Clarifying the association of depressive symptoms with cortico-limbic tau, cerebral blood flow, neurodegeneration, and longitudinal cognitive decline in individuals with mild cognitive impairment

Project Summary Symptoms of depression, including mild subsyndromal symptoms of depression (SSD) and more severe Late Life Major Depression (LLD), are among the strongest predictors of accelerated cognitive decline and have been associated with up to a 4-fold increased risk of dementia. However, studies linking depressive symptoms to amyloid-β (Aβ), neurodegeneration (brain volume), and measures of cerebrovascular disease (white matter hyperintensities; WMH) in older adults have not sufficiently explained accelerated cognitive decline in these individuals. There is now compelling evidence to suggest that greater spread and accumulation of hyperphosphorylated tau protein (neurofibrillary tangles) is more strongly associated with depressive symptoms than Aβ deposition and is likely also a significant factor contributing to cognitive dysfunction and cognitive decline attributed to depressive symptoms in older adults. Emerging data also suggests that reductions in cerebral blood flow (CBF) and brain volumes associated with depressive symptomatology are also linked to tau accumulation. However, there have been no previous studies that have investigated the relationship of cortico-limbic tau burden in MCI with more severe symptoms of depression, i.e., LLD. Further, nearly all extant studies investigating tau deposition in neurodegenerative diseases of aging exclude both current major depression and significant depression history. Evaluating individuals with chronic LLD is an important avenue to clarify the relationships of tau with depressive symptomatology which would inform development of targeted interventions for cognitive decline in older adults. Recent advances in Positron Emission Tomography (PET) radioligands with high sensitivity and specificity to tau accumulation in limbic structures are ideally suited for this work. The goals of this study are to: 1) Evaluate the association of depressive symptoms, and features of depression, with cortico- limbic tau binding in a diverse sample of individuals with MCI; 2) Clarify the relative associations of depression severity and tau deposition, in addition to brain volume, Aβ, CBF, and WMH with cognition at baseline; and 3) Evaluate the relative association of baseline cortico-limbic tau and other neurobiological features (brain volume, Aβ, CBF, WMH) with accelerated cognitive decline and course of depressive symptoms over 30 months. For the proposed five-year study, 110 MCI participants with chronic LLD will be enrolled at the University of California - San Francisco (UCSF) to obtain measures of regional [18F]-MK-6240 tau PET and florbetaben Aβ PET binding, magnetic resonance imaging (MRI) measures of brain volume, CBF, and WMH, and genetic and clinical data. Data from 165 MCI SSD and 165 MCI with no depressive symptoms (MCI ND) participants will be obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-4) database for statistical analyses. We will use advanced image harmonization methods to integrate imaging datasets and dissect patterns of neuropathology (Aβ and tau), neurodegeneration, CBF, and WMH associated with depressive symptomatology and cognitive dysfunction.