Syrjanen, Jeremy A.

AbstractBackgroundThere is increasing need for noninvasive biomarkers of Alzheimer’s Disease (AD) neuropathologic change for early detection and intervention through risk‐factor modification and disease‐modifying therapies. One such biomarker is the prediction of chronological age from routine clinical tests such as an electrocardiogram (EKG) to discriminate between observed biological age from chronological age for healthy aging. Deviation of true age from predicted age has been associated with heart failure, hypertension, and coronary heart disease. However, the association between EKG‐based age and underlying neuropathology has not been studied.MethodWe used a cohort of 336 participants from the Mayo Clinic Study of Aging, a population‐based prospective study of residents in Olmsted County, Minnesota, with antemortem EKG and post‐mortem brain autopsy (Table 1 & 2). Age was predicted from EKG using a validated convolutional neural network algorithm. We used ordinal logistic regression to identify associations between lower neuropathologic scores of AD (Thal phase, neuritic plaque score, Braak stage, and overall AD neuropathologic change) and the Age‐Gap, defined as EKG‐predicted age minus chronological age. Results were controlled for true age, sex, and APOE e4 carrier status. Neuropathologic scales were grouped into none, low, intermediate, and high categories. Observations were weighted by the inverse of years between last EKG and time of death to account for the time difference between acquisition of EKG and autopsy.ResultWe found that an increasing Age‐Gap (i.e. older predicted age) was inversely associated with lower overall AD neuropathologic change (OR 0.93 [0.89, 0.97], p = 0.002). Investigation of the components of AD neuropathologic change showed that an increasing Age‐Gap was also inversely associated with lower amyloid metrics such as Thal phase (OR 0.85 [0.80, 0.89], p < 0.001) and neuritic plaque scores (OR 0.91 [0.87, 0.96], p < 0.001), but not tau metrics like Braak staging (OR 1.05 [1.00, 1.10], p = 0.05).ConclusionIn this work, we show that older predicted age on EKG, a noninvasive biomarker associated with vascular and biological aging, is associated with higher amyloid burden and neuropathologic change of AD.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aβ42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aβ42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aβ42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aß42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aß42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aß42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractBackgroundThe Progressive Supranuclear Palsy Quality of Life (PSP‐QoL) scale is a 45‐question participant‐completed questionnaire used to evaluate physical and cognitive task difficulties. Participants enrolled in the ALLFTD research program are asked to complete this questionnaire annually during their study visits.MethodPSP‐QoL responses were analyzed at baseline visits. Our analysis focused on responses to the overall satisfaction of life (range 0‐100, with 0 being extremely dissatisfied and 100 being extremely satisfied) relative to disease severity (CDR®+NACC‐FTLD global scores) and as a function of clinical phenotypes. A Kruskal‐Wallis test was used to compare overall satisfaction ratings against CDR®+NACC‐FTLD global score.Result788 PSP‐QoL survey responses were analyzed (participant mean age 55.3 ±15 years, 50.5% female). Analysis included responses from 372 (47.2%) asymptomatic participants (CN; CDR®+NACC‐FTLD = 0), 140 prodromal (17.8%) CDR®+NACC‐FTLD = 0.5, 160 (20.3%) CDR®+NACC‐FTLD = 1, 106 (13.5%) CDR®+NACC‐FTLD 2, and 10 (1.3%) CDR®+NACC‐FTLD = 3. All symptomatic groups were similar in PSP‐QOL overall satisfaction of life rating: (mean overall satisfaction CDR®+NACC‐FTLD = 0.5: 74.5 (SD 22.5); CDR®+NACC‐FTLD = 1: 74.1 (SD 24.7) and CDR®+NACC‐FTLD = 2/3: 74.1 (SD 25.8)), but these differed from asymptomatic (cognitively normal): (mean 83.7, (SD 14.6); p<0.0001). Similarly, when including the CN group and symptomatic phenotype groups, a statistically significant difference in ratings was seen: mean overall satisfaction CN = 83.7 (SD 14.7), MCI = 78.3 (SD 16.6), PPA = 71.6 (SD 26.9), PSP = 66.3 (SD 28.2), bvFTD = 76.8 (SD 23.8), and other = 70.6 (SD 23.2). However, even after removing the CN group, a difference amongst symptomatic phenotypes remained (p = 0.036).ConclusionMean overall life satisfaction as measured by the PSP QoL questionnaire was lower in all symptomatic compared to clinically normal participants, regardless of disease severity or phenotype. Further longitudinal analyses are needed to better understand how clinical progression impacts overall satisfaction of life.

AbstractBackground and AimsPhysical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community‐dwelling individuals free of dementia.MethodsLongitudinal study among 4173 individuals aged ≥50 years (mean age 71 years; 2078 males; median follow‐up 4 years) enrolled in the Mayo Clinic Study of Aging. Self‐reported late‐life PA was used to calculate overall PA and moderate‐vigorous PA (MVPA) scores. Gait was assessed using GAITRite® and Zeno™ systems. Incident falls information was based on diagnostic codes retrieved from medical records. We ran linear mixed effects models to examine associations between z‐scored PA variables and longitudinal gait parameters, adjusted for age, sex, education, body mass index (BMI), medical comorbidities, and including interactions between PA and time since baseline. In secondary analyses, we calculated Cox Proportional hazard models with age as time scale predicting incident falls by PA, adjusting for sex, education, BMI, medical comorbidities, and falls history.ResultsAt baseline, higher PA was associated with higher velocity (overall PA: estimate 2.9935; MVPA: 2.2961; p < 0.001), higher cadence (overall PA: 1.0665; MVPA: 0.9073; p < 0.001), greater stride length (overall PA: 2.0805; MVPA: 1.4726; p < 0.001), shorter double support time (overall PA: −0.0257; MVPA: −0.0205; p < 0.001), and lower stance time variability (overall PA: −0.0204, p < 0.001; MVPA: −0.0152; p = 0.006). Overall PA was longitudinally associated with less decline in cadence, and MVPA with less increase in intraindividual stance time variability. Overall PA (Hazard ratio 0.892, 95% confidence interval 0.828–0.961, p = 0.003) and MVPA (HR 0.901; 95% CI 0.835–0.973, p = 0.008) were associated with a decreased risk of incident falls.ConclusionLate‐life PA was associated with favorable gait outcomes and decreased risk of incident falls. Thus, late‐life PA may help to maintain gait performance and decrease fall risk in old age.

Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants’ medical records within the context of brain aging and Alzheimer’s disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person’s life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample ( n = 1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results.