This study seeks to better understand the relationship of brain pathology to cognitive function in aging and dementia. There is striking variability in how individuals'mental abilities change with age;some people change little, if any, others have major, debilitating drops. Why, is unknown. One explanation is brain pathologies such as Alzheimer's disease (AD) and infarcts (strokes). AD, which is the predominant cause of dementia, develops slowly and may actually begin to appear in brain decades before overt symptoms are appear. Some degree of AD changes and vascular disease is present in most very old people. However, studies that relate pathology to cognitive function generally fail to explain most of the variance. One potential reason may be that the pathology has been inadequately measured. Alternatively, it may be that brain pathology, no matter how exquisitely measured, will never explain cognitive losses adequately because of factors that moderate the impact of pathology. This explanation has been developed in the concept of "reserve", the idea that some set of innate and acquired characteristics form a buffer that provides a degree of protection against the impact of brain pathology. It is a concept that holds enormous potential importance for public health because it suggests that, to the degree these factors are modifiable, people can take steps to substantially protect themselves against a broad array of common and debilitating brain conditions. We propose to measure cerebral pathology better than has been done previously, to model the effects of pathology on cognitive function, and then to use these improved models to better understand the role of reserve as a moderator of the impact of brain pathology. A major barrier to previous investigation has been the inability to measure the presence of Alzheimer's disease during life. The recent development of tracers for beta amyloid (an abnormal protein fragment critical in AD) changes this. We will use PET with the tracer Pittsburgh B (PIB) to quantify the extent of cerebral amyloid, and will obtain MRI measures of structural brain pathology (atrophy, infarcts and white matter lesions) and thus model the joint effects of the two major age- associated pathologies on cognitive function. We will then use the results of that effort to study reserve. We will do so in an ethnically diverse sample that has a wide range of education, which is generally thought to be a marker for reserve, and will use neuropsychological tests with superior measurement properties. Thus we will be able to characterize brain pathology levels during life better than has ever been done before and relate those findings to cognitive function that is measured especially well across a broad spectrum of putative reserve.

Public Health Relevance

This project focuses on how pathology affects mental function and on the notion that "reserve" may buffer these effects. Reserve is a concept that holds enormous potential importance for public health because, to the extent reserve is based in lifetime experiences-cognitively stimulating activities, for example-- it suggests that people can take steps to protect themselves against a broad array of common and debilitating brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031563-05
Application #
8446394
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Wagster, Molly V
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$339,463
Indirect Cost
$43,762
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Reed, Bruce; Villeneuve, Sylvia; Mack, Wendy et al. (2014) Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol 71:195-200
Maillard, Pauline; Fletcher, Evan; Lockhart, Samuel N et al. (2014) White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. Stroke 45:1721-6
Rog, Lauren A; Park, Lovingly Quitania; Harvey, Danielle J et al. (2014) The independent contributions of cognitive impairment and neuropsychiatric symptoms to everyday function in older adults. Clin Neuropsychol 28:215-36
Marchant, Natalie L; Reed, Bruce R; Sanossian, Nerses et al. (2013) The aging brain and cognition: contribution of vascular injury and aýý to mild cognitive dysfunction. JAMA Neurol 70:488-95
Farias, Sarah Tomaszewski; Park, Lovingly Quitania; Harvey, Danielle J et al. (2013) Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging. J Int Neuropsychol Soc 19:430-41
He, Jing; Carmichael, Owen; Fletcher, Evan et al. (2012) Influence of functional connectivity and structural MRI measures on episodic memory. Neurobiol Aging 33:2612-20
Maillard, Pauline; Fletcher, Evan; Harvey, Danielle et al. (2011) White matter hyperintensity penumbra. Stroke 42:1917-22
Tomaszewski Farias, Sarah; Mungas, Dan; Harvey, Danielle J et al. (2011) The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales. Alzheimers Dement 7:593-601
Perneczky, R; Wagenpfeil, S; Lunetta, K L et al. (2010) Head circumference, atrophy, and cognition: implications for brain reserve in Alzheimer disease. Neurology 75:137-42
Reed, Bruce R; Mungas, Dan; Farias, Sarah Tomaszewski et al. (2010) Measuring cognitive reserve based on the decomposition of episodic memory variance. Brain 133:2196-209

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