Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an unprecedented opportunity to understand early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. To maximize the benefit from disease-modifying therapies, individuals must be identified and treated in the early stages, including mild cognitive impairment (MCI). Only by doing so, is it possible to prevent progressive spreading of neuropathology and emergence of cognitive deficits and neuropsychiatric symptoms (NPS). Multi-radiotracer PET studies of Aβ and 5-HT by the PI and colleagues in amnestic, multi-domain, MCI (aMCI- MD) and cognitively normal elderly demonstrated progressive, cortical and limbic 5-HT degeneration over the course of MCI, linked to network dysfunction, that was greater and more widespread than cortical Aβ, cerebral atrophy or cerebral blood flow deficits. Cortical and limbic 5-HT degeneration was a more powerful predictor of cross-sectional and longitudinal memory impairment than Aβ. Human data and animal models show the synergistic effect of Tau on both Aβ and 5-HT degeneration. Tau overlaps more than Aβ with loss of 5-HT in cortical and 5-HT-rich limbic regions, is more temporally linked to cognitive deficits and decline and is better correlated with cognitive impairment. Thus, in vivo imaging of 5-HT combined with Tau and Aβ, may represent a powerful predictor of cognitive decline and emergence of NPS. Lower 5-HT transporters (SERT) overlapped to a greater extent with Tau in limbic regions than Aβ. A longitudinal molecular imaging study is proposed in normal aging and amnestic, multi-domain, MCI (aMCI-MD) with high resolution PET scans for 5-HT transporter availability (SERT), Tau and Aβ. To evaluate SERT, and its relationship to Tau and Aβ, in aMCI-MD and normal controls at baseline and longitudinal follow-up. 2. To evaluate SERT, Tau and Aβ in relation to cognitive deficits and NPS, in aMCI-MD and normal controls at baseline and longitudinal follow-up. The hypotheses will be tested that relative to healthy controls, patients with aMCI-MD will have lower baseline and longitudinal decreases in SERT, higher baseline and greater increases in Tau and less baseline difference and less change over time in Aβ .Lower SERT and decreases over time, in combination with greater increases in Tau, in contrast to increases in Aβ, will be associated with greater cognitive deficits (episodic, verbal memory) and NPS (affective cluster) and worsening of cognition and NPS to a greater extent in aMCI-MD compared to controls. Elucidating the role of 5-HT in relation to Tau and Aβ in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT, studies of other neurotransmitters vulnerable to neurodegeneration (norepinephrine) and hypothesized mechanisms underlying their vulnerability (e.g. oxidative stress, neuroinflammation).

NARRATIVE Individuals with mild cognitive impairment (MCI) and demographically matched controls will undergo scans to measure a brain chemical called serotonin and the tau and beta-amyloid proteins that are related to the loss of nerve cells in Alzheimer’s Disease (AD). We will test the hypotheses that tau and beta-amyloid are associated with a lower concentration of the brain chemical, serotonin, and that these aspects of pathology will help us to better understand cognitive and behavioral symptoms in MCI, as well as the process that causes these symptoms to worsen over time and lead to a diagnosis of AD.