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Answers to frequently asked questions
What are the principles behind the VMT system
The VMT testing procedure exploits the well-known PD related deficits in motor control that involve
feed-forward (open loop) modes of action. The VMT test necessitates precise control of horizontal
hand movements, so as to replicate in space and time the movement of a target across a vertical
computer screen. Visual information that can be used to guide hand movements does not include sight
of the moving hand itself, yet, movement of the hand must correspond to that of the screen target in
space and time. This setting challenges high-level motor planning in a way that no other current
diagnostic testing procedure for movement disorders does. In addition, an important component of the
test challenges the executive capabilities of the subject in a language and culture independent mode,
providing quantitative assessment of this domain. Since cognitive-executive functionality declines in
PD patients even before motor impairments are conspicuous, visuo-motor testing by VMT provides
another important layer for PD diagnosis. The standard neurological examination is based on subjective
assessment of simple postures and movements. Therefore, there are inherent differences between the
motor skills tested by the VMT system versus those tested in the standard neurological examinations,
and in the motor/cognitive processes which underlay such skills.
Visually controlled movements are known to involve the pre-motor (PM) and supplementary motor (SMA) cortical fields. There is no simple functional dichotomy between PM and SMA and control of visually guided movements seems to pertain to both. Neuronal activity in the SMA, which is a main component of the basal ganglia motor-loop, is reduced in untreated PD patients and this field does not become active during task performance in the "off "state of drug treated patients. In contrast, the primary motor cortex, which is also targeted by basal ganglia outputs, can be activated during both "on" and "off" states. Accordingly, "simple" and "complex" movements are affected differentially in PD, reflecting the different involvement of MI SMA and PM in their execution. Performing a task that requires indirect visuo-motor control depends on high level transformations that probably exploit the basal ganglia connections with SMA/PM more heavily than performance of simple repetitive movements. Because testing of visuo-motor functions applies to a higher level of information processing, the VMT system is a far more powerful tool for detection of PD-related motor control deficits than quantification of disease symptoms by tremor, rigidity, or simple repetitive movements. The VMT is thus able to detect changes at an early disease stage when dopaminergic loss in the basal ganglia is already above normal but neurological symptoms can not yet be discerned with confidence. What does the VMT offer?
The VMT offers a range of tasks that exploit current knowledge on PD related deficits, in a 20 minute,
non invasive test. The range of tasks endows the system with a wide dynamic range, so that the
condition of patients at different PD stages can be assessed quantitatively, without loss of sensitivity.
This quantitative nature not only opens up the possibility to describe the patient's clinical state in
objective, quantitative terms, but also provides means for quantitative evaluation of the effects of drug
treatment.
The VMT system has been used to collect clinical data from several hundred PD patients at different disease stages. A study performed with 37 very early PD patients (Hoehn and Yahr score of 1.9 ± 0.6), all before initiation of medical treatment, and 28 controls, revealed a highly significant ability (p<0.0001) to separate between the two groups (see attached report). In a study performed with 25 PD patients to evaluate the effects of deprenyl monotherapy, the system was able to show a pronounced improvement in performance after 30 days of drug treatment. Ongoing studies suggest that the system is highly capable of discrimination between "off "and "on" states in moderate patients on Levdopa therapy What Other Diagnostic Methods are currently available?
Conventional clinical evaluation of patients is based on subjective observations of disease symptoms such as tremor, rigidity, slowness of movement, gait and postural instability, which are integrated into Neurological Evaluatio n by Visuo-Motor Testing
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the unified Parkinson's disease rating scale (UPDRS). However, diagnosis is tricky due to the ambiguous nature of early symptoms (may be confused with age related changes in function) and the subjective nature of evaluation. There is general agreement among physicians and researchers on the need for an objective and quantifiable rating of PD. When evaluating the wide range applicability of a proposed system, the following requirements should be addressed: Sensitivity that will enable early diagnosis and detection of subtle changes in PD status. Reliability in differentiation of PD from age related symptoms or other neurological disorders. Wide dynamic range, so that advanced patients can still be monitored for drug effects. Ease of testing, reducing examination time and patient discomfort. A definite method for diagnosis of PD, although with obvious limitations, is postmortem identification of typical histological changes (appearance of Lewi bodies) in brain slices. Otherwise, reliable diagnosis of PD can be obtained by brain imaging of Dopamine synthesis and Dopamine receptors in the Basal Ganglia, using positron emission tomographic scanning. This is not only a very costly and restricted method, requiring access to expensive equipment, but it also involves considerable discomfort to the patient. Another approach, the diagnosis of PD by the administration of L-Dopa and the evaluation of the immediate response (LDOPA challenge), is a too lengthy and uncomfortable method to gain widespread use. It is also uncertain how such a method can be used for tracking disease progression in patients who already receive L-Dopa medication. A deficit in olfaction was shown in recent years to constitute an early symptom of PD. Olfactory testing has become a promising early diagnosis methodology for PD. However, this procedure is not easy to apply and suffers from inherent limitations that render it less conclusive than originally hoped. As for biochemical markers, we have not seen evidence that methods, based on such markers and capable of PD diagnosis will be available in the near future. Other Kinesiologic methods available or in development concentrate on quantitative measurement of one of the symptoms related to Parkinsonism - tremor, rigidity, or increase in reaction time. Since neither of these symptoms provides sufficient discrimination power by itself, a battery of tests is required to provide a sensitive and reliable diagnosis, bearing back on examination time and cost. An example of a Kinesiologic method offered for evaluation of PD is the PLM test, offered by Qualisys Inc. The system comprises of a two dimensional motion measurement system (the MacReflex) which includes a video camera, a video-processor, a laptop computer, and software. Kinesiologic methods are also in use for diagnosis of other postural and movement disorders, such as a 3-D Motion Analysis System offered by Zebris, which is used for quantification of movement disorders such as ataxia or paresis. The price of these systems is four to 10 times the price of the VMT. To conclude, it appears that at present the VMT system is unique in its approach to quantification of PD, in its diagnostic power and in its low price. What are the benefits of early diagnosis and quantification of Parkinson's Disease ?
Studies comparing clinical or PD drug consumption records to population surveys reveal an under
diagnosis rate of 30% and up to 70%. In addition, many PD patients are misdiagnosed. Therefore, the
impact of an affordable system which can diagnose PD reliably through a twenty minutes noninvasive
test is likely to be significant. An added value of the VMT system is its affordability as a large scale
screening methodology for the elderly populations. If this goal is attained, it will be possible to offer
treatment to many PD patients that at present do not receive it.
Parkinson's Disease (PD) is a debilitating chronic illness which results from progressive degeneration of the dopamine-producing neurons in the Substantia Nigra (SNc). The clinical symptoms of PD are Neurological Evaluatio n by Visuo-Motor Testing
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late to appear with respect to the course of the biological degeneration process - typically, over 70% of the dopaminergic neurons in the SNc die before a person is recognized as suffering from PD. Since these Neurons can not be revived, treatment of PD is mainly symptomatic - either through administration of levodopa (the precursor for dopamine synthesis), which can help restore dopamine level, through stimulation of dopamine receptors by dopamine-mimetic drugs or by inhibiting dopamine metabolism so as to prolong its effect. Among the later, Deprenyl (a drug that inhibits dopamine breakdown) has been shown to delay the need for L-dopa treatment in new patient. Although the beneficial effect of this drug in terms of overall disease progression is marginal, it may still buy some quality years at early disease stages. Another more recent drug that works in a similar way – Rasagiline, has a more potent protective effect, but still cannot arrest the disease. In recent years neurobiological studies have indicated the interference with pathologies of protein misfolding may cure PD (as well as other neurodegenerative illnesses). These are extremely exciting developments but apparently, they are still 5 to 10 years away from practical application. When on the market, drugs of this type will render early diagnosis of PD invaluable. In addition to the above, it is important to recognize the need for an effective means to monitor disease progression and optimize medication dosage: as the brain continues to change drug treatments loose their effectiveness (wearing-off phenomena). Furthermore, excessive use of L-dopa may eventually lead to severe side effects involving involuntary movements of the limbs and psychological disturbances. Therefore, symptomatic treatment of PD patients must be monitored with care, so that control of the disease symptoms is attained with minimal dosage. Neurological Evaluatio n by Visuo-Motor Testing

Source: http://www.greenmanage.biz/vmt/pdf/VMT-FAQ.pdf

2700681_1.doc

Case 5:08-cv-00479-PD Document 169-1 Filed 05/16/12 Page 1 of 66 IN THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF PENNSYLVANIA KYLE J. LIGOURI and TAMMY L. HOFFMAN individually and on behalf of all others similarly situated, CIVIL ACTION NO. 5:08-CV-00479-PD WELLS FARGO & COMPANY, WELLS FARGO BANK, N.A., NORTH STAR MORTGAGE GUARANTY REINSURANCE COMPANY,

1475-2875-7-255.fm

ReviewAzithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancyR Matthew Chico*1, Rudiger Pittrof2, Brian Greenwood1 and Daniel Chandramohan1 Address: 1Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK and 2Enfield Town Clinic, Wenlock House, 33 Eaton Road, Enfield, EN1 1NJ, UK