Rhinorrhea: A common nondopaminergic feature of Parkinson's disease

We compared the frequency of rhinorrhea between 34 Parkinson's disease (PD) subjects and 15 normal controls (NC) and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using [¹¹C]dihydrotetrabenazine (DTBZ) brain positron emission tomography imaging. Sixty‐eight percent (23 of 34) of PD subjects reported rhinorrhea of any cause compared with 27% (4 of 15) of NC (χ² = 7.07, P = 0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12 of 34) of PD versus 7% (1 of 15) of NC (χ² = 4.38, P = 0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or nonmotor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, χ² = 5.85, P = 0.02). Rhinorrhea is a common nondopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD. © 2010 Movement Disorder Society     

Slowing Parkinson's disease progression: recent dopamine agonist trials

In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.     

Long-duration Parkinson's disease: Role of lateralization of motor features

BackgroundA mean of 10 years elapse before patients with Parkinson's disease (PD) reach Hoehn & Yahr (H&Y) stage 4, and 14 years for stage 5. A small proportion of PD patients survive and are ambulatory for ≥20 years. We sought to identify features associated with long-duration PD (dPD).MethodsThis five-center, case–control study compared 136 PD patients with ≥20 years of duration and H&Y stage ≤4 (dPD) to 134 H&Y-, age- and gender-matched PD patients between 10 and 15 years of disease (cPD).ResultsBy study design, there were no between-group differences in age, gender and H&Y. dPD subjects were younger at onset (p < 0.0001), had more psychosis (p: 0.038), were receiving higher levodopa equivalent daily doses (p: 0.02), were predominantly left-handed (p: 0.048), and had greater frequency of left-sided onset (p: 0.015) compared to cPD subjects. Both groups had similar rates of resting tremor, dementia and REM sleep behavior disorder.ConclusionsEarly disease onset, left-handedness and left-sided onset are associated with long disease and ambulatory PD survival. The neurobiological basis of the prognostic value of lateralization deserves further investigation.     

Does long-term aggravation of Parkinson's disease result from nondopaminergic lesions?

The motor score with and without levodopa was estimated in 193 parkinsonian patients with variable length of evolution. The effect of levodopa on akinesia, rigidity, and tremor remained quite stable during the course of the disease. In contrast, the aggravation of gait disorder, postural instability, and dysarthria was more severe, with decreased percentage of improvement on levodopa in patients with longer evolution. It is suggested that aggravation of Parkinson's disease mainly results from increasing severity of cerebral nondopaminergic lesions.     

Survival in Parkinson's disease. Relation with motor and non-motor features

BackgroundSurvival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease.MethodsA broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease.ResultsAfter a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms.ConclusionsHigher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features.     

Prevalence of non motor features in a cohort of Parkinson's disease patients

Background

There is a lack of awareness among physicians of the considerable disability caused by non-motor symptoms (NMS) in PD. The aim of this work is to estimate the prevalence of NMS in a series of patients with Parkinson's disease (PD).

Materials and methods

We studied 112 patients with Parkinson's disease. Motor symptoms were scored on the Unified Parkinson's Disease Rating Scale (UPDRS) part III and the Hoehn and Yahr (HY) Scale. Other symptoms were quantified with the Non-Motor Symptom Questionnaire and Scale (NMSQuest and NMSS) as well as Minimental State Examination (MNSE).

Results

Analysis of the data from the NMSS showed that mood/cognition was the most commonly affected domain (prevalence rate = 87.5%), followed by sleep disturbance/fatigue second (78.6%). However, all other non-motor symptoms scored highly: gastrointestinal and urinary (76.8% for both), sexual dysfunction (73%), cardiovascular (70.5%) with significantly higher percentage in predominantly akinetic/rigid patients. Perceptual problems/hallucinations (9.9%) were infrequent in this population. Dementia was recorded in 22.3% of patients, most of them having a mild degree of dementia. UPDRS scores were correlated with total scores in both NMSQuest and NMSS.

Conclusions

Mood/cognition, sleep disorders, GIT, and sexual disorders were common non motor manifestations in this population of PD patients.     

Neuroprotection in Parkinson's disease: clinical trials

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.     

Neurodegenerative 'overlap' syndrome: Clinical and pathological features of Parkinson's disease, motor neuron disease, and Alzheimer's disease

Parkinson's disease (PD), Alzheimer's disease (AD), and motor neuron disease (MND) share epidemiological, clinical, and pathological features. Few studies have reported comprehensively on individuals who demonstrate a neurodegenerative 'overlap' syndrome, comprising idiopathic parkinsonism, dementia, and motor neuron dysfunction. We describe clinical, electrophysiological, and pathological features in six patients with neurodegenerative 'overlap' syndrome. All had cardinal features of PD (duration 6-26 years), and any mixture of dementia (slowly advancing), fasciculations, hyperreflexia, Babinski signs and mild atrophy and weakness of distal muscles (slowly progressive). EMG often demonstrated a lack of denervation in conjunction with abnormal MEPs (high thresholds). Patients had either 6FD-PET or pathological studies consistent with PD. Pathological studies also demonstrated moderate numbers of neurofibrillary tangles and plaque formation, typically with sparing of motor neurons in the spinal cord. We conclude that neurodegenerative 'overlap' syndrome may represent forme frustes of traditionally accepted diagnostic categories. Patients with parkinsonism, fasciculations, hyperreflexia and mild atrophy are unlikely to demonstrate active denervation on EMG; their prognosis is better than for classical MND. Neurodegenerative overlap syndrome (clinicopathological mixtures of PD, AD, and MND) may develop in some individuals as a reflection of common etiology, pathogenesis or susceptibility.     

Treatment of motor and non-motor features of Parkinson's disease with deep brain stimulation

Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson's disease. Several deep brain nuclei have been stimulated, producing a wide range of effects on the motor and non-motor symptoms of Parkinson's disease. Long-term, high-quality evidence is available for stimulation of the subthalamic nucleus and globus pallidus internus, both of which uniformly improve motor features, and for stimulation of the thalamic ventralis intermedius, which improves tremor. Short-term data are available for stimulation of other deep brain targets, such as the pedunculopontine nucleus and the centremedian/parafascicular thalamic complex. Some non-motor symptoms improve after DBS, partly because of motor benefit or reduction of drug treatment, and partly as a direct effect of stimulation. More evidence on the effects of DBS on non-motor symptoms is needed and specifically designed studies are warranted.     

The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease

The objective was to update previous evidence-based medicine reviews of treatments for motor symptoms of Parkinson's disease published between 2002 and 2005. Level I (randomized, controlled trial) reports of pharmacological, surgical, and nonpharmacological interventions for the motor symptoms of Parkinson's disease between January 2004 (2001 for nonpharmacological) and December 2010 were reviewed. Criteria for inclusion, clinical indications, ranking, efficacy conclusions, safety, and implications for clinical practice followed the original program outline and adhered to evidence-based medicine methodology. Sixty-eight new studies qualified for review. Piribedil, pramipexole, pramipexole extended release, ropinirole, rotigotine, cabergoline, and pergolide were all efficacious as symptomatic monotherapy; ropinirole prolonged release was likely efficacious. All were efficacious as a symptomatic adjunct except pramipexole extended release, for which there is insufficient evidence. For prevention/delay of motor fluctuations, pramipexole and cabergoline were efficacious, and for prevention/delay of dyskinesia, pramipexole, ropinirole, ropinirole prolonged release, and cabergoline were all efficacious, whereas pergolide was likely efficacious. Duodenal infusion of levodopa was likely efficacious in the treatment of motor complications, but the practice implication is investigational. Entacapone was nonefficacious as a symptomatic adjunct to levodopa in nonfluctuating patients and nonefficacious in the prevention/delay of motor complications. Rasagiline conclusions were revised to efficacious as a symptomatic adjunct, and as treatment for motor fluctuations. Clozapine was efficacious in dyskinesia, but because of safety issues, the practice implication is possibly useful. Bilateral subthalamic nucleus deep brain stimulation, bilateral globus pallidus stimulation, and unilateral pallidotomy were updated to efficacious for motor complications. Physical therapy was revised to likely efficacious as symptomatic adjunct therapy. This evidence-based medicine review updates the field and highlights gaps for research.     

Neuroprotection trials in Parkinson's disease: Systematic review

Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double‐blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO‐B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow‐up averaged <16 months in all but two trials. Detailed randomization methods and success of double‐blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes. © 2008 Movement Disorder Society     

Kinases as targets for Parkinson's disease: from genetics to therapy

Intense research efforts are currently directed at elucidating the etiology of Parkinson's disease (PD). One approach that has begun to shed light on the PD pathogenic pathways is the identification of disease genes through genetic linkage or association studies. These studies have revealed that several kinases may be involved in PD, as some PD genes encode kinases themselves while other PD genes are found in the same cellular pathways as kinases. Two of these kinases stand out as potential drug targets for novel PD therapy, namely leucine rich repeat kinase 2 (LRRK2) and the alpha-synuclein (α-syn) phosphorylating polo-like kinase 2 (PLK2). Indeed, both α- syn and LRRK2 show genetic linkage as well as genetic association with PD, indicating their relevance to a large number of PD cases. Also, due to the dominant mode of α-syn and LRRK2 inheritance and based on current knowledge of LRRK2 and α-syn phosphorylation by PLK2, inhibition of LRRK2 and PLK2 may constitute a potential therapy for PD. Here we discuss the function of these kinases as well as progress in their validation as drug targets for the treatment of PD.     

Ophthalmologic features of Parkinson's disease

Patients with Parkinson's disease (PD) commonly complain of impaired visual function and difficulty reading, despite normal visual acuity. Although previous studies have evaluated contrast sensitivity, color vision, visuospatial processing, visual hallucinations, and ocular movements, none has systematically evaluated the ocular complaints and ocular findings of PD patients. Thirty patients with early untreated PD and 31 control subjects without neurologic or known ocular diseases were ophthalmologically evaluated for the frequency of visual complaints, dry eyes, blepharitis, visual hallucinations, reduced blink rate, blepharospasm, and convergence insufficiency. Ocular complaints suggesting ocular surface irritation, altered tear film, visual hallucinations, blepharospasm, decreased blink rate, and decreased convergence amplitudes were more common in PD patients than in control subjects. These findings likely account for many of the visual difficulties commonly encountered by PD patients. These ocular abnormalities frequently respond to treatment.     

The influence of age and approaching death on the course of nondopaminergic symptoms in Parkinson's disease

IntroductionThe influence of approaching death in addition to age and their interaction on the course of a broad spectrum of nondopaminergic features in Parkinson's disease (PD) has not been well studied. This study addresses this issue in a prospectively designed study.MethodsDuring five years, the severity of axial symptoms, cognitive impairment, psychotic symptoms, autonomic dysfunction, depressive symptoms, and daytime sleepiness was annually evaluated in PD patients. For each domain a linear mixed-effect model was used to examine changes during follow-up and relations with age and death.ResultsOf 378 included patients, 43 died during follow-up. Higher age was associated with increased severity of all nondopaminergic features except depression, and with a higher rate of progression of axial symptoms and cognitive impairment. Patients who died during follow-up had a higher severity of all nondopaminergic features except autonomic dysfunction, and a higher rate of progression of axial symptoms, cognitive impairment, and psychotic symptoms, compared to patients who survived.ConclusionThis study shows that the severity of most nondopaminergic features and the progression rate of axial and psychotic symptoms and cognitive impairment increase before PD patients die, independent of the influence of age. An interaction between age and approaching death did not have a significant effect on the course of the symptoms. Improving our understanding of the fundamental biology underlying these factors and the interaction with factors intrinsic to the disease, may have profound implications for the treatment of PD.