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability. RESULTS: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ­39, Schwab-England ADL assessment, and sleep scores). CONCLUSION: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease.

Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome.

The basal ganglia and thalamus may play a critical role for behavioral inhibition mediated by prefrontal, parietal, temporal, and cingulate cortices. The cortico-basal ganglia-thalamo-cortical loop with projections from frontal cortex to striatum, then to globus pallidus or to substantia nigra pars reticulata, to thalamus and back to cortex, provides the anatomical substrate for this function. In-vivo neuroimaging studies have reported reduced volumes in the thalamus and basal ganglia in individuals with Tourette Syndrome (TS) when compared with healthy controls. However, patterns of neuroanatomical shape that may be associated with these volume differences have not yet been consistently characterized. Tools are being developed at a rapid pace within the emerging field of computational anatomy that allow for the precise analysis of neuroanatomical shape derived from magnetic resonance (MR) images, and give us the ability to characterize subtle abnormalities of brain structures that were previously undetectable. In this study, T1-weighted MR scans were collected in 15 neuroleptic-naïve adults with TS or chronic motor tics and 15 healthy, tic-free adult subjects matched for age, gender and handedness. We demonstrated the validity and reliability of large-deformation high dimensional brain mapping (HDBM-LD) as a tool to characterize the basal ganglia (caudate, globus pallidus and putamen) and thalamus. We found no significant volume or shape differences in any of the structures in this small sample of subjects.

Intravenous levodopa administration in humans based on a two-compartment kinetic model.

Levodopa, when combined with a decarboxylase inhibitor, essentially delivers dopamine directly to the brain, with no net effect on brain blood vessels. For future neuroimaging studies of Parkinson disease and Tourette syndrome, we sought to rapidly produce a biologically relevant levodopa concentration in plasma and then maintain that concentration long enough to assess motor, cognitive, emotional, and neuroimaging responses, while minimizing side effects in levodopa-naive individuals. Based on available pharmacokinetic data and a two-compartment model, we designed a decreasing-exponential-rate infusion to meet these goals. This report gives results of double-blind levodopa and placebo infusions in six healthy subjects. Mean plasma levodopa concentrations were within 3% of their 1200 ng/mL target at 20 and 40 min into the infusion, and within 20% between approximately 12 and 90 min. Levodopa significantly reduced serum prolactin and raised serum growth hormone concentrations. Volunteers had no significant side effects.

Levodopa challenge neuroimaging of levodopa-related mood fluctuations in Parkinson's disease.

Some patients with advanced Parkinson's disease (PD) develop dose-related fluctuations in mood. This may reflect alterations in dopamine-influenced brain circuits that mediate emotion. However, there is no available information to localize which dopamine-influenced neurons may be most affected. Eight patients with PD and clinically significant levodopa-related mood fluctuations (mania, depression, or anxiety) were compared to 13 patients with similarly severe PD and fluctuations of motor function but not of mood. Regional cerebral blood flow (rCBF) was measured with positron emission tomography before and after levodopa (in the presence of carbidopa). The rCBF response to levodopa in medial frontal gyrus and posterior cingulate cortex (PCC) significantly differed between mood fluctuators and control patients (corrected p<0.02). Other regions with uncorrected p<0.001 in this comparison were cortical Brodmann areas 22, 40, 13, 11, and 28, hippocampus, and claustrum. The levodopa activation paradigm detected group differences not evident in a comparison of resting rCBF. Abnormalities of dopamine innervation may produce mood fluctuations via effects on PCC, an area strongly linked to mood and anxiety and with known rCBF responsiveness to levodopa or D2-like dopamine receptor agonists. We speculate that mood fluctuations may arise in parkinsonian patients who have abnormal dopaminergic modulation of caudate nucleus, anterior cingulate cortex, or orbital frontal cortex, all of which innervate PCC. The findings require confirmation in larger and better-matched groups.

Cognitive-pharmacologic functional magnetic resonance imaging in tourette syndrome: a pilot study.

BACKGROUND: Dopamine agonists and antagonists can reduce abnormal movements and vocalizations (tics) in Tourette syndrome (TS); however, dopamine-responsive abnormal function in specific brain regions has not been directly demonstrated in TS. We sought to identify dopamine-modulated brain regions that function abnormally in TS by combining functional magnetic resonance imaging (fMRI), a working memory (WM) task, and infusion of the dopamine prodrug levodopa (while blocking dopamine production outside the brain). METHODS: We obtained complete fMRI data in 8 neuroleptic-naive adults with a chronic tic disorder and in 10 well-matched tic-free control subjects. RESULTS: Different task-sensitive brain regions responded differently to the WM task depending on levodopa status and diagnostic group (analysis of variance [ANOVA], p <.001). Four regions showed interactions with diagnosis (ANOVA, p <.001). In TS subjects, the task induced excessive brain activity in parietal cortex, medial frontal gyrus, and thalamus. Levodopa normalized the excess activity. In left parietal cortex, the degree of normalization was greater in patients with higher levodopa plasma concentrations (n = 6; Spearman's r = -.84, p =.04) and a greater degree of diagnostic confidence of TS (r = -.71, p =.05). CONCLUSIONS: These results are consistent with a dopamine-influenced functional abnormality of brain response in TS and suggest testable hypotheses about the mechanism by which dopamine antagonists and agonists alleviate tics.

Rapid intravenous loading of levodopa for human research: clinical results.

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).

Clinical features and comorbidity of mood fluctuations in Parkinson's disease.

Parkinson's disease (PD) patients commonly develop fluctuations in their motor responses to levodopa within several years of initiation of treatment; some also develop nonmotor fluctuations. The authors performed a case-control study comparing the frequency of comorbid symptoms in 70 PD patients who experienced clinically apparent mood changes during their motor "on" or "off" states with two control groups with no mood fluctuations. Mood fluctuators had significantly younger age at onset and longer disease duration and were significantly more likely to have dementia, psychosis, clinical depression, and motor complications. This association remained after removing effects of age and disease duration.