1. TASK-EVOKED PUPIL DILATION Pupil dilation is a validated psychophysiological index of effortful resource allocation (cogintive effort). Increased cognitive load greater effortful resource allocation increased pupil dilation. When beyond capacity system breakdown and failure to increase pupil dilation. If 2 people have the same cognitive score, the one needing more effort to attain that score may be at higher risk for cognitive decline. Task-evoked pupil dilation is controlled by the locus coeruleus (LC) (Aston-Jones & Cohen 2005). (See Figure below). Tauopathy assoicated with AD may begin in the LC and can be presernt early in life (Braak et al 2011). GOA L: To test task-evoked pupil response as a psychophysiological biomarker for MCI. William Kremen 1,2, Eric Granholm 1,3, Matthew Panizzon 1, Carol Franz 1, Richard Hauger 123, Amy Jak 1,3, Weijian Liu 4, Hong Xian 4, Michael Lyons 5 1 University of California, San Diego, 2 VA San Diego Center of Excellence for Stress & Mental Health 2 VA San Diego Healthcare System, 5 Boston University Pupil Dilation During a Cognitive Task: A Psychophysiological Biomarker Differentiating Early MCI and Normal Cognitive Function  Task-evoked pupil response shows promise as a novel, cost-effective psychophysiologial biomarker that can differentiate cognitively normal from MCI in late middle age.  It is a marker of LC actitivty, suggesting dysfunction of the LC adrenergic system and related attention networks, and possibly tauopathy in the LC. 1. BACKGROUND 2. METHODS 5. CONCLUSIONS PARTICIPANTS 921 middle-aged men ages 56-66 in wave 2 of the Vietnam Era Twin Study of Aging (VETSA). Note: These analyses are not twin analyses. PUPIL DILATION Dilation was measured during low, moderate, and high load digit span recall tasks: 3, 6, and 9 digits. All analyses adjusted for max span length. MCI We previously showed that early identification of MCI is possible, even in adults in their 50s (Kremen et al 2014). MCI was defined according to the Jak/Bondi approach (Bondi et al 2014). Neuropsychologically-defined MCI using this approach appears to have advantages over tradiitional clinical diagnosis in ADNI (Bondi et al 2014). proportion convert to AD. proportion revert to normal. proportion with APOE-ε4 alleles. proportion with abnormal CSF Aβ and tau. Impairment: Defined as a domain with ≥ 2 measures that are ≥ 1.5 SDs below the normative mean, after adjusting for general cognitive ability, which was assessed at age 20. Supported by NIA grants: AG018384, AG018386, AG022381, AG022982 3. RESULTS 4. RESULTS Figure 2: COGNITIVELY NORMAL VS. MCI S-MCI require greater effort than CN subjects and show greater system breakdown when beyond capacity. M-MCI show an inability to adapt or modulate effortful resource allocation to cognitive load. M-MCI appear to be functioning as if they are overwhelmed and experiencing system breakdown at all cognitive load levels. Results were not accounted for by age, education, general cognitive ability, depression, head injury, or APOE-ε4 status. No difference between amnesitc and non-amnestic. Results were independent of digit span performance— Max spans: CN=7.0; S-MCI=6.7; M-MCI=6.3. Figure 1: PROOF of CONCEPT Low load (3 digits): People with higher capacity (higher max span) require less effort to do the task based on their smaller pupil dilation. Moderate Load (6 digits): Similar pattern. All (except those with a max span of 4 digits) increase dilation when cognitive load increases from 3 to 6. Those with max span of 4 do not increase dilation when trying to recall 6 digits, but they are already near capacity at 3 digits. High Load (9 digits): Substantial reductions in pupil dilation, consistent with being well beyond capacity. Only those with max spans of 8 or 9 maintain or increase pupil dilation at 9 digits, bur they are not well beyond their capacity.