Rapid communicationBiological markers for therapeutic trials in Alzheimer’s disease: Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease
Section snippets
Introduction and aims of the present review
Alzheimer’s disease (AD) is the most common neurodegenerative disease and afflicts about 10% of the population over 60. While diagnostic accuracy for the disease has improved, the differential diagnosis for the disorder is still problematic. In the very early stages of disease, frequently classified as mild cognitive impairment (MCI), delineating disease process from “normal ageing” may be difficult; in later stages of the disease distinguishing AD from a number of neurodegenerative diseases
Amyloid β peptide 40 and 42 (Aβ40 and Aβ42)
The major component of neuritic plaques is the amyloid β (Aβ) protein, a small 42 residue protein derived through proteolytic processing of a larger membrane bound glycoprotein, the amyloid protein precursor (APP) [128]. Secreted soluble Aβ is a product of normal cell metabolism, and found in various body fluids including plasma and CSF [91]. Recent studies have shown that in AD brain, Aβ protein ending at residue 42 (Aβ42) is deposited first and is the predominant form in senile plaques;
Glutamine synthetase
Glutamine synthetase is a widely expressed enzyme. In the brain, it is made by astrocytes, and plays a role in detoxifying ammonia. Its levels increase after injury, and the temporal lobe of patients with AD show increased immunostaining for glutamine synthetase, most likely due to astrogliosis [153]. Levels in CSF were increased in a small number of patients with AD relative to controls, but intermediate increases were also seen in vascular dementia and amyotrophic lateral sclerosis.
APP isoforms in platelet membranes
APP is abundant in platelets, predominantly as the 770 isoform. After the platelets are activated, soluble forms of cleaved APP are released, analogous to processing in neurons, after platelets are activated [23]. Two research groups have measured relative amounts of two platelet isoforms in platelet membrane preparations, and reported a decrease in the amount of the higher (130 kDa) band compared to the lower (110 kDa band) [10], [33]. It is not clear why systemic abnormalities of short-lived
Discussion
The value of the samples of physiologic fluids to be collected will be greatly enhanced by the breadth and scope of imaging and classical clinical assessments to be available in the same well-characterized subjects. For this reason it is expected that, in general, samples for biological measures would be collected at each time point for which there are also images and cognitive data collected. Furthermore, patient documentation should include potential confounding factors such as chronobiology
Conclusion
Such a resource as this database and sample repository would be of unique value in the development of new medications and should be freely available to any applicant, public or private. Special additional considerations would need to be given to immortalized cell lines as a source of DNA. It is recognized, however, that the physical samples in storage, as distinguished from the imaging data, would represent a finite resource and therefore a review body would need to be established for the
Conflict of interest statement
The following conflicts of interest were declared by the authors with respect to publication of this paper: Richard A. Frank is an employee of Pharmacia Corporation. Douglas Galasko is a paid consultant of Elan Pharmaceuticals Inc., Pharmacia Inc., and Takeda Pharmaceuticals Inc. Mony de Leon is an employee of NYU School of Medicine and holds a patent on CSF biomarker dilution factor corrections by MRI. Joseph Rogers holds equity in Elan Pharmaceuticals and a patent on the use of
Acknowledgements
Authors are grateful to Neil Buckholtz (NIA), Frank Faltraco (Ludwig-Maximilian University), Susan Molchan (NIA), William Potter (Lilly) for helpful discussions.
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Biomarker-guided clustering of Alzheimer's disease clinical syndromes
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