Actigraphy Detects Greater Intra-Individual Variability During Gait in Non-Manifesting LRRK2 Mutation Carriers.

BACKGROUND: With recent advances in the search for disease-modifying therapies for Parkinson's disease (PD) the importance of identifying prodromal markers becomes greater. Non-manifesting LRRK2 mutation carriers (NMC) are at risk for developing PD, and provide a population in which to identify possible markers. OBJECTIVE: The aim of this study was to test the hypothesis that NMC have differences in daily activity, fragmentation of sleep, arm swing asymmetry, and movement variability during walking, detectable by actigraphy, as compared to matched control subjects. METHODS: Eleven NMC, fourteen PD patients (4 LRRK2-PD, 10 idiopathic PD (iPD)), and twenty-nine controls wore wristbands containing an accelerometer for seven days, and performed a daily walking task. Outcome measures included daily activity, fragmentation of activity, fragmentation of sleep, arm swing asymmetry during walking, and intra-individual variability. RESULTS: Compared to healthy controls, both NMC and LRRK2/iPD showed higher intra-individual variability in activity during walking compared to healthy controls. Individuals with LRRK2-PD/iPD, but not NMC, tend to have lower activity levels, more arm swing asymmetry and less increase of arm swing with transition from slow to faster walking speed compared to healthy controls. CONCLUSION: Higher intra-individual variability of gait-associated movements might be a useful biomarker of prodromal PD. These results encourage replication in a larger sample and longitudinal analysis is warranted.

Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.

Movement disorders and other motor abnormalities in adults with 22q11.2 deletion syndrome.

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice.

Current use of domperidone and co-prescribing of medications that increase its arrhythmogenic potential among older adults: a population-based cohort study in Ontario, Canada.

BACKGROUND AND OBJECTIVES: Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone. METHODS: This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included. RESULTS: A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users. CONCLUSIONS: Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic.

BACKGROUND: Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS). OBJECTIVES: The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic. METHODS: We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable. RESULTS: Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS-). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS- patients (p<0.0001). DAWS+ and DAWS- patients did not differ in other variables. CONCLUSION: DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.

Normative data and determinants for the timed "up and go" test in a population-based sample of elderly individuals without gait disturbances.

OBJECTIVE: To define the standard performance of elderly people without gait disturbances in the "Timed Up and Go" test (TUG) and investigate its determinants. METHODS: A population-based sample of 527 community-dwelling subjects, 71 to 99 years of age, was studied using a clinical, neurological, and cognitive standardized protocol which included the TUG (time to get up, walk 3 meters, go back and sit down again). RESULTS: Sixty one subjects were unable to perform the TUG and 158 were excluded because of abnormal gait. 308 subjects without gait disturbances performed the TUG (mean age 77.5 +/- 5.2 years); males 171, (55%) in 10.2 +/- 3.1 seconds (range 5-25). The TUG time was higher in females (11.2 +/- 3.2 seconds; males: 9.3 +/- 2.8), was positively correlated with age (r = 0.25, p < 0.001). Mean TUG times by age group were: 71-75 years: 9.5 +/- 2.5 sec.; 76-80 years: 9.9 +/- 3 sec.; 81-85 years: 11.2 +/- 3.6 sec; and 86-99 years: 12 +/- 3.8 seconds). TUG times were also related to cognitive impairment (Global Deterioration Scale, r = 0.27, p < 0.001), weight (r = -0.18, p < 0.001), height (r = -0.29, p <0.001), head circumference (r = -0.24, p < 0.001) and nutritional status (Mini Nutritional Assessment, r = -0.31, p < 0.001). A regression model explaining 25.8% of TUG variance included age, gender, weight, nutritional status and cognitive impairment as independent determinants of TUG scores. CONCLUSIONS: The TUG performance of elderly people over 70 without apparent gait disturbances depends on age and other non motor variables such as female gender, weight, nutritional status and cognitive impairment.

Impact of fatigue in Parkinson's disease: the Fatigue Impact Scale for Daily Use (D-FIS).

The Fatigue Impact Scale for Daily Use (D-FIS) was used in a cross-sectional study including 142 consecutive Parkinson's disease (PD) patients. Usual clinical measures for PD, the Montgomery-Asberg Depression Rating Scale and the Parkinson's Disease Questionnaire-8 items were applied. In addition to the D-FIS, patients with fatigue (67.6%, PWF) completed the Multidimensional Fatigue Inventory (MFI), a visual analogue scale for fatigue (VAS-F) and a Global Perception of Fatigue scale (GPF). Relevant psychometric D-FIS results were: floor effect = 4.2%; ceiling effect = 1.1%; skewness = 0.44; item homogeneity = 0.63; Cronbach's alpha = 0.93; item-total correlation = 0.68 (item 1)-0.82 (item 8); standard error of measurement = 2.15; convergent validity with other fatigue measures = 0.54 [GPF]-0.62 [VAS-F] (p<0.001). In a multiple linear regression model, fatigue, depression, and disability independently influenced HRQoL, as measured by the PDQ-8. Patients on amantadine had lower prevalence of fatigue. In PD, D-FIS is a consistent and valid measure for fatigue, a frequent symptom previously found to impair patients' HRQoL. Fatigue was also linked to depression and disability in this study.

Evolution of cognitive impairment after stroke and risk factors for delayed progression.

BACKGROUND AND PURPOSE: Cognitive decline occurs in approximately 30% of stroke patients. Acute risk factors have been identified, but long-term risk has not been examined in large samples. The purpose of this research was to determine factors associated with the progression of cognitive impairment after stroke. METHODS: Consecutive stroke patients (193) without previous dementia were assessed 3 months after stroke with an extensive neuropsychological battery and diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition criteria and the Clinical Dementia Rating as normal (139), cognitive decline without dementia (18), or dementia (18 mild, 10 moderate, and 8 severe). After a 24-month follow-up, they were classified as stable, progressing, or improving, according to change in Clinical Dementia Rating score. The determinants of progression of cognitive decline were ascertained by logistic regression analysis of all clinical, neuroimaging, and complementary data. RESULTS: Cognitive status at 24 months was stable in most cases (151; 78.2%), decline progressed in 27 (14%; 6 demented and 21 nondemented), and improved in 15 (7.8%; 7 demented and 8 nondemented). Seven nondemented patients became demented at 24 months, and 5 demented became nondemented. The age (odds ratio [OR], 1.05; 95% CI, 1.01 to 1.1), mental decline before stroke (OR, 1.14; 95% CI, 1.02 to 1.27), number of prescribed drugs (OR, 1.34; 95% CI, 1.05 to 1.72), diastolic blood pressure on admission (OR, 0.96; 95% CI, 0.93 to 0.99), and episodes of hypotension during admission (OR, 7.61; 95% CI, 1.11 to 52.1) were significantly associated with cognitive deterioration. CONCLUSIONS: Cognition is rather stable for 2 years after stroke. Both progression and improvement of cognitive impairment are frequent in demented patients. Age, previous cognitive decline, polypharmacy, and hypotension during admission are risk factors for progression.

Health-related quality of life evaluation by proxy in Parkinson's disease: approach using PDQ-8 and EuroQoL-5D.

Patient- and caregiver-based scores were compared and agreement levels ascertained to determine the reliability of proxy evaluation of Parkinson's Disease (PD) patients' health-related quality of life (HRQoL) using the EuroQoL and PD questionnaire (PDQ)-8. Of 72 patient-caregiver pairs, 64 (88.88%) returned the questionnaires. The degree of agreement varied for individual dimensions. Proxy evaluation of PD patients' HRQoL showed limitations mainly with assessments using the EuroQoL and especially in patients with severe disease and depression.

Patients', doctors', and caregivers' assessment of disability using the UPDRS-ADL section: are these ratings interchangeable?

This multicenter study sought to analyze the validity and reliability of the Unified Parkinson's Disease Rating Scale (UPDRS)-section 2 (Activities of Daily Living, ADL) as applied by patients and caregivers. Sixty pairs of PD patients-caregivers were enrolled for study purposes. Neurologists used a set of scales to determine disease severity and patients' functional state. Patients and caregivers used adapted versions of the UPDRS-section 2 in tandem with other measures. Wilcoxon and Mann-Whitney tests, weighted kappa, intraclass and Spearman's correlation coefficients, as well as multivariate linear regression models were applied. On the whole, PD patient self-assessment and caregiver evaluation of patients' disability showed close concordance with neurologists' ratings. Correlation between caregiver ratings and clinical evaluation tended to be slightly lower than that for patient-based self-assessment. Depression showed a positive correlation with disability and had a nonsystematic influence on UPDRS-section 2 (ADL) scores. As expected, there was a significant correlation between perceived disability and health-related quality of life measures. Caregiver burden did not reduce the level of agreement with neurologists as to the overall rating of any given patient's disability. In PD, UPDRS-section 2-based assessment of disability by patients themselves and caregivers is a valid and reliable outcome.