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Script for MDS Journal Podcast

Volume 27, Issue 5

HOST: On behalf of the Movement Disorder Society, welcome to our monthly series of reports on movement disorders research. In this podcast you will hear a reading of the abstracts from the April 2012 Special Issue: Prodromal Parkinson's Disease of the Movement Disorders Journal. You can learn more about the work of The Movement Disorder Society at www [dot] movementdisorders [dot] org. To access the Movement Disorders Journal on the web, visit movementdisordersjournal [dot] com

Lewy pathology and neurodegeneration in premotor Parkinson's disease

Authors: Kelly Del Tredici and Heiko Braak The foremost motor manifestations of Parkinson's disease are resting tremor, cogwheel rigidity, hypokinesia/bradykinesia, and postural instability. Epidemiological and clinical data reveal that a wide variety of additional complaints (nonmotor symptoms), also considerably impair patients' quality of life parallel to the chronic-progressive neurodegenerative disorder. This article reviews the neuropathology and anatomy of Lowy pathology-related neurodegeneration in relation to selected nonmotro and prodromal dysfunctions.

Premotor Parkinson's disease: Concepts and definitions

Authors: Andrew Siderowf and Anthony E. Lang Parkinson's disease (PD) has a prodromal phase during which nonmotor clinical features as well as physiological abnormalities may be present. These premotor markers could be used to screen for PD before motor abnormalities are present. The technology to identify PD before it reaches symptomatic Braak Stage 3 (substantia nigra compacta [SNc] involvement) already exists. The current challenge is to define the appropriate scope of

OFFICIAL SCRIPT use of predictive testing for PD. Imaging technologies such as dopamine transporter imaging currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools, and abnormalities on these studies would only be evident at Braak Stage 3 or higher. Efficiency is greatly enhanced by combining imaging with a prescreening test such as olfactory testing. This 2-step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Alternatively, or in concert with this approach, evaluating high-risk populations (eg, patients with rapid eye movement behavior disorder or LRRK2 mutations) would enrich the sample for cases with underlying PD. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large-scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Future research will establish more definitive biomarkers capable of revealing the presence of disease in advance of SNc involvement with the promise of the potential for introducing disease-modifying therapy even before the development of evidence of dopamine deficiency.

Identifying prodromal Parkinson's disease: Pre-Motor disorders in Parkinson's disease

Authors: Ronald B. Postuma, Dag Aarsland, Paolo Barone, David J. Burn, Christopher H. Hawkes, Wolfgang Oertel, Tjalf Ziemssen

Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

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Motor signs in the prodromal phase of Parkinson's disease

Authors: Walter Maetzler and Jeffrey M. Hausdorff Relatively subtle deterioration of the motor system likely occurs well before the patient meets established motor criteria for a clinical diagnosis of Parkinson's disease; ie, the occurrence of at least 2 of the cardinal motor deficits: bradykinesia, rigidity, tremor, and/or postural instability. Powerful compensatory mechanisms may mask these clinical symptoms and make them difficult to identify and evaluate in the earliest stages of the illness. This review summarizes our current knowledge of motor signs that are thought to occur in the prodromal phase of Parkinson's disease and suggests how motor assessment batteries could be designed to detect these subclinical motor deficits with a high degree of accuracy and sensitivity.

Neuroimaging: Current role in detecting pre-motor Parkinson's disease

Authors: Jana Godau, Anna Hussl, Praween Lolekha, A. Jon Stoessl, Klaus Seppi Convergent evidence suggests a pre-motor period in Parkinson's disease (PD) during which typical motor symptoms have not yet developed although dopaminergic neurons in the substantia nigra have started to degenerate. Advances in different neuroimaging techniques have allowed the detection of functional and structural changes in early PD. This review summarizes the state of the art knowledge concerning structural neuroimaging techniques including magnetic resonance imaging (MRI) and transcranial B-mode-Doppler-sonography (TCS) as well as functional neuroimaging techniques using radiotracer imaging (RTI) with different radioligands in detecting pre-motor PD.

Biochemical premotor biomarkers for Parkinson's disease

Authors: Brit Mollenhauer, Jing Zhang A biomarker is a biological characteristic that is objectively measured and evaluated as an indicator of normal biological or pathologic processes or of pharmacologic responses to a therapeutic intervention. We reviewed the current status of target protein biomarkers (eg, total/oligomeric -synuclein and DJ-1) in cerebrospinal fluid, as well as on unbiased processes that can be used to discover novel biomarkers. We have also provide details about strategies toward potential populations/models and technologies, including the need for standardized sampling techniques, to pursue the identification of new biochemical markers in the premotor stage of Parkinson's disease in the future.

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Prerequisites to launch neuroprotective trials in Parkinson's disease: An industry perspective

Authors: Johannes R. Streffer, Igor D. Grachev, Cheryl Fitzer-Attas, Baltazar GomezMancilla, Babak Boroojerdi, Juliana Bronzova, Susanne Ostrowitzki, Stephen J. Victor, Paulo Fontoura, Robert Alexander Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease-modifying treatments should be initiated in the earliest stages of Parkinson's disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or pre-motor populations in PD, new markers have been proposed. We address the prerequisites needed to use these pre-motor markers in clinical trials for the selection of subjects, definition of populations, and monitoring of disease progression. This may require the development of new diagnostic criteria potentially based on non-motor clinical signs, imaging techniques, or biological features, all requiring discussion in a regulatory framework. Questions addressed include: Which steps must be taken to gain a broad consensus in the field from academic opinion leaders, patient advocacy groups, regulatory bodies, and industry? How do we prevent the selection of subgroups, which may not be representative of the full disease spectrum? Is there a way forward in personalized medicine? How do we balance risk and benefit in an at-risk population? While many tools are available, a concerted effort is required to develop integrated data sets, as well as to achieve the necessary standardization for multicenter clinical trials. To this end, public-private consortia (including academic centers, patient advocacy groups, and industry) will be of crucial importance to prospectively investigate and define the best tools and treatment paradigms.

Defining at-risk populations for Parkinson's disease: Lessons from ongoing studies
Authors: Daniela Berg, Ken Marek, George W. Ross, Werner Poewe It is currently widely acknowledged that the natural history of PD includes a preclinical phase, and there are increasing efforts to identify markers that would allow the identification of individuals at risk for PD. Here, we discuss the issues related to defining at-risk populations for PD and review findings of current population-based cohorts that have reported potential biomarkers for PD, such as the Honolulu-Asia Aging Study (HAAS) and the PRIPS (Prospective Validation of Risk factors for the development of Parkinson Syndromes) study. We also discuss enriched risk cohorts designed to evaluate specificity and predictive value of markers exemplified by the PARS (Parkinson Associated Risk Study) and the TREND (Tbinger evaluation of Risk factors for the Early detection of NeuroDegeneration) study. Although there is still a long way to go, studies designed according to these concepts might eventually provide sufficient data to

OFFICIAL SCRIPT form the basis for future screening programs for PD risk to be applied at a population level.

The significance of defining preclinical or prodromal Parkinson's disease

Authors: C. Warren Olanow and Jos A. Obeso A body of clinical and pathologic evidence supports the concept that there a preParkinson state exists prior to the time when Parkinson's disease (PD) can be formally diagnosed. The ability to define the preclinical or prodromal PD state has many important implications. First, understanding the timing and sequence of pathologic change that occurs in PD could provide important clues as to the etiology and pathogenesis of PD, and provide insight into cell vulnerability factors. Second, defining a population of patients with preclinical PD would provide a potentially important group of subjects for clinical trials attempting to define disease-modifying therapies. And, finally, being able to determine that a person has PD at an earlier time point than is currently possible would permit the introduction of a putative disease-modifying therapy at a time when it could have more profound and long-lasting effects. This paper reviews the clinical significance of defining preclinical PD. *** HOST: This concludes this months podcast of the Movement Disorders Journal, April 2012 Special Issue. Thank you for listening and we hope you will join us again next month.