Is obstructive sleep apnea a problem in Parkinson’s disease?

BackgroundParkinson’s disease (PD) is associated with sleep disorders and daytime sleepiness. Upper airway dysfunction in PD may promote obstructive sleep apnea. However, the frequency and clinical relevance of sleep-disordered breathing in PD remains unclear.MethodsSleep apnea symptoms, cardiovascular events and treatment were collected in 100 patients with PD (50 unselected, consecutive patients matched for age, sex and body mass index with 50 patients referred for sleepiness) and 50 in-hospital controls. The motor and cognitive status was evaluated in patients with PD. The 150 subjects underwent a video-polysomnography.ResultsSleep apnea (defined as an apnea–hypopnea index greater than 5) was less frequent in the PD group (27% patients, including 6% with mild, 11% with moderate and 10% with severe sleep apnea) than in the control group (40% in-hospital controls, p < 0.002). Sleep apnea was not associated with increased sleepiness, nocturia, depression, cognitive impairment and cardiovascular events in patients with PD. Sleep apnea was more frequent and severe in the most disabled patients. Patients with PD did not display sleep hypoventilation, stridor and abnormal central sleep apnea. In patients with REM sleep behavior disorders, snoring and obstructive sleep apnea occurred during REM sleep, although the chin muscle tone was maintained.ConclusionObstructive sleep apnea does not seem to be a clinically relevant issue in PD. Daytime sleepiness, nocturia and cognitive impairment are mostly caused by other, non-apneic mechanisms. The maintenance of chin muscle tone during REM sleep behavior disorder has no influence on the frequency of apneic events.     

Bladder and bowel dysfunction in Parkinson’s disease

Summary. Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson’s disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients’ quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency. Correspondence: Ryuji Sakakibara, Sakura Medical Center, Neurology Division, Department of Internal Medicine, Toho University, 564-1 Shimoshizu, Sakura 285-8741, Japan     

Parkinson’s disease: a multi-faceted disease

Journal of Neurology -     

Is Alzheimer’s disease a homogeneous disease entity?

The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences.     

Parkinson’s disease: Is the initial treatment established?

Recent studies have suggested that initial dopamine agonist therapy with pramipexole or ropinirole may slow the progression of Parkinson’s disease (PD) and also reduce the subsequent risk of levodopa motor complications. This presumed effect on PD progression, however, could be artifactual, resulting from the influence of chronic drug treatment on regulation of dopamine system proteins. With respect to levodopa motor complications, there is no dispute that pramipexole and ropinirole are effective in reducing levodopa dyskinesias and motor fluctuations; however, it is not clear that they must be started early, as opposed to initiation only after the levodopa complications develop. Levodopa therapy has numerous advantages that include greater efficacy, much lesser expense, simpler administration, and a lower frequency of hallucinosis and somnolence. Carbidopa/levodopa, pramipexole, and ropinirole are all appropriate first choices in the treatment of PD.     

Pramipexole-related chronic lower limb oedema in a patient with Parkinson’s disease

Pramipexole is a non-ergot dopamine agonist that is used frequently as a single therapy or in combination for the management of Parkinson’s disease. Common side effects are daytime drowsiness, hypotension, hallucinations and compulsive behaviour. We describe a patient who developed severe chronic and extensive lymphoedema after pramipexole was introduced and that resolved after its cessation.     

Driving in Parkinson’s disease—a health hazard?

Abstract. Background: The driving safety of Parkinsons disease (PD) patients has lately been questioned after several authors reported road accidents caused by sleep attacks in PD patients on dopaminergic medication. Objectives: To determine 1) whether PD patients in general and those on dopaminergic medication in particular are especially prone to cause severe road accidents and 2) whether there are PD symptoms or dopaminergic side effects with the potential to compromise driving safety. Data source: Relevant articles were identified by electronic search of biomedical databases (1966–2002: MEDLINE, EMBASE, PASCAL, PUBMED), the Cochrane Controlled Trials Register, and reference lists of located articles. Results: Despite frequent occurrence of potentially hazardous dopaminergic side effects (2–57 %) and disabling parkinsonian non-motor and motor disabilities (16–63 %), the two existing studies on accident rates suggest that PD patients are not more prone to cause road accidents than the rest of the population. Five further reports including 1346 patients and focusing on dopaminergically induced sleep attacks provided comparably low accident figures (yearly incidence: 0%–2%). Because of low figures meta-analysis was intended but finally deemed inappropriate as the methodology of included studies varied greatly and was frequently flawed. Conclusion: Further prospective community-based well designed studies on accident risk in PD patients are needed to provide evidence based driving recommendations.     

Is increased spinal nociception another hallmark for Parkinson’s disease?

Augmented spinal nociception during the “off” phase has been observed early in Parkinson’s disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson’s disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined “off” state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies.     

Is there room for new non-dopaminergic treatments in Parkinson’s disease?

The contribution of non-dopaminergic degeneration to disability in Parkinson’s disease (PD) is still debated. It has been argued that no additional advance can be expected in the management of PD by the development of new dopaminergic agents and suggested that future research should mainly focus on therapies targeting the non-dopaminergic systems involved in the pathogenesis of levodopa resistant motor and non-motor symptoms. We believe this is only partially true and the achievement of a stable dopaminergic restoration and modulation of the dopaminergic system is still an important, unmet need of current pharmacological therapies in PD. Currently available oral levodopa and dopamine agonist medications provide insufficient benefit, as the therapeutic window progressively narrows and motor fluctuations eventually develop in most patients. Conversely, the application of infusion and surgical therapies is limited by selective indications and possible irreversible adverse events and device-related problems. Research of new, safer and less invasive strategies, able to modulate the dopaminergic circuits, would certainly improve the management of motor complications, and most importantly such treatments would be also beneficial to axial and non-motor symptoms, which are universally regarded as the major cause of PD functional disability. Indeed, gait and balance problems may improve with dopaminergic treatment in most patients and they become unresponsive only at the very late stages of the disease. Moreover, several non-motor disturbances, including cognition and depression are often linked to oscillation of dopamine concentrations, and are frequently relieved by treatments providing continuous dopaminergic delivery. Finally, drug trials testing non-dopaminergic treatments for motor and non-motor symptoms of PD provided so far disappointing results. Despite the impressive advances of PD therapeutic strategy, we think there is still need for safe, non-invasive and easily manageable dopaminergic treatments able to provide constant dopamine receptor stimulation and ensure a more stable control of dopamine responsive motor and non-motor symptoms at any stage of the disease.     

Is neuromelanin changed in Parkinson’s disease? Investigations by magnetic spectroscopies

Summary. Human mesencephalic neuromelanin (NM) is characterized by an irregular, undefined structure, making its characterization by usual physico-chemical methodologies quite difficult. NM isolated from controls and from Parkinson’s Disease (PD) patients was compared by high-resolution solid-state nuclear magnetic resonance (NMR). The pigment from PD patients appeared to be mainly composed of highly cross-linked, protease-resistant lipo-proteic material, with disappearance of melanin NMR resonances, suggesting melanin breakout due to oxidative stress conditions. Moreover, alpha-synuclein was detected in NM of PD patients and controls after cleavage of the melanin backbone under solubilizing conditions. NM stores iron ions as oxyhydroxide iron clusters containing thousands of iron atoms. Electron Paramagnetic Resonance (EPR) investigations and magnetic susceptibility measurements confirmed the occurrence of magnetic coupling among iron atoms, whereas in synthetic melanin the occurrence of isolated Fe³⁺ ions was evident. NM from PD patients showed a lower total magnetization, possibly suggesting a progressive Fe migration from its storage environment (i.e., NM) to the cytosol.     

Neuroimaging in Parkinson’s disease

In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson’s disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.     

Aetiopathogenesis of Parkinson’s disease

Parkinson’s disease (PD) is characterised both clinically and pathologically by features that distinguish it from other parkinsonian disorders including, for instance, multiple system atrophy and progressive supranuclear palsy. The aetiologies of PD includes both genetic and environmental influences. Several single gene causes of autosomal dominant and recessive PD have been described. Recent genome-wide association (GWA) studies have identified a number of risk alleles for PD. No specific environmental cause has been defined but several factors have been described which influence the risk for PD. Mitochondrial dysfunction, free radical mediated damage, inflammatory change and proteasomal dysfunction have been thought to play a role in PD pathogenesis. Autophagy is now recognised as an important component of the cell’s mechanism for protein turnover and has relevance for PD. There is some convergence and overlap of pathogenetic pathways between environmental and genetic factors. The importance of identifying the molecular and biochemical events that lead to PD lies in the prospect that novel drug targets will emerge and that new compounds will be developed that slow the progression of the disease.

     

Depression in Parkinson’s disease

Among the recently well appreciated non-motor symptoms in Parkinson’s disease (PD), depression plays a prominent role due to its frequency and impact on quality of life. However, depression may be confounded by motor symptoms, especially akinesia and other non-motor symptoms such as apathy, anxiety and dementia. Data on specific diagnostic tools or treatment for depressive symptoms in PD patients are still sparse. Here we summarize an expert opinion based on available data and clinical experience.