ABSTRACT
We have used structural equation models to explicitly distinguish functional status and therefore "dementia-relevant" variance in cognitive task performance (i.e., "δ" for dementia). Our approach is modular and can be directed to other targets. In this analysis, we construct a δ ortholog representing the "cognitive correlates of age" (cAGE). cAGE largely mediates age's effects on dementia severity, as rated by the Clinical Dementia Rating Scale Sum of boxes and has an area under the receiver operating curve = 0.96 for the diagnosis of Alzheimer's Disease versus controls. We then test cAGE's association with serum insulin-like growth factor binding protein 2 (IGF-BP2), which has previously been associated with age-related cognitive changes in animals, and with cortical atrophy in older humans. IGF-BP2's adverse effects on cognition are largely mediated through cAGE, independent of education, ethnicity, gender, depression ratings, serum homocysteine levels, hemoglobin A1c, and apolipoprotein e4 status. This suggests that age-specific cognitive decline may be moderated by IGF-BP2 and that modulation of that protein's function(s) might ameliorate age-specific cognitive impairments.
Subject(s)
Aging/genetics , Aging/psychology , Cognition/physiology , Insulin-Like Growth Factor Binding Protein 2/blood , Aged , Aged, 80 and over , Atrophy/genetics , Cerebral Cortex/pathology , Cognition Disorders/genetics , Female , Humans , Insulin-Like Growth Factor Binding Protein 2/adverse effects , Insulin-Like Growth Factor Binding Protein 2/physiology , Male , Models, StatisticalABSTRACT
Insulin-like growth factor-1 (IGF-1) is a growth and survival factor for oligodendrocyte lineage cells and induces myelination. Its actions are modulated by IGF binding proteins (IGFBPs) that are present in the extracellular fluids or on the cell surface. Additionally, IGFBPs are also known to exert actions that are independent of IGF-1. We studied whether IGF-binding proteins (IGFBPs)-1 and -2 modulate rat oligodendrocyte precursor (O2A) cell survival and differentiation in vitro both in the absence and presence of exogenously added IGF-1. The data reveal that IGFBP-1 and -2 reduced O2A cell survival in the absence and presence of exogenously added IGF-1. The effects of IGFBP-1 on cell survival in the presence of exogenously added IGF-1 were IGF-1-dependent, whereas IGFBP-2 displayed both IGF-1-dependent and IGF-1-independent effects. Furthermore, IGFBP-1 and -2 inhibited O2A cell differentiation in the presence of IGF-1 as reflected by decreased expression levels of two myelin proteins, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase) and MAG (myelin associated glycoprotein). Analysis of medium samples revealed that O2A cells do not secrete proteases that degrade these IGFBPs. Taken together the data show that IGFBP-1 and -2 are negative effectors of oligodendrocyte survival and differentiation. Accordingly, the role of IGFBPs should be explicitly taken into account when investigating IGF-1 effects on oligodendrocytes, especially in the context of therapeutic purposes.
