http://www.neurology.org/content/75/...ement_1/S9.ful


Current understanding and management of Parkinson disease
Five new things
James F. Morley, MD, PhD and Howard I. Hurtig, MD


Next SectionGENETICS OF PD
Clinicians are frequently faced with the question, posed by a newly diagnosed patient or family member: “Is Parkinson's genetic?” This apparently simple question has a complex answer...
...Next SectionPREMOTOR DIAGNOSIS
Development of disease-modifying therapies for neurodegenerative disorders, including PD, is hindered by the substantial burden of pathology that has already accumulated by the time clinical signs appear. Although recent clinical trials suggest that one currently available drug may have neuroprotective properties, convincing proof may be difficult to demonstrate simply because therapeutic intervention may be too late to slow or halt progression of neurodegeneration after symptoms have become apparent, given the long preclinical evolution of the underlying neuropathology.7

...How can a disease be diagnosed before symptoms appear? The search for molecular biomarkers of premotor PD in blood, CSF, and urine has been active but nonproductive at the present time. On the other hand, the search for a biomarker in the brain, using the neuroimaging techniques of PET and SPECT, has shown more promise...
...An effort to understand both genetic and environmental causes will be key to defining what leads to the first of a presumed cascade of stages of neurodegeneration...
SectionDEEP BRAIN STIMULATION SURGERY
...Deep brain stimulation (DBS) was introduced in the early 1990s as an effective treatment for select patients with PD and other tremor disorders. Briefly, DBS for PD involves stereotactic surgical implantation of an electrode with 4 contacts into deep gray nuclei (globus pallidus interna [GPi] or subthalamic nucleus [STN]). Chronic high-frequency stimulation is then provided through an implantable pulse generator residing in the anterior chest wall. .. DBS has been increasingly affirmed in a variety of clinical trials, but questions have remained regarding the most prudent timing of the procedure, the best anatomic target for stimulation, ways to mitigate perioperative and postoperative adverse effects, and which patients should be selected to have the procedure...


Nexct SectionNEUROPROTECTION
While medical and surgical therapy can provide long-lasting symptomatic benefit, the holy grail of therapeutics in PD (and other neurodegenerative disorders) is the development of drugs that slow or halt progression of disease—so-called neuroprotection or disease modification. Ideally, a neuroprotective agent would modify the underlying pathophysiology that causes neurodegeneration and cell death.... None has had a clear impact on clinical outcomes in initial studies, although some agents (creatine, CoQ10) have shown sufficient promise to warrant larger, currently ongoing, phase III trials. Additionally, a recent meta-analysis of epidemiologic studies suggested that nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of incident PD by 15%, possibly by inhibiting a neuroinflammatory pathway.13 ..
Though considered mainstays of symptomatic therapy, drugs that directly (levodopa, dopamine agonists) or indirectly (monoamine oxidase [MAO-B] inhibitors) influence dopamine signaling have also been evaluated for neuroprotective activity but with controversial results...

One potential answer to the conflict between a symptomatic vs neuroprotective effect of a drug is to use an independent and objective biomarker of disease progression, such as PET or SPECT imaging of nigrostriatal dopamine terminals...
The recently reported clinical trial ADAGIO (Attenuation of Disease progression with Azilect Given Once daily)15 used a novel delayed-start trial design in an attempt to separate symptomatic from neuroprotective or disease-modifying effects of the MAO-B inhibitor rasagiline (Azilect). .. A similar delayed-start clinical trial of the dopamine agonist pramipexole in early PD (the PROUD PD study) has been completed. Although the results have not been published, presentations at meetings indicate that pramipexole does not have disease-modifying properties.

Despite these disappointments, disease modification remains in sharp focus as a worthy objective in the overall search for PD therapeutics...

Next SectionNONMOTOR SYMPTOMS: IMPACT AND MANAGEMENT
Although PD is a clinically defined movement disorder characterized by tremor, rigidity, bradykinesia, and postural instability, numerous NMS including cognitive, mood, behavioral, sleep, and olfactory disturbances have attracted the attention of clinical investigators in recent years because of their growing importance...

The high impact of NMS on the management of PD led the American Academy of Neurology's Quality Standards Subcommittee to review the literature and issue a set of guidelines for practitioners.19...
Previous SectionNext SectionCONCLUSION
In this brief review of 5 new things, we have highlighted only a few of the many areas of active investigation that are shaping contemporary thinking on the pathogenesis and treatment of PD...
Previous SectionNext SectionDISCLOSURE...