Methods for Determining Biomarkers of AD
Gene Expression Patterns in AD
DiaGenic (Oslo, Norway) has developed a test for diagnosis of AD using gene expression patterns in peripheral blood cells based on its patented technology. Positive results were obtained by analyzing blood samples from patients with AD and controls. NEW ADtect® for diagnosis of AD has received CE approval in Europe and will be marketed through a network of distributors. Test analysis will be performed by DNA Vision in Belgium. The disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future. MCItect® (DiaGenic aims to detect AD in MCI patients within 2 years prior to onset of dementia. FDA has cleared this test and a clinical study has been initiated in the USA.
Magnetic Resonance Spectroscopy in AD
Proton MR spectroscopy (MRS) is sensitive to within-individual changes in the concentration of brain metabolites over time. MRS studies have found both decreased N-acetylaspartate (NAA) and increased myo-inositol in the occipital, temporal, parietal, and frontal regions of patients with AD, even at the early stages of the. This diffuse NAA decline is independent of regional atrophy and probably reflects a decrease in neurocellular viability. Reports of such metabolite changes are now emerging in the mild cognitive impairment (MCI) and in investigation of the medial temporal lobe. In vivo quantitation of neural choline in AD has been inconclusive because of poor test-retest repeatability. Less robust evidence using phosphorous MRS has shown significant phosphocreatine decline and increments in the cell membrane phosphomonoesters in the early, and possibly asymptomatic, stages of the disease. These phosphorous metabolite disturbances normalize with disease progression. Phosphodiester concentration has been found to correlate strongly with AD plaque counts. MRS of AD has therefore introduced new pathophysiologic speculations. Studies of automated MRS for AD diagnosis have reported high sensitivity and moderate specificity, but are yet to test prospective samples and should be extended to include at least two MRS regions of interest. MRS has promise for predicting cognitive status and monitoring pharmacological efficacy, and can assess cortical and subcortical neurochemical change.
Myoinositol, a compound found in the brains of AD patients and those with mild brain problems, can be detected by MRS and may help to identify those at risk of developing AD. Myoinositol is a marker of inflammatory changes in the brain that are part of AD and explain the rise in brain level of this substance. There is an association of metabolic changes in the brain detected by MRS with ApoE genotype and neuropsychological measures of memory and cognition in normally aging elderly, and in patients with mild cognitive impairment (MCI) and AD. Myoinositol (MI)/creatine is a more specific biomarker for neuropsychological dysfunction associated with neurodegenerative disease. However, N-acetylaspartate /MI ratio may be the most efficient predictor of memory and cognitive function in patients with MCI and AD.
Choline therapy should promote decreased cholinergic membrane breakdown and so lead to relative decreases in MRS-visible choline. Choline is significantly decreased in the drug takers versus placebo control subjects. There is greater choline decrement in pharmacological responders versus nonresponders. The combination of therapeutic intervention, repeat MRS, and cognitive assessment is likely to be a useful research design in the investigation of AD.