Surrogate Markers Of Ad

A surrogate marker should accurately reflect disease activity, track course of illness, or index treatment outcome. To fulfill the requirement of a surrogate marker or endpoint, the marker should be directly in the causative pathway to disease outcome (Fleming and DeMets, 1996). Such biomarkers could be important in diagnostic practice, but most will have their major value in tracking the course of disease or monitoring effects of therapeutic interventions. Examples of surrogate markers include CD4 cell counts and measures of viral load in HIV research, and the number of hyperintense plaques on MR brain scan in multiple sclerosis. In AD, there are as yet no accepted biomarkers as surrogate outcomes, although measures of brain atrophy show promise. The basis of dementia in AD is neuronal loss and decreased synaptic contacts, which are the proximate causes of dementia (Gomez-Isla et al., 1996, 1997). If there were a treatment that prevented or even slowed neuronal death and atrophy, how could this effect best be detected? Quantitative analysis of MR brain scans suggest an answer. Although there is regional specificity in the distribution of neuronal loss, the entire brain shrinks over time; at autopsy, brain weight is usually 10% or less than in control brains. In serial measures of whole brain volume using MRI, Fox et al. (1999a) documented a 2-3% per year decrease in brain volume in AD patients compared to less than a 0.5% per year decrease in non-demented control subjects. In a subsequent study, they found that the rate of brain atrophy was significantly correlated to decline on a measure of cognition (Fox et al., 1999b). This observation reinforces the clinical relevance of this surrogate marker in detecting brain atrophy for tracking the course of illness and possibly for monitoring effects of treatment.

Surrogate markers can also be used to verify mode of drug action. The next generation of drugs developed for AD will probably target amyloid and seek to alter APP processing (Felsenstein, 2000) or block amyloid deposition in brain

(Schenk et al., 1999). The rationale for this approach rests upon the fact that p-amyloid (Ap) deposits in the neuropil are one of the defining histopatho-logical signatures of AD. Because an excessive amount of Ap may be toxic to neurons (Yankner et al., 1990), attempts to lower the amyloid burden and prevent Ap deposits is a major goal in drug development for AD. In testing these therapies, clinical trials should incorporate efforts to detect the desired effect of treatment by measuring amyloid derivatives in either blood or CSF. A recent study by Nitsch et al. (2000) illustrates that this strategy is feasible. They administered the selective mj-agonist AF102B to 19 AD patients based upon preclinical studies showing that activation of the m1 receptor subtype inhibited Ap secretion from cultured cells (Hung et al., 1993). In the human studies, they measured total Ap levels in CSF obtained before treatment and again 4 weeks later during treatment and found that overall CSF total Ap levels decreased significantly by 20% during treatment with AF102B. CSF Ap levels did not change significantly in nine AD patients treated according to identical protocols with the acetylcholinesterase inhibitor physostigmine nor in another ten patients treated with the anti-inflammatory drug hydroxychloroquine. These findings confirmed the hypothesized specificity of mj receptor activation in affecting APP processing and illustrate the value of CSF Ap measures as a way to detect the effect of a drug in vivo.

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