Tanya Simuni

Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results

We present a clinimetric assessment of the Movement Disorder Society (MDS)‐sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS). The MDS‐UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS‐UPDRS has four parts, namely, I: Non‐motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item‐specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS‐UPDRS (65 items) to 877 English speaking (78% non‐Latino Caucasian) patients with Parkinsons disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS‐UPDRS showed high internal consistency (Cronbachs alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS‐UPDRS across‐part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.

The Parkinson Progression Marker Initiative (PPMI)

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

Donepezil for dementia in Parkinson’s disease: a randomised, double blind, placebo controlled, crossover study

Objective: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson’s disease (PD). Methods: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5–10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAScog). Results: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson’s Disease Rating Scale. There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Conclusions: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

Nonmotor manifestations of Parkinson's disease.

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. Traditionally, attention has focused on the motor symptomatology of PD, but it is now appreciated that the nonmotor symptoms affecting neuropsychiatric, sleep, autonomic, and sensory domains occur in up to 88% of PD patients and can be an important source of disability. Nonmotor manifestations of PD play a significant role in the impairment of disease‐related quality of life. The cause of nonmotor manifestations of PD is multifactorial, but to a large extent, these manifestations are related to the nature of the neurodegenerative process and the widespread nondopaminergic neuropathological changes associated with the disease. Recognition of nonmotor disability is essential not only for ascertaining the functional status of patients but also for better appreciating the nature of the neurodegenerative process in PD. In addition, a number of nonmotor manifestations can precede the onset of motor symptoms in PD and can be used as screening tools allowing for early disease identification and for trials of possible disease‐modifying interventions. This article reviews depression, sleep, and autonomic dysfunction in PD. Ann Neurol 2008;64 (suppl):S65–S80

Neuro-QOL Brief measures of health-related quality of life for clinical research in neurology

Objective: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. Methods: Drawing from larger calibrated item banks, we developed short measures (8–9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. Results: Internal consistency (Cronbach α) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82–0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1–2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. Conclusion: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function.

The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration

Diagnosis of neurological and psychiatric conditions associated with disturbances of dopaminergic functioning can be challenging, especially in the early stages, and may be assisted with biomarkers such as dopamine system imaging. Distinguishing between Alzheimers disease and dementia with Lewy bodies is a major diagnostic challenge. Clinical diagnosis of Parkinsons disease is straightforward with classic presentation, but accurate distinction among Parkinsonian variants may be difficult; non-Parkinsons disease conditions are commonly misdiagnosed as Parkinsons disease, and ~20% of patients with Parkinsons disease are not clinically diagnosed despite coming to medical attention. Early and accurate diagnosis is desirable to improve management. Imaging of the dopamine transporter using single-photon emission computed tomography may be of particular utility in this regard. Abnormal imaging indicates underlying nigrostriatal neurodegeneration, supportive of a diagnosis of Parkinsons disease, atypical parkinsonism or dementia with Lewy bodies, and identifies patient groups in whom dopaminergic therapy may be beneficial. Normal imaging supports diagnosis of a condition not involving nigrostriatal neurodegeneration such as Alzheimers disease, essential tremor or drug-induced parkinsonism and hence a different therapeutic approach. In patients in whom there was diagnostic uncertainty between degenerative parkinsonism and non-degenerative tremor disorders, baseline imaging with the dopamine transporter ligand [(123)I]ioflupane (DaTscan™) has shown 78% sensitivity and 97% specificity with reference to clinical diagnosis at 3 years, versus 93% and 46%, respectively, for baseline clinical diagnosis. In a Phase III trial of [(123)I]ioflupane in patients with initial clinical diagnosis of probable or possible dementia with Lewy bodies or non-Lewy body dementia, mean specificity for excluding non-Lewy body dementia (predominantly Alzheimers disease) was 90.4%. Using clinical diagnosis as a reference against which to assess sensitivity and specificity of dopamine transporter imaging is a limitation, but definitive diagnosis via pathological confirmation is generally not feasible. In a series of patients with post-mortem brain examination, imaging using [(123)I]ioflupane has demonstrated higher sensitivity (88%) and specificity (100%) for differentiating dementia with Lewy bodies from non-Lewy body dementia than clinical diagnosis (75% and 42%, respectively). Dopaminergic system imaging may be particularly valuable in patients with clinically inconclusive parkinsonism or a clinical diagnosis of possible dementia with Lewy bodies; it is not helpful in differentiating between Parkinsons disease and atypical parkinsonism, although postsynaptic dopaminergic imaging may be of utility. Other potential uses of dopamine transporter imaging include identification of patients with premotor Parkinsons disease, monitoring disease progression in testing novel therapeutics, and as an inclusion criterion for entry into clinical trials.

Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study.

To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At‐Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40‐item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty‐six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration.

Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease

IMPORTANCE Diurnal fluctuations of motor and nonmotor symptoms and a high prevalence of sleep-wake disturbances in Parkinson disease (PD) suggest a role of the circadian system in the modulation of these symptoms. However, surprisingly little is known regarding circadian function in PD and whether circadian dysfunction is involved in the development of sleep-wake disturbances in PD. OBJECTIVE To determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness, and disease metrics. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study from January 1, 2009, through December 31, 2012, of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. Both groups underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions at the Parkinsons Disease and Movement Disorders Center of Northwestern University. INTERVENTIONS Twenty-four hour monitoring of serum melatonin secretion. MAIN OUTCOMES AND MEASURES Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale), and circadian markers of the melatonin rhythm, including the amplitude, area under the curve (AUC), and phase of the 24-hour rhythm. RESULTS Patients with PD had blunted circadian rhythms of melatonin secretion compared with controls; the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD patients (P < .001). Markers of the circadian phase were not significantly different between the 2 groups. Compared with PD patients without excessive daytime sleepiness, patients with excessive daytime sleepiness (Epworth Sleepiness Scale score ≥10) had a significantly lower amplitude of the melatonin rhythm and 24-hour melatonin AUC (P = .001). Disease duration, Unified Parkinsons Disease Rating Scale scores, levodopa equivalent dose, and global Pittsburgh Sleep Quality Index score in the PD group were not significantly related to measures of the melatonin circadian rhythm. CONCLUSIONS AND RELEVANCE Circadian dysfunction may underlie excessive sleepiness in PD. The nature of this association needs to be explored further in longitudinal studies. Approaches aimed to strengthen circadian function, such as timed exposure to bright light and exercise, might serve as complementary therapies for the nonmotor manifestations of PD.

Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease

This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinsons disease (PD).

A recommended scale for cognitive screening in clinical trials of Parkinson's disease

Cognitive impairment is common in Parkinsons disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Forces evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD.