Alzheimer's disease (AD) is preceded by a period when detectable changes in brain function occur without warning symptoms. This period may be twenty years or longer. Activation measured by functional magnetic resonance imaging is reduced during confrontation naming in normal women who have increased risk of late-onset Alzheimer's disease, at an average age of only 53 years. These same individuals have reduced activation in the posterior cingulate cortex during a memorization task, among other disparities. Our hypothesis is that the altered functional MRI responses in naming, working memory and memorization will quantifiably worsen with age, due to progressive underlying Alzheimer's disease pathology. Disease-modifying treatments applied in this early, pre-symptomatic stage of AD could have profound impact, by preventing the onset of cognitive symptoms. Millions are currently being spent on large-scale prevention trials, with AD symptoms as end-points. By providing a biomarker of pre-symptomatic AD progression, fMRI could potentially reduce the duration and costs of such trials. This continuation proposal is designed to detect changes in brain function in high-AD risk individuals over time. We will study normal education-matched groups of high- and low-AD risk subjects in the age ranges 40-65 and 65-90 years, using fMRI stimulus tasks which have previously demonstrated regional disparities in high-AD risk individuals. In addition, we will repeat the naming and fluency fMRI studies performed previously in high- and low-AD risk individuals after an interval of five years, in order to detect longitudinal changes in activation. The convergence of evidence from these cross-sectional and longitudinal studies could provide powerful evidence for a model of Alzheimer's disease as a relentless, slowly progressive brain pathology that begins early in adult life, but remains compensated until it produces clinical symptoms in its late stages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036660-07
Application #
7002185
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Refolo, Lorenzo
Project Start
1997-09-30
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
7
Fiscal Year
2006
Total Cost
$312,651
Indirect Cost
Name
University of Kentucky
Department
Neurology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Smith, Charles D (2012) Structural imaging in early pre-states of dementia. Biochim Biophys Acta 1822:317-24
Gold, Brian T; Johnson, Nathan F; Powell, David K et al. (2012) White matter integrity and vulnerability to Alzheimer's disease: preliminary findings and future directions. Biochim Biophys Acta 1822:416-22
Andersen, Anders H; Rayens, William S; Liu, Yushu et al. (2012) Partial least squares for discrimination in fMRI data. Magn Reson Imaging 30:446-52
Smith, Charles D; Chebrolu, Himachandra; Andersen, Anders H et al. (2010) White matter diffusion alterations in normal women at risk of Alzheimer's disease. Neurobiol Aging 31:1122-31
Martin, Sarah B; Smith, Charles D; Collins, Heather R et al. (2010) Evidence that volume of anterior medial temporal lobe is reduced in seniors destined for mild cognitive impairment. Neurobiol Aging 31:1099-106
Gold, Brian T; Powell, David K; Andersen, Anders H et al. (2010) Alterations in multiple measures of white matter integrity in normal women at high risk for Alzheimer's disease. Neuroimage 52:1487-94
Smith, Charles D; Lori, Nicolas F; Akbudak, Erbil et al. (2009) MRI diffusion tensor tracking of a new amygdalo-fusiform and hippocampo-fusiform pathway system in humans. J Magn Reson Imaging 29:1248-61
Conturo, Thomas E; Williams, Diane L; Smith, Charles D et al. (2008) Neuronal fiber pathway abnormalities in autism: an initial MRI diffusion tensor tracking study of hippocampo-fusiform and amygdalo-fusiform pathways. J Int Neuropsychol Soc 14:933-46
Liu, Xun; Steinmetz, Nicholas A; Farley, Alison B et al. (2008) Mid-fusiform activation during object discrimination reflects the process of differentiating structural descriptions. J Cogn Neurosci 20:1711-26
Smith, C D; Chebrolu, H; Wekstein, D R et al. (2007) Brain structural alterations before mild cognitive impairment. Neurology 68:1268-73

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