Disease progression model in subjects with mild cognitive impairment from the Alzheimer’s disease neuroimaging initiative: CSF biomarkers predict population subtypes. Br J Clin Pharmacol

Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, Titusville, New Jersey, and Spring House, Pennsylvania, USA.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 01/2013; 75(1). DOI: 10.1111/j.1365-2125.2012.04308.x


• Amnestic mild cognitive impairment MCI) represents the prodromal stage of Alzheimer's dementia and this disease progresses in a non-linear fashion.
• Disease progression depends on a variety of demographic, biochemical, genetic and cognitive factors.
• Baseline CSF biomarkers carry information about disease pathology and critical thresholds for these markers (Aβ and p-tau181P) have been identified that allow segregation of the population into MCI progressers and non-progressers.
AIM The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years.
METHOD Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers.
RESULTS CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test.
CONCLUSION CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

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Available from: Victor Lobanov, Mar 13, 2015
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    • "Biomarkers that can be utilized as surrogate markers of underlying pathological change have become of central importance for detection of early and preclinical AD. Efforts have been made by researchers worldwide to identify and validate different biomarkers for the early diagnosis and/or prediction of progression from MCI to AD, including positron emission tomography (PET) imaging ligands , archetypically Pittsburgh compound B (PiB), which bind to amyloid-(A), PET imaging with 18 F-FDG to measure local glucose metabolism [7] [8] [9] [10], structural magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biochemical biomarkers, especially A 1-42 , total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau 181 ) either alone, or in combination with imaging and CSF biomarkers [11] [12] [13] [14]. It has been reported that the combination of increased CSF concentrations of t-tau or p-tau 181 and decreased concentration of A 1-42 improves sensitivity and specificity in the diagnosis of AD, and that these markers are predictive of future conversion from MCI to AD [15] [16] [17] [18]. "
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