Summary Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) manifests as unpleasant dreams and vigorous behaviours during REM sleep that can result in injuries. Patients with IRBD ...have no known neurological diseases or motor or cognitive complaints; however, this sleep disorder is not harmless. In most cases, IRBD is the prelude of the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or, less frequently, multiple system atrophy. Patients can show abnormalities that are characteristic of the synucleinopathies, and longitudinal follow-up shows that most patients develop parkinsonism and cognitive impairments with time. Thus, diagnosis of IRBD needs to be accurate and involves informing the patient of the risk of developing a neurodegenerative disease. It is extraordinary for a sleep disorder to precede the full expression of a neurodegenerative disease, which renders IRBD of particular interest in studies of the prodromal stage of the synucleinopathies, and in the development of neuroprotective interventions to stop or slow neurodegenerative deterioration before motor and cognitive symptomatology emerges. Such therapeutics do not currently exist, and thus represent an unmet need in IRBD.
Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson's disease (PD). Oral levodopa has been widely used for over 40 years, often in ...combination with a dopa-decarboxylase inhibitor (DDCI), which reduces many treatment complications, extending its half-life and increasing levodopa availability to the brain. Entacapone, a catechol-O-methyltransferase inhibitor, can also be used to improve the bioavailability of levodopa, especially when used in conjunction with a DDCI. During early-stage PD, treatment will depend on the severity of symptoms; if greater symptomatic effect is required then levodopa or dopamine agonists are usually the drugs of choice. The ability to remain employable or physically active is an important goal in younger patients, therefore, in some instances levodopa initiation should be considered early on, either as a monotherapy or in combination with other drugs. The clinical use of levodopa may eventually be limited by the development of various treatment-related complications, including response fluctuations, dyskinesia and psychiatric problems. Motor complications are related to the intermittent delivery of dopamine-replacing drugs to the brain. Triple combination of levodopa/carbidopa/entacapone available in a single tablet in multiple levodopa dose strengths offers flexibility and helps control response fluctuations. Recent developments in treatment with levodopa try to obtain continuous delivery with levodopa and include duodenal infusion of a levodopa/carbidopa, transdermal levodopa patch, and oral pro-levodopa. Levodopa remains the most potent dopaminergic therapy for PD.
Summary Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which ...disease-modifying therapies—ie, those aimed at delaying or preventing the progression to overt disease and its many complications—could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials.
Clinical, neuroimaging, and pathologic studies have provided data suggesting that a variety of nonmotor symptoms can precede the classic motor features of Parkinson disease (PD) by years and, ...perhaps, even decades. The period when these symptoms arise can be referred to as the "premotor phase" of the disease. Here, we review the evidence supporting the occurrence of olfactory dysfunction, dysautonomia, and mood and sleep disorders, in this premotor phase of PD. These symptoms are well known in established PD and when presenting early, in the premotor phase, should be potentially considered as an integral part of the disease process. Even though information on the premotor phase of PD is rapidly accumulating, the diagnosis of premotor PD remains elusive at this time. Should a safe and effective treatment with disease-modifying or neuroprotective potential in PD become available, identifying individuals in the premotor phase will become a serious priority.
PDF
