Future Aspects

With the aging of the population, the incidence of neurodegeneration is increasing dramatically in the absence of either effective therapeutic interventions or a clear understanding of the discrete pathophysiology of neurogenerative disease states. In the AD area, following the identification of Ab and tau/NFTs as potential targets for disease amelioration, there has been a wealth of research around these two targets, using both biochemical and genetic information with multiple approaches to their modulation. Despite this, there has been little practical outcome as successive mechanistic targets, some with substantive retrospective data sets, e.g., indometacin, estrogen, have failed to show efficacy in prospective controlled clinical trials or resulted in the identification of unacceptable side effects. Similarly, in the PD area, while new palliative approaches are showing promise, e.g., istradefylline, treatments for disease amelioration, despite robust preclinical data, have failed to show efficacy, e.g., CEP1347, TCH346. There are a number of challenges with current approaches to both finding and testing novel treatments for AD and PD:

1. The numerous hypotheses related to disease causality have yet to be validated, and require a safe and efficacious NCE that can be demonstrated to be effective in the human disease state. Thus, current approaches require the testing of both the hypothesis (which may be multifactorial) and the NCE (the effects of which may be redundant in the context of the complexity of the human disease state).

2. The majority of the biological systems in which NCEs are being evaluated are highly sophisticated, synthetically engineered models of hypothetical concepts of the disease causality rather than true reflections of the human disease state, with many, if not all, transgenic mouse models, recapitulating the molecular hypothesis of disease causality rather than the disease. Thus, NCEs are tested in a highly reductionistic mode, with both the NCEs and the models representing a self-contained loop that lacks real relevance to the actual disease, thus achieving Glass Bead Game status.109

3. Many of the genetic findings that have been applied to understanding causality have been controversial in that they have not been replicable and have usually focused on familial rather than the more typical idiopathic forms of the disease.

4. The anticipated endpoints to measure the effects of NCEs that modify disease outcomes in AD and PD are complex, require large patient cohorts, and are lengthy. This necessitates biomarker approaches for both disease diagnosis and assessment of disease progression that are as predictively robust and noninvasive as possible. To date, such biomarkers have been difficult to validate.11

5. In the absence of biomarkers to diagnose neurodegenerative diseases appropriately, when the signs and symptoms of PD and AD appear, it is usually far too late to treat the disease effectively. Thus, promising approaches that could have major benefit if used early enough in the disease process usually prove ineffective at advanced disease stages, further elaborating on the urgency for biomarkers.

Nonetheless, there is considerable optimism110 that the past 20 years of research have provided the basis for true advances in neurodegenerative disease modification therapy. This will however require a less reductionistic approach to preclinical research, with less dependence on transgenic models, in vivo test tubes, and a concerted effort in the area of translational medicine to develop robust biomarkers of disease progression.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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