Design issues in crossover trials involving patients with Parkinson's disease.

Background and objectives: Crossover designs are frequently used to assess treatments for patients with Parkinson's disease. Typically, two-period two-treatment trials include a washout period between the 2 periods and assume that the washout period is sufficiently long to eliminate carryover effects. A complementary strategy might be to jointly model carryover and treatment effects, though this has rarely been done in Parkinson's disease crossover studies. The primary objective of this research is to demonstrate a modeling approach that assesses treatment and carryover effects in one unified mixed model analysis and to examine how it performs in a simulation study and a real data analysis example, as compared to other data analytic approaches used in Parkinson's disease crossover studies. Methods: We examined how three different methods of analysis (standard crossover t-test, mixed model with a carryover term included in model statement, and mixed model with no carryover term) performed in a simulation study and illustrated the methods in a real data example in Parkinson's disease. Results: The simulation study based on the presence of a carryover effect indicated that mixed models with a carryover term and an unstructured correlation matrix provided unbiased estimates of treatment effect and appropriate type I error. The methods are illustrated in a real data example involving Parkinson's disease. Our literature review revealed that a majority of crossover studies included a washout period but did not assess whether the washout was sufficiently long to eliminate the possibility of carryover. Discussion: We recommend using a mixed model with a carryover term and an unstructured correlation matrix to obtain unbiased estimates of treatment effect.

Possible selves in patients with right- versus left-onset Parkinson's disease.

Possible selves can be used to self-regulate and guide behavior towards what is desired to be achieved or avoided in life. Previous work suggests laterality effects exist within the brain regarding approach and avoidance systems to achieve self-regulation. A modified version of the possible selves task was administered to 45 patients with PD (22 right-onset and 23 left-onset) and 25 community dwelling control subjects (CS). Only 11.1% of patients exhibited balance among their hoped-for and feared possible selves versus 28% of CS. More right-onset patients used a promotion strategy whereas more left-onset patients used a prevention strategy. Patients with left-onset PD thought more about their feared selves, exhibiting reduced goal-directed behavior. Findings among the left-onset group indicate relative dependence of self-regulation on right-sided avoidance brain systems. This may point to an inability to move away from negative outcomes and to work towards rewarding outcomes, which could affect psychological health.

Impacts of religious semantic priming on an intertemporal discounting task: Response time effects and neural correlates.

The purpose of this study is to test the hypothesis that religious primes would influence intertemporal discounting behaviors in neurotypical older adults, but not in participants with Parkinson's disease (PD). Furthermore, we predicted that this priming effect would be related to functional connectivity within neural networks mediating religious cognition, decision-making, reward valuing, and prospection processes. Contrary to past research with young adults, we found a significant positive relationship between religiosity and discounting rates. Religious semantic primes did not reliably shift individual discounting rates. But religious controls did respond more quickly to intertemporal decisions under the religious priming condition than the neutral condition, compared to response time differences among the participants with PD. Differences in response time were significantly associated with functional connectivity between the nucleus accumbens and various regions, including the left anterior cingulate cortex and Brodmann areas 10 and 46 in the right dorsolateral prefrontal cortex. These results suggest that religious primes influence discounting behavior via dopaminergic meso-limbic and right dorsolateral prefrontal supporting cognitive valuation and prospection processes.

A potential case of remission of Parkinson's disease.

We present the case of a 78-year-old male who, 16 years ago, was diagnosed with Parkinson's disease (PD) by a neurologist. He initially presented with left-hand tremor, stooped posture, shuffling gait, and frequent falls, which eventually progressed to bilateral motor symptoms after 3 years. Since 2012, his symptoms and signs have almost completely remitted, and he has been off all pharmacotherapy for that time. The accuracy of the initial PD diagnosis is supported by an appropriate clinical presentation, history of positive response to Sinemet, and an abnormal SPECT DaT scan; thus this case suggests the possibility of remission of symptoms in some patients. We propose that the patient's long history of meditation practice may have been one contributing factor of this improvement as meditation has been shown to release dopamine in the striatum.

Novelty seeking in patients with right- versus left-onset Parkinson disease.

OBJECTIVE AND BACKGROUND: In patients with Parkinson disease, the personality trait "novelty seeking" has been linked to higher-than-normal risk for impulse control disorders. We measured novelty seeking to test whether side of onset of Parkinson disease predicted patients' risk for impulsivity. METHODS: We evaluated 38 patients with Parkinson disease (19 right onset, 19 left onset) and 44 community-dwelling neurotypical controls. All participants completed demographic and mood measures and the Temperament and Character Inventory personality questionnaire. The right- and left-onset groups were nearly the same in background and clinical variables, including use of dopamine agonists. RESULTS: The patients with right-onset disease exhibited significantly higher levels of novelty seeking than the patients with left-onset disease. CONCLUSIONS: Our results suggest that patients with right-onset Parkinson disease who are taking dopamine agonists and who exhibit high novelty seeking are at greater risk for developing impulse control disorders than are patients with left onset who are also taking dopamine agonists.

Younger age at onset of sporadic Parkinson's disease among subjects occupationally exposed to metals and pesticides.

An earlier age at onset of Parkinson's disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides (n=36) were significantly (p=0.013) younger than unexposed controls (n=22). These subjects were then divided into three groups [high (n=18), low (n=18), and unexposed (n=22)] to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly (p=0.0121) younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect.

Apathy in patients with Parkinson disease as a function of side of onset.

BACKGROUND: In previous studies among patients with Parkinson disease (PD) who were administered the Apathy Evaluation Scale (AES), between 12% and 51% evidenced clinically significant apathy. Although apathy is a risk factor for dementia, its causes and clinical correlates have not been adequately studied. In particular, side of onset of disease, though a likely predictor of apathy and dementia, has not been thoroughly investigated. METHODS: A total of 30 mid-stage patients with PD and 35 community-dwelling elderly control patients (CPs) were administered the AES (self version) along with a battery of cognitive and neuropsychiatric assessments. Persons close to patients with PD and CPs completed the AES--other (informant) version about the patient or CP. Multiple linear regression analysis examined predictors of apathy severity after controlling for mood, levodopa dosage equivalents (LDEs), gender, age, and disease severity (Hoehn--Yahr [H-Y] stage). RESULTS: Patients with right-onset disease more frequently exhibited apathy and evidenced significantly higher total AES scores than left-onset patients with PD or CPs (P < .03). Of all the patients, 42% with right-onset PD versus 11.1% of the patients with left-onset PD exhibited clinically significant levels of apathy. There were no differences for self versus informant scores for right-onset patients with PD. The AES scores were not correlated with depression, stress, anxiety, LDEs, gender, age, and H-Y stage. There were no gender differences for any AES variables. CONCLUSION: Clinically significant levels of apathy are much more likely to occur in patients with right-onset disease. These patients may be at greater risk of PD-related dementia.

A rapid non invasive L-DOPA-¹³C breath test for optimally suppressing extracerebral AADC enzyme activity - toward individualizing carbidopa therapy in Parkinson's disease.

BACKGROUND: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability. OBJECTIVE: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment. METHODS: A single center, randomized, double-blind study was carried out recruiting 5 Parkinson's disease (PD) patients already on LD/CD and 1 treatment näve PD patient using stable isotope labeled LD-1-¹³C as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-¹³C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite ¹³CO2 in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-¹³C and homovanillic acid (HVA) were measured for 4 hours. RESULTS: HVA in plasma and ¹³CO2 in breath are metabolic products of LD. We found a significant positive correlation of ¹³CO2 DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-¹³C for all 5 doses of CD (r² = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD.We found an inverse correlation of the 13CO2 DOB AUC with serum LD-¹³C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from ¹³CO2 generation in breath. CONCLUSIONS: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker ¹³CO2 in breath, a first step in personalizing CD doses for PD patients.

Disease-associated differences in religious cognition in patients with Parkinson's disease.

OBJECTIVE: We sought to establish whether patients with Parkinson's disease (PD) exhibit change in religiosity as a function of disease progression and asymmetry, medication regimens, mood dysfunction, sex, and age. METHOD: We assessed both controlled (conscious reflection) and automatic (semantic priming) modes of religiosity. In the main study, self-reported religiosity, cognitive, and clinical measures were assessed in 71 patients with midstage PD and 75 age-matched controls with non-neurological chronic health conditions. To understand a potential mechanism associated with change in religiosity in PD patients, we supplemented the findings with pilot investigations. The pilot included 21 PD patients and utilized a different self-report measure than that of the main study and assessed automatic activation of religious concepts both on and off levodopa. RESULTS: The main study results demonstrated that PD patients consistently scored lower in five of six dimensions of religiosity. Multivariate linear regression demonstrated that self-reported religiosity was related to disease stage, asymmetry, and male gender. Results are discussed in the context of other neurologic correlates of religiosity. The pilot study on religious concept activation suggested that the mechanism is organic and hemisphere dependent. On/off drug testing confirmed these findings to be independent of medication effects. Gain/decay semantic modeling suggested that right and left forebrain pathways selectively mediated the time constant of gain and decay, respectively, for religious concepts. CONCLUSION: PD patients exhibit significant differences in both controlled and automatic access to religious concepts with mid/late-stage, male, left-onset patients most impaired in access to religious cognition. The findings indicate that aspects of religious/spiritual cognition appear related to specific cerebral structures.

Side of onset in Parkinson's disease and alterations in religiosity: novel behavioral phenotypes.

Behavioral neurologists have long been interested in changes in religiosity following circumscribed brain lesions. Advances in neuroimaging and cognitive experimental techniques have been added to these classical lesion-correlational approaches in attempt to understand changes in religiosity due to brain damage. In this paper we assess processing dynamics of religious cognition in patients with Parkinson's disease (PD). We administered a four-condition story-based priming procedure, and then covertly probed for changes in religious belief. Story-based priming emphasized mortality salience, religious ritual, and beauty in nature (Aesthetic). In neurologically intact controls, religious belief-scores significantly increased following the Aesthetic prime condition. When comparing effects of right (RO) versus left onset (LO) in PD patients, a double-dissociation in religious belief-scores emerged based on prime condition. RO patients exhibited a significant increase in belief following the Aesthetic prime condition and LO patients significantly increased belief in the religious ritual prime condition. Results covaried with executive function measures. This suggests lateral cerebral specialization for ritual-based (left frontal) versus aesthetic-based (right frontal) religious cognition. Patient-centered individualized treatment plans should take religiosity into consideration as a complex disease-associated phenomenon connected to other clinical variables and health outcomes.

The Impact of Clinical and Cognitive Variables on Social Functioning in Parkinson's Disease: Patient versus Examiner Estimates.

Purpose. To assess the impact of clinical variables on social skills and behaviors in Parkinson's disease (PD) patients and patient versus examiner estimates of social functioning. Methods. Twenty-eight patients with PD and 32 controls with chronic disease were assessed with a battery of neuropsychologic, personality, mood, and social function tests. Results. Patients' estimates of their own social functioning were not significantly different from examiners' estimates. The impact of clinical variables on social functioning in PD revealed depression to be the strongest association of social functioning in PD on both the patient and the examiner version of the Social Adaptation Self-Evaluation Scale. Conclusions. PD patients appear to be well aware of their social strengths and weaknesses. Depression and motor symptom severity are significant predictors of both self- and examiner reported social functioning in patients with PD. Assessment and treatment of depression in patients with PD may improve social functioning and overall quality of life.

Social cognition of indirect speech: Evidence from Parkinson's Disease.

We examined potential neurocognitive mechanisms of indirect speech in support of face management in 28 patients with Parkinson's disease (PD) and 32 elderly controls with chronic disease. In experiment 1, we demonstrated automatic activation of indirect meanings of particularized implicatures in controls but not in PD patients. Failure to automatically engage comprehension of indirect meanings of indirect speech acts in PD patients was correlated with a measure of prefrontal dysfunction. In experiment 2, we showed that while PD patients and controls offered similar interpretations of indirect speech acts, PD participants were overly confident in their interpretations and unaware of errors of interpretation. Efficient reputational adjustment mechanisms apparently require intact striatal-prefrontal networks.

Deficits in the automatic activation of religious concepts in patients with Parkinson's disease.

Religion is central to the lives of billions of people worldwide. To probe processing dynamics of religious cognition and its potential brain correlates, we used a novel priming procedure to assess the integrity of religious and control semantic networks in patients with Parkinson's disease (PD) and controls. Priming for control, but not religious, concepts was intact in PD patients. Patients with left-onset (right-forebrain disease) evidenced severe impairment activating religious concepts. We next modeled the priming performance with modified cable equations. These analyses suggested that deficient performance of PD patients on activation of religious concepts was due to a change in the time constants governing gain and rate of decay of activation in these semantic networks. These modeling results are consistent with dopaminergic dysfunction in right-sided striatal-prefrontal networks. We conclude that right striatal-prefrontal dopaminergic networks support activation of complex religious concepts but not equally complex and related control concepts.

Mood, side of motor symptom onset and pain complaints in Parkinson's disease.

OBJECTIVE: Patients with Parkinson's disease (PD) present with a variety of non-motor symptoms including sensory complaints and mood disturbances. In the current pilot study, we aimed to explore pain complaints and the association between mood and pain in PD. We hypothesized that pain ratings would be elevated in patients with PD relative to controls. As PD is lateralized at onset and studies have found lateralization of some non-motor symptoms in PD, we also hypothesized that PD patients would exhibit differing pain profiles depending on side of onset of the disease. METHODS: Twenty-three PD patients (11 right-onset (RPD), 12 left-onset (LPD) disease), and 11 control participants (CS) completed a mood questionnaire (Depression Anxiety Stress Scale; DASS) as well as the short form of the McGill Pain Questionnaire. RESULTS: Both PD groups reported higher present pain intensity scores (p = 0.001), more evaluative pain intensity (p = 0.02), and more overall pain (p = 0.02) than control participants. There was a significant association between mood and all of the McGill pain ratings in the LPD patients, with those reporting more mood symptoms rating higher on all pain scales (all p-values < 0.001). This association was not found in the RPD group. CONCLUSIONS: Our results suggest an association between mood and pain in patients with PD that may be related to the differential contribution of right-hemispheric neural networks in processing of mood and pain states. These findings merit further investigation into the relation between mood and pain in patients with PD.

Hallucinations, dreaming, and frequent dozing in Parkinson disease: impact of right-hemisphere neural networks.

OBJECTIVE: To relate sleep disturbances in Parkinson disease (PD) to hemispheric asymmetry of initial presentation. BACKGROUND: Sleep disturbances are common in PD arising from the neurodegenerative process underlying the disease, which is usually lateralized at onset. Patients with left-side Parkinson disease onset (LPD: right hemisphere dysfunction) exhibit reduced vigilance relative to those with right-side Parkinson disease onset (RPD: left hemisphere dysfunction), leading us to hypothesize that sleep-related disturbances, particularly excessive daytime sleepiness, would be more severe for LPD than for RPD. METHODS: Thirty-one nondemented participants with PD (17 RPD and 14 LPD) and 17 age-matched control (CO) participants with chronic health conditions were administered the Parkinson Disease Sleep Scale and polysomnography was performed on a subset of the PD participants. RESULTS: Both PD subgroups exhibited more nighttime motor symptoms than the CO group, but only LPD endorsed more nocturnal hallucinations and daytime dozing. Controlling for mood additionally revealed more vivid dreaming in LPD than RPD. There were no significant differences between LPD and RPD on measures of sleep architecture. CONCLUSIONS: Increased dreaming, hallucinations, and daytime somnolescence in LPD may be related to changes in right-hemisphere neural networks implicated in the generation and control of visual images, arousal, and vigilance. Our results underscore the need to consider side of onset in regard to sleep disturbances in PD.

Alterations of the sense of self and personality in Parkinson's disease.

PURPOSE: We hypothesized that alterations of subcomponents ('harm-avoidance') of personality and the sense of Self in patients with PD would be associated with executive cognitive dysfunction. METHODS: Thirty-four patients with PD and 17 age-matched controls with chronic disease were assessed with a set of neuropsychologic, personality and mood tests as well as an experimental assessment of the sense of Self. RESULTS: On personality and self tests, PD patients evidenced higher harm avoidance, lower novelty seeking scores, and lower recall rates of personally experienced events from childhood than controls and this PD personality profile was associated with poor performance on neuropsychologic tests of executive prefrontal function. PD patients, however, did not differ significantly from controls in their subjectively felt congruence between their present Selves and their hoped-for Selves. CONCLUSIONS: We suggest that harm-avoidance personality and Self-related changes of PD are due, in part, to a memory disorder associated with frontal dysfunction.

"Machiavellianism" and frontal dysfunction: evidence from Parkinson's disease.

INTRODUCTION: A number of reports have identified significant personality differences in patients with Parkinson's disease (PD) when compared with age-matched controls. We hypothesised that these differences may be related to impairment in prefrontal inhibitory functions resulting in the expression of new "Machiavellian" personality traits. METHODS: Thirty-five patients with PD and 17 age-matched controls were assessed with a set of neuropsychologic, personality and mood tests as well as the Mach IV scale, which measures a set of "Machiavellian" personality characteristics. RESULTS: PD patients with elevated Machiavellian traits ("high Machs") were selectively impaired on tests of prefrontal function relative to "low Mach" patients. In addition, while high Machs did not differ from low Machs in terms of age, educational level, Hoehn-Yahr stage, mood function, or Mini Mental State Exam score, they indicated greater willingness to affiliate with a fictional Machiavellian character and scored significantly lower on the "cooperativeness" and "self-directedness" subscales of the Cloninger Temperament and Character Inventory. CONCLUSIONS: We suggest that (1) PD patients with frontal impairment are vulnerable to dramatic personality change, and (2) the frontal lobes are required for maintenance of prosocial personality traits.

Life goals of patients with Parkinson's disease: A pilot study on correlations with mood and cognitive functions.

OBJECTIVE: To identify the life goals of people with Parkinson's disease, to assess whether patients felt that these goals were 'on track', and to assess the relation of these life goals to neuropsychologic and mood function. DESIGN: Cross-sectional descriptive study with an age-matched control group. SETTING: Outpatient Movement Disorders Clinics Veterans Hospital. SUBJECTS: Twenty-two patients with mid-stage Parkinson's disease and 22 age-matched controls. MEASURES: Rivermead Life Goals Inventory, neuropsychological and mood scales. RESULTS: People with Parkinson's disease were less likely than age-matched controls to cite religion, social contacts, leisure activities and personal care as 'extremely important life goals'. People with Parkinson's disease assigned significantly lower 'importance' ratings to leisure activities and religion than did controls. In addition, people with Parkinson's disease assigned significantly lower 'on track' ratings for leisure activities, work, social contacts, religion and financial affairs compared with controls' rating on the same items. Although people with Parkinson's disease showed significantly greater levels of cognitive and mood dysfunction than did controls, their mean importance ratings on life goals correlated only with mood function scores. CONCLUSIONS: The leisure activities, work, social contacts, religion and financial affairs of people with Parkinson's disease are less 'on track' than are their personal and family relationships. Subjective importance ratings of particular life goals of people with Parkinson's disease were found to be significantly related to mood function and not to cognitive function. Goal derailment ratings on the other hand were significantly related to both mood and cognitive impairment.

Neuropharmacological treatment of mental dysfunction in Parkinson's disease.

Many patients with Parkinson's Disease (PD) experience significant cognitive and mood impairment -even early in the course of the disease. These mental impairments are only partially responsive to levodopa treatment and are often as disabling as the motor impairment, particularly in mid and late stages of the disease. Investigators have recently begun a search for new agents that can effectively treat mental dysfunction of PD. Although there have been only a handful of properly controlled clinical trials of interventions targeted at amelioration of mental dysfunction in PD, progress has been made. Based on the available evidence, targeting catecholaminergic and cholinergic function may be an effective strategy for amelioration of cognitve, mood and psychiatric disturbances in PD.

Religiosity in patients with Parkinson's disease.

OBJECTIVE: To study clinical correlates of religiosity in Parkinson's disease (PD). METHODS: Measures of life goals, religiosity, mood, and neuropsychologic function were assessed in 22 persons with mid-stage PD and 20 age-matched healthy controls. Levodopa dose equivalents (LDE) were also computed for the patients. RESULTS: Relative to other major life goals parkinsonian patients were significantly more likely to report that "my religion or life philosophy" was less important than were age-matched controls. Scores on a battery of religiosity scales were consistently lower for Parkinson's patients than those of age-matched controls. While Mini Mental State Exam, logical memory recall, Stroop, and selected (depression and anxiety) mood scales reliably distinguished patients from controls, only measures of prefrontal function correlated with religiosity scores. CONCLUSIONS: Patients with PD express less interest in religion and report consistently lower scores on measures of religiosity than age-matched controls. Prefrontal dopaminergic networks may support motivational aspects of religiosity.