William J. Weiner

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.

Variable expression of Parkinson's disease: A base‐line analysis of the DAT ATOP cohort

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinsons disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (≤40 years, N = 33) reached the same level of disability as the late-onset PD (≥70 years, N = 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression (“malignant PD”; duration of symptoms <1 year and Hoehnflahr stage of 2.5, N = 11) as compared with those with a relatively slow rate of progression (“benign PD”; duration of symptoms >4 years, N = 65). Comparisons of tremor-dominant PD (mean tremor score/ mean PIGD score ≤1.5, N = 441) with the PIGD-dominant type (mean tremor score/mean PIGD score ≥1.0, N = 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Non-recognition of depression and other non-motor symptoms in Parkinson's disease.

BACKGROUND Depression, anxiety, fatigue and sleep disorders occur commonly in patients with Parkinsons disease (PD). These non-motor symptoms often contribute to the reduction of functional abilities in PD patients. OBJECTIVE This study was designed to evaluate the diagnostic accuracy of the treating neurologist for a variety of behavioral symptoms commonly associated with PD. METHODS A prospective evaluation of 101 patients with PD selected in no particular order was conducted. All patients were evaluated with the Unified Parkinsons Disease Rating Scale (UPDRS), Hoehn & Yahr Stage (H/Y), and the Schwab & England Scale (S/E). The patients completed a brief screening questionnaire for depression and anxiety followed by the administration of a battery of standardized tests including the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Fatigue Severity Scale (FSS), and the Pittsburgh Sleep Quality Inventory (PSQI). RESULTS Standardized testing showed evidence of a problem with depression in 44% of patients, anxiety in 39%, fatigue in 42% and sleep disturbance in 43%. The prevalence of these conditions, identified by the treating neurologist was lower: 21% with depression, 19% with anxiety, 14% with fatigue and 39% with sleep disturbance. The diagnostic accuracy for the treating neurologists was 35% for depression, 42% for anxiety, 25% for fatigue, and 60% for sleep disturbance. CONCLUSION This study demonstrates that during routine office visits, neurologists failed to identify the presence of depression, anxiety, and fatigue more than half of the time and failed to recognize sleep disturbance in 40% of patients. Awareness of the likelihood of underrecognition of behavioral symptoms in PD should generate approaches to improve diagnostic accuracy and facilitate timely therapeutic interventions.

Criteria for the diagnosis of corticobasal degeneration.

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.

Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To make evidence-based treatment recommendations for patients with Parkinson disease (PD) with dementia, depression, and psychosis based on these questions: 1) What tools are effective to screen for depression, psychosis, and dementia in PD? 2) What are effective treatments for depression and psychosis in PD? 3) What are effective treatments for PD dementia or dementia with Lewy bodies (DLB)? Methods: A nine-member multispecialty committee evaluated available evidence from a structured literature review using MEDLINE, and the Cochrane Database of Health and Psychosocial Instruments from 1966 to 2004. Additional articles were identified by panel members. Results: The Beck Depression Inventory-I, Hamilton Depression Rating Scale, and Montgomery Asberg Depression Rating Scale should be considered to screen for depression in PD (Level B). The Mini-Mental State Examination and the Cambridge Cognitive Examination should be considered to screen for dementia in PD (Level B). Amitriptyline may be considered to treat depression in PD without dementia (Level C). For psychosis in PD, clozapine should be considered (Level B), quetiapine may be considered (Level C), but olanzapine should not be considered (Level B). Donepezil or rivastigmine should be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B). Conclusions: Screening tools are available for depression and dementia in patients with PD, but more specific validated tools are needed. There are no widely used, validated tools for psychosis screening in Parkinson disease (PD). Clozapine successfully treats psychosis in PD. Cholinesterase inhibitors are effective treatments for dementia in PD, but improvement is modest and motor side effects may occur.Objective:To make evidence-based treatment recommendations for patients with Parkinson disease (PD) with dementia, depression, and psychosis based on these questions: 1) What tools are effective to screen for depression, psychosis, and dementia in PD? 2) What are effective treatments for depression and psychosis in PD? 3) What are effective treatments for PD dementia or dementia with Lewy bodies (DLB)? Methods:A nine-member multispecialty committee evaluated available evidence from a structured literature review using MEDLINE, and the Cochrane Database of Health and Psychosocial Instruments from 1966 to 2004. Additional articles were identified by panel members. Results:The Beck Depression Inventory-I, Hamilton Depression Rating Scale, and Montgomery Asberg Depression Rating Scale should be considered to screen for depression in PD (Level B). The Mini-Mental State Examination and the Cambridge Cognitive Examination should be considered to screen for dementia in PD (Level B). Amitriptyline may be considered to treat depression in PD without dementia (Level C). For psychosis in PD, clozapine should be considered (Level B), quetiapine may be considered (Level C), but olanzapine should not be considered (Level B). Donepezil or rivastigmine should be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B). Conclusions:Screening tools are available for depression and dementia in patients with PD, but more specific validated tools are needed. There are no widely used, validated tools for psychosis screening in Parkinson disease (PD). Clozapine successfully treats psychosis in PD. Cholinesterase inhibitors are effective treatments for dementia in PD, but improvement is modest and motor side effects may occur.

Comorbidity of the nonmotor symptoms of Parkinson's disease.

Many patients with Parkinsons disease (PD) have clinically significant anxiety, depression, fatigue, sleep disturbance, or sensory symptoms. The comorbidity of these nonmotor symptoms and their relationship to PD severity has not been extensively evaluated. Ninety‐ nine nondemented PD patients were evaluated with the following battery of tests: Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), a sensory symptom questionnaire, Unified Parkinsons Disease Rating Scale (UPDRS), Hoehn & Yahr (H/Y) Stage, and the Schwab & England ADL scale (S/E). The comorbidity of the nonmotor symptoms and their relationship to PD severity was analyzed. Thirty‐six percent of the study population had depression (BDI ≥10), 33% had anxiety (BAI ≥10), 40% had fatigue (FSS > 4), 47% had sleep disturbance (PSQI > 5), and 63% reported sensory symptoms. Only 12% of the sample had no nonmotor symptoms. Fifty‐nine percent of the patients had two or more nonmotor symptoms, and nearly 25% had four or more. Increased comorbidity was associated with greater PD severity (P < 001). This study reveals that the nonmotor symptoms of PD frequently occur together in the same patients. Increased comorbidity of the five nonmotor symptoms was associated with greater PD severity. These results suggest that recognition of these diverse nonmotor symptoms may be enhanced by looking for others when one nonmotor symptom has been identified.

Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review: Report of the Quality Standards Subcommittee of the American Academy of Neurology

In 1993, the last AAN Practice Parameter on medical treatment of Parkinson’s disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence).

Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain

Nerve growth factor (NGF) receptors were visualized in the basal human forebrain using an immunohistochemical procedure with a monoclonal antibody previously shown to recognize human melanoma cell NGF receptors. The receptors were found to be exclusively located in the medical septal nucleus, the diagonal band of Broca, and the nucleus basalis. This location coincided with that of cell bodies of ascending cholinergic neurons of the basal forebrain. In addition, NGF receptor-positive cells were costained for acetylcholinesterase. These findings indicate that cholinergic neurons of the basal forebrain but none of the other neurons located in this area express receptors for NGF. Results suggest that NGF acts as a trophic factor for cholinergic neurons in the human brain in a similar way as has been established in recent years for the rat brain.

Cognitive impairments associated with early Parkinson's disease

We administered a battery of cognitive tests to 41 recently diagnosed Parkinson patients and 41 controls to assess the early neuropsychological changes associated with Parkinsons disease (PD). Parkinson subjects did as well as controls on tasks assessing attention and select language and visuospatial measures. However, PD subjects did significantly worse on embedded figures, facial recognition, proverbs, and verbal and figural memory measures, and made more perseverative responses on a set shifting task. A discriminant function of measures of proverbs, embedded figures, and memory accounted for 22% of the variance between groups. These data suggest that the cognitive changes in early PD are more pervasive than originally described and may reflect the onset of a more widespread pathologic process.