Cognitive impairment in Parkinson's disease: Associations between subjective and objective cognitive decline in a large longitudinal study.

BACKGROUND: Cognitive decline creates substantial morbidity and cost in Parkinson's disease (PD) and clinicians have limited tools for counseling patients on prognosis. We aimed to use data from a randomized, controlled trial of isradipine in Parkinson's disease (STEADY-PD III) to determine which objective cognitive domain deficits drive patient complaints of cognitive symptoms. METHODS: Neuro-Quality of Life (Neuro-QoL) Cognition: General Concerns (GC), and Cognition: Executive Function (EF) (subjective measures), were administered at baseline, 1, 2, and 3 years in 324 people with PD. Baseline Montreal Cognitive Assessment (MoCA) was divided into 4 domains: visuospatial/executive, memory, attention, and language (objective measures). Spearman rank correlations and multiple regression models adjusted for other clinical variables evaluated associations between baseline Neuro-QoL domains and individual MoCA domains. Multiple regression models evaluated the association between baseline MoCA domain performance and Neuro-QoL change over three years. Cox proportional hazards predicted development of PD-MCI based on baseline and time-varying Neuro-QoL reporting. RESULTS: Higher MoCA memory performance was associated with better Neuro-QoL-GC (ß = 0.75, SE = 0.391, p = 0.05) and Neuro-QoL-EF (ß = 0.81, SE = 0.36, p = 0.02) at baseline. There was a trend for baseline MoCA memory to predict the degree of subjective cognitive decline on the Neuro-QoL-EF (ß = 0.70, SE = 0.42, p = 0.09). Baseline depression and anticholinergic use were associated with worsened Neuro-QoL-EF and Neuro-QoL-GC. Increasing subjective cognitive complaints in Neuro-QoL-EF were associated with development of PD-MCI over 3 years of follow-up (HR = 0.95, CI = 0.90-1.0, p = 0.039). CONCLUSIONS: Objective memory impairment may be a stronger predictor than executive or visuospatial dysfunction for the presence of subjective cognitive complaints in early PD.

Assessing Retinal Structure in Patients with Parkinson's Disease.

OBJECTIVE: The retina is an extension of the central nervous system (CNS), and ocular symptoms can precede manifestations of CNS disorders. Given that several neurodegenerative conditions that affect the brain exhibit ocular symptoms, the retina may be an accessible biomarker to monitor disease progression. Dopamine, the key neurotransmitter related to Parkinson's disease (PD), is contained in amacrine and interplexiform cells, which reside in specific retinal layers. Understanding how loss of dopaminergic cells affects retinal anatomy could be relevant for monitoring disease progression. Here, our objective is to evaluate retinal structure (foveal pit morphology and thickness) in patients with PD. METHODS: Thirty-three Caucasian subjects diagnosed with PD and 40 age-matched Caucasian control subjects underwent retinal imaging with spectral-domain optical coherence tomography (SD-OCT). Axial length measurements were used to correct the lateral scale of each macular volume scan. From these corrected volumes, foveal morphology was quantified with previously described algorithms, and Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and incorporated into a logistic regression model to predict PD. RESULTS: Interocular foveal morphology measurements were highly symmetrical in PD patients and control subjects. There were no significant differences in foveal pit morphology between PD patients and control subjects. Using a model incorporating sex and axial length corrected ETDRS regions, we generated a receiver operating characteristic curve with a C-statistic of 0.80. CONCLUSION: Our study, which to our knowledge is the first to properly scale OCT measurements when quantifying retinal thickness, demonstrates that PD patients retain foveal symmetry between eyes. When constructing a model to predict PD, sex, along with the center 1 mm and temporal outer ETDRS regions, were significant predictors of PD. In addition to proper scaling of OCT measures, gender and racial differences in retinal anatomy should be considered in building future predictive PD models when using OCT.

Consensus-Based Attributes for Identifying Patients With Spasmodic Dysphonia and Other Voice Disorders.

Importance: A roadblock for research on adductor spasmodic dysphonia (ADSD), abductor SD (ABSD), voice tremor (VT), and muscular tension dysphonia (MTD) is the lack of criteria for selecting patients with these disorders. Objective: To determine the agreement among experts not using standard guidelines to classify patients with ABSD, ADSD, VT, and MTD, and develop expert consensus attributes for classifying patients for research. Design, Setting and Participants: From 2011 to 2016, a multicenter observational study examined agreement among blinded experts when classifying patients with ADSD, ABSD, VT or MTD (first study). Subsequently, a 4-stage Delphi method study used reiterative stages of review by an expert panel and 46 community experts to develop consensus on attributes to be used for classifying patients with the 4 disorders (second study). The study used a convenience sample of 178 patients clinically diagnosed with ADSD, ABSD, VT MTD, vocal fold paresis/paralysis, psychogenic voice disorders, or hypophonia secondary to Parkinson disease. Participants were aged 18 years or older, without laryngeal structural disease or surgery for ADSD and underwent speech and nasolaryngoscopy video recordings following a standard protocol. Exposures: Speech and nasolaryngoscopy video recordings following a standard protocol. Main Outcomes and Measures: Specialists at 4 sites classified 178 patients into 11 categories. Four international experts independently classified 75 patients using the same categories without guidelines after viewing speech and nasolaryngoscopy video recordings. Each member from the 4 sites also classified 50 patients from other sites after viewing video clips of voice/laryngeal tasks. Interrater κ less than 0.40 indicated poor classification agreement among rater pairs and across recruiting sites. Consequently, a Delphi panel of 13 experts identified and ranked speech and laryngeal movement attributes for classifying ADSD, ABSD, VT, and MTD, which were reviewed by 46 community specialists. Based on the median attribute rankings, a final attribute list was created for each disorder. Results: When classifying patients without guidelines, raters differed in their classification distributions (likelihood ratio, χ2 = 107.66), had poor interrater agreement, and poor agreement with site categories. For 11 categories, the highest agreement was 34%, with no κ values greater than 0.26. In external rater pairs, the highest κ was 0.23 and the highest agreement was 38.5%. Using 6 categories, the highest percent agreement was 73.3% and the highest κ was 0.40. The Delphi method yielded 18 attributes for classifying disorders from speech and nasolaryngoscopic examinations. Conclusions and Relevance: Specialists without guidelines had poor agreement when classifying patients for research, leading to a Delphi-based development of the Spasmodic Dysphonia Attributes Inventory for classifying patients with ADSD, ABSD, VT, and MTD for research.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

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 Parkinson's 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.

Parkinson's disease disrupts both automatic and controlled processing of action verbs.

The problem of how word meaning is processed in the brain has been a topic of intense investigation in cognitive neuroscience. While considerable correlational evidence exists for the involvement of sensory-motor systems in conceptual processing, it is still unclear whether they play a causal role. We investigated this issue by comparing the performance of patients with Parkinson's disease (PD) with that of age-matched controls when processing action and abstract verbs. To examine the effects of task demands, we used tasks in which semantic demands were either implicit (lexical decision and priming) or explicit (semantic similarity judgment). In both tasks, PD patients' performance was selectively impaired for action verbs (relative to controls), indicating that the motor system plays a more central role in the processing of action verbs than in the processing of abstract verbs. These results argue for a causal role of sensory-motor systems in semantic processing.

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 Parkinson's 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 Parkinson's 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 >or= 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 >or= 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.

A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations.

BACKGROUND: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN: A double-blind, randomized, comparative clinical trial. SETTING: Forty-four sites in the United States and Canada. PATIENTS: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE: Change from baseline in total daily TTON as measured using home diaries. RESULTS: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.

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 Parkinson's 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 Parkinson's 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.

Neural basis for impaired time reproduction in Parkinson's disease: an fMRI study.

Studies involving brain-lesioned subjects have used the paced finger tapping (PFT) task to investigate the neural systems that govern motor timing. Patients with Parkinson's disease (PD), for example, demonstrate abnormal performance on the PFT, characterized by decreased accuracy and variability changes, suggesting that the basal ganglia may play a critical role in motor timing. Consistent with this hypothesis, an fMRI study of healthy participants demonstrated that the medial frontostriatal circuit (dorsal putamen, ventrolateral thalamus, SMA) correlated with explicit time-dependent components of the PFT task. In the current fMRI study, PD patients and healthy age-matched controls were imaged while performing the PFT. PD patients underwent 2 imaging sessions, 1 on and the other off dopamine supplementation. Relative to controls, PD patients were less accurate and showed greater variability on the PFT task relative to controls. No PFT performance differences were observed between the on and off medication states despite significantly greater motor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) in the off medication state. Functional imaging results demonstrated decreased activation within the sensorimotor cortex (SMC), cerebellum, and medial premotor system in the PD patients compared to controls. With dopamine replacement, an increase in the spatial extent of activation was observed within the SMC, SMA, and putamen in the PD patients. These results indicate that impaired timing reproduction in PD patients is associated with reduced brain activation within motor and medial premotor circuits. Despite a lack of improvement in PFT performance, PD patient's brain activation patterns were partially "normalized" with dopamine supplementation. These findings could not be attributed to greater head movement artifacts or basal ganglia atrophy within the PD group.

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 Parkinson's 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 Parkinson's 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.