1. Analyzing the Potential of a Diagnostic Tool for PD Ben Oren, Ezra Brettler, Uri Ron, and Ying Wang MKTG 897 - 401

2. Client: Jafar Sabbah, CEO, Dental Devices Ltd. Technology in question: a novel computerized system for automatic quantification and measurement of time-space patterns of facial features during facial expression System is intended as a monitoring and decision support tool for the detection, and progression evaluation of medical disorders that affect the performance of facial muscles Currently system is exploited in a study on Parkinson’s Disease (PD) Project Background

3. Determining whether there is a real market need for an objective diagnostic computerized system for degenerative diseases such as PD This is the central question in the decision of whether to provide the inventors with seed money and bring the technology into the NGT Project Objectives

4. Parkinson’s Disease is the most common neurodegenerative disorder after Alzheimer's disease 4-6 million people worldwide have been diagnosed with PD ~1 million people in U.S. It is estimated that an additional 3 million people have undiagnosed PD in the U.S. The prevalence (of those diagnosed with PD) is estimated at being 0.3% in the whole population in industrialized countries Rising to 1% in those over 60 years of age 4% of the population over 80 Mean age of onset is ~60 years, but 5-10% of cases are considered young onset (cases with PD beginning between the ages of 20 and 50) U.S. incidence is ~17 per 100,000 of population per year PD Prevalence and Incidence

5. Physicians arrive at a diagnosis of PD using both subjective judgment and interpretation Assessing a patient’s history Performing a physical examination on the patient Requires intimate familiarity with the signs and symptoms found Accuracy of diagnosis increases with progression of the disease Current methods and scales: UPDRS UK Brain bank Criteria Gelb Criteria CAPIT Criteria Hoehn and Yahr Scale Current Diagnosis Protocol

6. Two of the four main symptoms must be present over a specific time period for a neurologist to consider a PD diagnosis Tremor or shaking Bradykinesia - Slowness of movement Rigidity (stiffness) of the arms, legs or trunk Postural instability - Balance problems and possible falls Brain changes that create neurodegenerative diseases are microscopic (on a chemical level) and are Not Revealed by scanning technology Current Scanning Methods: Electroencephalograms (EEGs) MRI and CAT Scans Positron Emission Tomography (PET Scan) Current Diagnosis Protocol - Cont’d

7. Goals of primary research:  Determine which of available methods is most preferred for both diagnosis and monitoring progression of PD  Gather more information about what specialists see as the most significant indicators of PD  Establish whether there is potential to fill an unmet need through the measurement of facial expressions Goals of primary research

8. According to our research based on industry standard survey (NOP World) Response to pharmacotherapy and MRIs are the most popular diagnostic and confirmatory procedures used (bottom right panel) PD patients experience more tremors (52%) than any other symptom. Wearing- off fluctuations and early morning akinesia symptoms are both seen in about a quarter of PD patients (bottom left Panel) According to NEURO’s, PCP’s are their largest referral source of PD patients. It would be very helpful if there were a reliable tool assisting PCP diagnosis. Results of primary research (1 of 4) % of PD Patients Who Undergo Each Procedure for Diagnosis % of Patients

9. One-on-one telephone and written interviews were conducted; focus on Neuros and PCP: Six Neurologists and one PCP were interviewed Head of Parkinson Disease Research, Education & Clinical Center in US Assistant Professor, General Internal Medicine, Johns Hopkins University Prof. Martin J. Rabey, Head of Neurology Dept., Assaf Harofe Medical Center Dr. Moshe Huberman, Deputy Head of Neurology Dept. at Meir Hospital Dr. Nirit Lev, Senior Neurologist, Rabin Medical Center Dr. Colin Klein, Head of Neurology Dept. at Meir Hospital Results of primary research (2 of 4)

10. Symptoms used to diagnose PD Asymmetric resting tremor Responsiveness to dopaminergic replacement therapy Cogwheel rigidity Facial asymmetry and twitching not highly prevalent, but rather facial masking (hypomimia), which can occur early Equipment used to diagnose PD Current equipment or methods used to diagnose PD are viewed as somewhat reliable, but rely on physicians’ experience for diagnosis. Some equipment requires a great deal of prep work and intensive training. Results of primary research (3 of 4)

11. What is the Greatest Unmet Need? A reliable tool whereby Physicians can diagnose PD accurately prior to referral to a Neurologist. Greatest challenges are diagnosing patients early on in the disease progression and differentiating PD from other atypical and secondary forms of Parkinsonism Interviewees’ opinion on the proposed method: Not asymmetry or facial twitching, which normally do not occur in PD, but Masked Faces (Hypomimia) might be useful for diagnosis; however, probably not as a biomarker of disease progression because it is treatment responsive and the degree of change over time is subtle. Results of primary research (4 of 4)

12. With more than 5 million diagnosed patients world-wide (and millions more not diagnosed), PD represents a very large potential market Methods for PD evaluation today are primarily based on physicians’ experience and are usually time consuming and costly  There exists a High Unmet Need for a reliable, objective diagnostic tool for PD detection and monitoring. Findings and Recommendations (1 of 2)

13. Findings and Recommendations (2 of 2) Main symptoms, potentially relevant for the proposed method and computerized tool, are: Hypomimia (Facial Masking) Involuntary Tremor/Twitching If the current proposed tool can theoretically detect these specific symptoms, there may be room to consider a controlled pilot study.

14. Demographics 1.Which category best describes your field: a researcher / involved in drug development for PD / physician or medical specialist? 2.How many patients do you diagnose as PD patients on average per month? 3.What % of patients from your diagnosis are in each of the 3 stages (Initial, bilateral, severe) of PD disease? Symptoms used to diagnose PD 4.What are the top three symptoms/traits you use to diagnose a PD patient? 5.Would you describe unusual twitches, etc. during facial expressions as a characteristic of PD for diagnosis? 6.If so – In which stages of PD would you say that the performance of facial muscles is affected? 7.How accurately and reliable do you view facial asymmetry and unusual twitches as a diagnostic tool? (e.g. are there PD patients without such phenomena?) Equipment used to diagnose PD patients 8.What are the current methods and scales you are aware of to diagnose PD patients (e.g. UPDRS)? 9.What are the current methods and scales you are aware of to monitor PD patient’s disease progression (e.g. UPDRS)? 10.If you are a physician – a)What top three methods and scales are you using to diagnose PD patients and their characteristics on a scale of 1 to 5? b)What top three methods and scales are you using to monitor PD patients’ disease progression? c)How would you characterize the level of unmet need in the available equipment for diagnosis of PD (please rate on scale of 1-5 with 1 being no need for new diagnostic tools and 10 being very high unmet need) d)Any other immediate improvements you can see in diagnosing a PD patient? e)What is the greatest challenge you face when diagnosing a PD patient? f)In your opinion, would it be possible to use facial expressions as a means to diagnose and evaluate the disease’s progression? Appendix – Interview Questions