The overall goal of the proposed research is to investigate whether clinically normal older individuals with evidence of fibrillar amyloid deposition are in the prodromal phases of Alzheimer's disease. We will study 100 clinically normal individuals (CDR 0;MMSE 27-30;performance within <1.5 SD on age and education matched neuropsychological test norms) with PIB PET amyloid imaging to accomplish three specific aims: 1) To investigate the factors associated with high amyloid deposition in normals, including age, cognitive reserve, family history and genetic risk-factors for AD;2) To investigate whether normals with high amyloid burden demonstrate abnormalities on functional and structural imaging measures, consistent with the alterations seen in prodromal AD;and 3) To determine if normals with high amyloid deposition are more likely to demonstrate clinical decline on sensitive measures of episodic memory and progress to a stage of mild cognitive impairment (MCI). Our preliminary data, as well as reports from other groups, suggest that a substantial proportion of clinically normal individuals have evidence of amyloid deposition on PIB PET imaging, in a pattern similar to that observed in clinical AD. Our preliminary data suggest that these normals with high amyloid deposition demonstrate functional and structural alterations in a specific set of brain regions, similar to the pattern of image abnormality commonly reported in MCI and AD. We hypothesize that higher levels of PIB retention will correlate with greater functional abnormality on functional MRI and FDG- PET imaging, as well as greater atrophy in medial temporal lobe and parietal cortices on volumetric MRI. Furthermore, we hypothesize that normals with high amyloid burden will manifest impairment on challenging episodic memory tests, and will demonstrate a higher likelihood of clinical decline towards MCI and ultimately clinical AD. This project will draw heavily on the resources of the MADRC, in particular, the Longitudinal Cohort of the Clinical Core, the Neuroimaging SubCore, and the Data/Statistics Core, as well as interface closely with the investigation of amyloid deposition in Projects 2 and 3.
The long presymptomatic phase of AD provides a critical opportunity for potential intervention with effective therapies. It is essential, however, to develop biological and imaging markers that will track disease progression in the presymptomatic phases and predict onset of clinical symptoms. This project will provide fundamental information on the relationship of amyloid deposition to brain dysfunction and clinical decline.
|Viswanathan, Anand; Greenberg, Steven M; Scheltens, Philip (2016) Role of Vascular Disease in Alzheimer-Like Progressive Cognitive Impairment. Stroke 47:577-80|
|Dhilla Albers, Alefiya; Asafu-Adjei, Josephine; Delaney, Mary K et al. (2016) Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly. Ann Neurol 80:846-857|
|Day, Gregory S; Musiek, Erik S; Roe, Catherine M et al. (2016) Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single-Family Case-Control Study. JAMA Neurol 73:1125-32|
|Ronquillo, Jay Geronimo; Baer, Merritt Rachel; Lester, William T (2016) Sex-specific patterns and differences in dementia and Alzheimer's disease using informatics approaches. J Women Aging 28:403-11|
|Herold, C; Hooli, B V; Mullin, K et al. (2016) Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. Mol Psychiatry 21:1608-1612|
|Serrano-Pozo, Alberto; Betensky, Rebecca A; Frosch, Matthew P et al. (2016) Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. Am J Pathol 186:375-84|
|Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-20|
|Ringman, John M; Monsell, Sarah; Ng, Denise W et al. (2016) Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol 75:284-90|
|Rentz, Dorene M; Dekhtyar, Maria; Sherman, Julia et al. (2016) The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials. J Prev Alzheimers Dis 3:8-12|
|Grogg, Kira S; Toole, Terrence; Ouyang, Jinsong et al. (2016) National Electrical Manufacturers Association and Clinical Evaluation of a Novel Brain PET/CT Scanner. J Nucl Med 57:646-52|
Showing the most recent 10 out of 717 publications