The defining neuropathologic lesions of Alzheimer's disease (AD) are amyloid-b plaques and tau neurofibrillary tangles, both of which appear many years before the onset of symptoms of cognitive impairment. The overarching goal of this proposal is to evaluate a novel PET tracer, known as [F18] T807, that detects the tau neurofibrillary tangles. We will address three specific contexts in which tau PET could potentially provide critical information useful in clinical AD research by identifying stages of T807 retention that reflect the levels and extent of PHF tau according to the established Braak staging scheme: 1) The identification of age- associated medial temporal lobe PHF-tau that is consistent with Braak Stage I/II, the slowly accumulating form that begins in the third decade of life, but in later years may possibly correlate with more subtle cognitive capacities or have predictive value for eventual development of impairment, perhaps when combined with biomarker evidence of Ab deposition;2) The identification of a neocortical PHF-tau cut point of positivity that indicates an impaired stage of cognitive and clinical function, which when evaluated as a continuous variable is closely correlated with phenotypic features of the illness;3) A determination of the links between deposition of tau and other biomarkers of AD, including amyloid-b, additional measures of neurodegeneration such as volumetric MRI, CSF tau, and measures of large-scale network disruption measured with fcMRI. This proposal builds on our previous work and existing multidisciplinary collaborations to develop clinically relevant, highly sensitive methods for tracking i) early tau deposition that may be linked to early impairment and ii) neocortical tau deposition that is hypothetically linked to dementia (Aim 1), to illuminate the relationship between more malignant, anatomically specific tau deposition that relates to local and generalized volume loss and network connectivity breakdown (Aim 2), and to relate directly in vivo for the first time the joint evolution of brain tau and amyloid-b deposition throughout the life span (Aim 3).
The proposed research will use PET scans to detect an abnormal form of a brain protein known as tau in living humans; and relate tau pathology to age; brain shrinkage; and cognitive impairment. In addition; the role of these measures of tau in Alzheimer's disease dementia will be explored in AD dementia patients and in normal elderly; in particular to relate tau measures to measures of a different abnormal protein known as amyloid-?. This research has public health impact as it may improve our ability to identify transitional stages between normal aging and Alzheimer's disease dementia.
|Gatchel, Jennifer R; Donovan, Nancy J; Locascio, Joseph J et al. (2017) Depressive Symptoms and Tau Accumulation in the Inferior Temporal Lobe and Entorhinal Cortex in Cognitively Normal Older Adults: A Pilot Study. J Alzheimers Dis 59:975-985|
|Xia, Chenjie; Makaretz, Sara J; Caso, Christina et al. (2017) Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease. JAMA Neurol 74:427-436|
|Marshall, Gad A; Aghjayan, Sarah L; Dekhtyar, Maria et al. (2017) Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly. J Prev Alzheimers Dis 4:81-86|
|LaPoint, Molly R; Chhatwal, Jasmeer P; Sepulcre, Jorge et al. (2017) The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage 157:612-622|
|Sepulcre, Jorge; Sabuncu, Mert R; Li, Quanzheng et al. (2017) Tau and amyloid ? proteins distinctively associate to functional network changes in the aging brain. Alzheimers Dement 13:1261-1269|
|Dagley, Alexander; LaPoint, Molly; Huijbers, Willem et al. (2017) Harvard Aging Brain Study: Dataset and accessibility. Neuroimage 144:255-258|
|Johnson, Keith A; Schultz, Aaron; Betensky, Rebecca A et al. (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110-9|
|Rieckmann, Anna; Hedden, Trey; Younger, Alayna P et al. (2016) Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity. Hum Brain Mapp 37:621-31|
|Chhatwal, Jasmeer P; Schultz, Aaron P; Marshall, Gad A et al. (2016) Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87:920-6|
|Xia, Chenjie; Dickerson, Bradford C (2016) Tau PET: the next frontier in molecular imaging of dementia. Int Psychogeriatr 28:1403-6|
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