Neurology February 2009 Volume 72 Issue 7

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.(C)2009AAN Enterprises, Inc.

Biomarkers are objective, accessible, and easily measurable biologic parameters that correlate either with the presence (trait) or the severity (state) of a disease. As the major neurodegenerative diseases, such as Alzheimer disease or Parkinson disease, are likely to be etiologically heterogeneous disorders, sensitive and reliable biomarkers that reflect the underlying disease process are urgently needed, and are a prerequisite for a more refined diagnosis and the development of novel disease-modifying therapeutic strategies. "Genetic biomarkers," in the form of disease genes or risk-modifying variants, are able to define the risk of an individual developing a disease, and allow stratification of patient populations according to the underlying molecular defect. Alterations of the transcriptome or the proteome, on the other hand, may provide a means to monitor disease progression or severity. However, because of the complex relationship of genotypes and phenotypes in neurodegenerative disorders, the development of useful biomarkers is still in an early phase.(C)2009AAN Enterprises, Inc.

The questions of when and how to start treatment for Parkinson disease (PD) remain extremely challenging. A variety of treatment- and patient-related factors must be taken into account when making these decisions. Ideally, neuroprotective therapy would be started at the time of diagnosis. However, no treatment has been unequivocally shown to modify disease progression, and those that have some evidence for this effect all provide confounding symptomatic benefits, which may also be important to supplement faltering compensatory mechanisms within the basal ganglia. Dopamine agonists are clearly associated with a reduction in the incidence of dyskinesias in the early years, but it is not certain that this translates into long-term benefit. In addition, a number of nonmotor side effects are more frequently associated with dopamine agonists than with levodopa. This review will highlight these and other issues that must be considered when deciding on the early treatment of PD.(C)2009AAN Enterprises, Inc.

"Neuroprotective" compounds that block dopamine cell death are expected to slow the progression of the neurologic symptoms of Parkinson disease (PD) and therefore "modify" the disease course. However, presently, no fully satisfying efficacy "disease-modification" study design exists, and no drug has yet been approved for that indication. This is inherent to the slow progression of PD with respect to the limited time for patient follow-up and exposure to placebo, the modest effects of investigated drugs, and the confounding effects of symptomatic medications used to treat patients with PD. Disease-modification trials assessing drug efficacy on PD progression are currently prospective, randomized, parallel-group, placebo-controlled, long-term (1-3 year) studies. Untreated patients with early PD represent the main target population because more neurons remain for protection, PD may progress faster, and symptomatic medications are not needed at this stage. "Long lasting" prevention/postponement of disability is a relevant objective for such trials and two main types of outcome and analysis are proposed: slopes analysis of cardinal clinical feature progression (Unified PD Rating Scale, UPDRS) or survival curve analysis of "time to emergence" of clinically relevant milestones (time to dopaminergic therapy, Hoehn and Yahr stage III, etc.). The use of biomarkers remains investigational. Wash-out and delayed-start designs have been proposed to disentangle symptomatic and neuroprotective mechanisms, although this clarification might not be so important practically, as long as the effect on disability is large and long-lasting. To observe clinically relevant changes, several years of follow-up is required, and controlled, randomized, pragmatic trials should be considered when establishing clinical development plans.(C)2009AAN Enterprises, Inc.

Although idiopathic Parkinson disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, there are still major unmet needs regarding its long-term management. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Current evidence suggests that these are related to mode of administration, whereby multiple oral doses of levodopa generate pulsatile stimulation of striatal dopamine receptors. Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A2 antagonists and [alpha]-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful. However, the ultimate goal of PD medical management is modifying disease progression, thereby delaying the evolution of motor and nonmotor complications of advanced disease. As understanding of preclinical markers for PD develops, there is new hope for neuropreventive strategies to target "at risk" populations before clinical onset of disease.(C)2009AAN Enterprises, Inc.