The Einstein Aging Study (EAS) renewal will explore risk factors and underlying biological mechanisms of age-related cognitive and locomotor dysfunction in a community residing elderly cohort. Cognitive decline and dementia are multifactorial in their clinical expression and underlying pathology. At post-mortem, individuals may exhibit combinations of Alzheimer's pathology, ischemic lesions, and hippocampal sclerosis (HpScI), among other pathologies. These observations, coupled with strong preliminary data, have led us to a broader exploration of risk factors and biological pathways that influence quantitative indices of cognitive and locomotor decline and risk of dementia. We have shown that measures of pain, stress, salivary Cortisol, vascular risk, and locomotion are inter-related, remediable, and that they independently predict cognitive decline and dementia. This proposal examines the influence glucocorticoid and vascular mechanisms on cognitive and locomotor status and decline and on related brain substrates. Both glucocorticoid dysregulation and vascular disease influence brain regions involved in cognitive and locomotor function. We propose four thematically integrated Projects supported by five Cores using a shared community sample. Project 1 will assess the role of the pain and stress in cognitive decline and dementia and the mediating role of glucocorticoid dysregulation. Project 2 will obtain measures of microvascular structure (standard grading of retinal photographs) and function (vascular reactivity to C02 challenge measured by Transcranial Doppler) to test the hypothesis that microvascular disease and cerebral hypoperfusion precede cognitive decline. Project 3 will assess simple and complex locomotor function in relationship to the pathways that lead to cognitive decline, and their role in predicting cognitive and functional outcomes. Project 4 will assess the role of progranulin (GRN) deficiency in the development of hippocampal pathology in humans and in transgenic mice subjected to restraint stress. GRN deficiency may modify the influence of pain, stress, glucocorticoids, and vascular disease on cognitive status and neurodegeneration. Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia.
Better understanding of the interrelationships of vascular factors, pain and stress pathways, and cognitive and locomotor function will elucidate targets for the prevention of dementia and suggestin possible avenues for remediation.
|Graff-Radford, Jonathan; Lesnick, Timothy G; Boeve, Bradley F et al. (2016) Predicting Survival in Dementia With Lewy Bodies With Hippocampal Volumetry. Mov Disord 31:989-94|
|Strauss, S B; Kim, N; Branch, C A et al. (2016) Bidirectional Changes in Anisotropy Are Associated with Outcomes in Mild Traumatic Brain Injury. AJNR Am J Neuroradiol :|
|Callisaya, Michele L; Ayers, Emmeline; Barzilai, Nir et al. (2016) Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. J Alzheimers Dis 53:1043-52|
|Allen, Mariet; Carrasquillo, Minerva M; Funk, Cory et al. (2016) Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Sci Data 3:160089|
|Williams, Kelly L; Topp, Simon; Yang, Shu et al. (2016) CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun 7:11253|
|Ezzati, Ali; Katz, Mindy J; Zammit, Andrea R et al. (2016) Differential association of left and right hippocampal volumes with verbal episodic and spatial memory in older adults. Neuropsychologia 93:380-385|
|Ezzati, Ali; Katz, Mindy J; Lipton, Michael L et al. (2016) Hippocampal volume and cingulum bundle fractional anisotropy are independently associated with verbal memory in older adults. Brain Imaging Behav 10:652-9|
|Carrasquillo, Minerva M; Barber, Imelda; Lincoln, Sarah J et al. (2016) Evaluating pathogenic dementia variants in posterior cortical atrophy. Neurobiol Aging 37:38-44|
|Zammit, Andrea R; Katz, Mindy J; Derby, Carol et al. (2016) Metabolic Syndrome and Smoking Are Associated with Future Development of Advanced Chronic Kidney Disease in Older Adults. Cardiorenal Med 6:108-15|
|Walton, Ronald L; Soto-Ortolaza, Alexandra I; Murray, Melissa E et al. (2016) TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet 2:e85|
Showing the most recent 10 out of 269 publications