Lee Ryan

The term Precision Aging describes an approach that focuses on multi-domain profiles of risks impacting individual trajectories of age-related cognitive functioning. The goal of the present study was to identify profiles of risk within a sample of 555 adults, ages 50 to 79, without diagnosis of dementia. Using cluster analyses, we considered 38 risk factors associated with five categories of risk known to negatively impact cognitive aging – cardiovascular insufficiency, glucose dysregulation, inflammation, immune dysfunction, and neuropathology. Results yielded five profiles, including a group with low risk in all five risk categories, and four groups with prominent risks in specific domains. Importantly, all four high risk groups performed more poorly relative to the low risk group on multiple memory measures from a well-established neuropsychological test, the Auditory Verbal Learning Test. The results highlight the importance of considering multiple domains of risk within the same cohort to predict age-related cognitive functioning.

Introduction: Changes to brain perfusion may be contributing to long-term cognitive dysfunction following COVID-19 infection. Lower brain perfusion beyond the acute phase of infection, as measured by perfusion MRI, has been observed in both hospitalized and non-hospitalized cases. Additionally, the hippocampus has been previously shown to be particularly sensitive to changes in blood flow. Therefore, the hippocampus may be vulnerable to perfusion changes associated with COVID-19, leading to long-term cognitive sequalae. The literature suggest that this may be particularly true among those with severe respiratory symptoms. However, the relationship between COVID-19 respiratory severity, perfusion, and cognitive dysfunction has yet to be thoroughly explored, especially after longer recovery times. Methods: Seventy-eight participants completed a neuroimaging session and two memory tests, the Mnemonic Similarity Task (MST) and Face-Name Associative Memory Exam (FNAME), tasks known to be mediated by the hippocampus. Participants were divided into four groups based on the severity of self-reported respiratory symptoms experienced during the acute infection: controls without a reported diagnosis of COVID-19, those with COVID-19 and without respiratory symptoms, those with COVID-19 and respiratory symptoms, and hospitalized participants with respiratory symptoms from COVID-19. On average, participants were 13 months from initial infection. Perfusion was measured with pseudo-continuous arterial spin labeled (pCASL) MRI. Total cortical gray and white matter perfusion, as well as gray matter perfusion in the territories of the anterior, middle, and posterior cerebral arteries were obtained using a mask adapted from previous studies. Results: The hospitalized group demonstrated lower total gray matter cortical perfusion compared to all groups, t 's > 1.74, p 's < 0.05. White matter perfusion showed no differences between groups. A similar pattern was observed within each arterial territory. Out of all memory measures, only pattern separation from the MST was related to gray matter perfusion, r = 0.30, p < 0.01, even after controlling for age and education. Discussion: Results provide evidence for global perfusion dysfunction among hospitalized participants with severe respiratory symptoms that persists for more than a year after COVID-19 infection. Additionally, there was a relationship between perfusion and pattern separation performance among all participants, suggesting that poorer perfusion may underlie some of the long-term COVID-19 cognitive symptoms.

Stress is a known risk factor for adverse cognitive outcomes; however, it remains unclear whether race/ethnicity is a moderating factor in the stress-cognition connection. In addition, the mechanisms underlying the influence of stress on learning and memory is an area of growing research, particularly among Hispanic/Latino individuals. The objective of this study was to investigate the associations between perceived stress, cardiometabolic risk, and learning and memory among matched Hispanic/Latino and non-Hispanic White individuals. Cross-sectional data were obtained from the MindCrowd longitudinal observational online study from Hispanic/Latino (n = 91) and age, sex, and education matched non-Hispanic White adults (n = 95). Participants completed the 10-item Perceived Stress Scale and an online measure of learning and memory, the paired associates learning task. Linear regression models were built to investigate the effects of perceived stress, cardiometabolic risk and race/ethnicity on paired associates learning scores. Mediation between perceived stress and paired associates learning through cardiometabolic risk was tested. We found an inverse association between perceived stress and PAL scores among both Hispanic/Latino and non-Hispanic White groups (b = -.08, SE = .03, p = .007). The association between perceived stress and PAL scores was partially mediated by cardiometabolic risk (b = -.01, SE = .008, 95% CI [-.03, -.001]). The associations between perceived stress, cardiometabolic risk, and PAL scores did not differ by race/ethnicity (ps > .05). A mediation model moderated by race/ethnicity indicated no difference in the cardiometabolic risk mediation between perceived stress and PAL (b = .007, SE = .01, 95% CI [-.02, .03]). Perceived stress is a risk factor for poorer paired associates learning scores among Hispanic/Latino and non-Hispanic White individuals. Cardiometabolic risk accounted for some of the association between perceived stress and paired associates learning performance. Further investigation is needed to better understand the complex mechanisms underlying stress-cognition associations among ethnically diverse samples.

Both mnemonic discrimination and object recognition tasks rely on the utilization of subtle visual details. Successful mnemonic discrimination utilizes the subtle details of an event to orthogonalize highly similar episodic memories, whereas object discrimination is a memory-free skill that utilizes details in order to distinguish between similar stimuli simultaneously presented. Additionally, neuroimaging studies have implicated areas of the medial temporal lobe as important for both mnemonic discrimination and object discrimination, further suggesting that performance on these two tasks are related. However, relatively limited data assessing the relationship between these two processes exist in the literature. Seventy-one cognitively normal participants completed both the Mnemonic Similarity Task (MST) and an object discrimination task used previously by our lab. The MST displayed common objects on a white background and participants identified if the object presented was old, similar, or new compared to objects previously seen in the task. For the object discrimination task, participants were shown a pair of stimuli (blobs or squares) that varied in difficulty (hard or easy). Outcome measures included correct responses to similar objects on the MST (mnemonic discrimination) and proportion of correct matches for hard and easy blobs and squares (object discrimination). Mnemonic discrimination for similar objects were correlated only with hard blobs after correcting for age, sex, and performance on easy trials ( r = 0.24). These results might suggest that difficulty with effectively using the subtle details to discriminate between similar objects likely have downstream consequences on mnemonic discrimination that also require the integration of multiple visual details.

Background: Numerous factors, including some modifiable factors as well as demographic factors, are associated with risk for age-related cognitive impairment. Evaluating the complex interaction of these factors and their trajectories across the adult lifespan requires large sample sizes with diverse cohorts. Online research has the potential to overcome barriers to research participation and provide the statistical power required to examine individual differences in cognitive functions. Understanding the complexity of cognitive aging is critical for developing individualized interventions aimed at promoting brain and cognitive health across the lifespan. Methods: Using a fully Web-based platform, MindCrowd-Expanded, we examined associations between age, sex, educational attainment, and cognitive performance in a large cohort of participants, aged 18–100. Tests were included from five cognitive domains – associative memory, information processing speed, and three components of executive function – inhibition, updating/working memory, and set shifting. Results: Increased age was associated with poorer performance across all domains, especially in conditions that reflected increased task complexity. Age effects were not confined to the 6th decade and beyond but were evident across the entire age range in a relatively linear fashion. Considerable individual differences in performance were also observed, especially among older adults. We also report robust sex effects that depended on the task – males showed faster simple response times than females, while females outperformed males on associative memory. Increased level of educational attainment showed small but consistent benefits across all domains. Conclusion: The study adds to a growing body of research demonstrating the feasibility and utility of online cognitive testing for reaching large cohorts of individuals across the adult lifespan. We report findings that mirror the existing literature on cognitive aging but also provide unique insights into the trajectory of cognitive functioning. We discuss the benefits, challenges, and future promise of Web-based testing.

Background: Previous research has shown that in-lab motor skill acquisition (supervised by an experimenter) is sensitive to biomarkers of Alzheimer disease (AD). However, remote unsupervised screening of AD risk through a skill-based task via the web has the potential to sample a wider and more diverse pool of individuals at scale. Objective: The purpose of this study was to examine a web-based motor skill game (“Super G”) and its sensitivity to risk factors of AD (eg, age, sex, APOE ε4 carrier status, and verbal learning deficits). Methods: Emails were sent to 662 previous MindCrowd participants who had agreed to be contacted for future research and have their APOE ε4 carrier status recorded and those who were at least 45 years of age or older. Participants who chose to participate were redirected to the Super G site where they completed the Super G task using their personal computer remotely and unsupervised. Once completed, different Super G variables were derived. Linear and logistic multivariable regression was used to examine the relationship between available AD risk factors (age, sex, APOE ε4 carrier status, and verbal learning) and distinct Super G performance metrics. Results: Fifty-four participants (~8% response rate) from the MindCrowd web-based cohort (mean age of 62.39 years; 39 females; and 23 APOE ε4 carriers) completed 75 trials of Super G. Results show that Super G performance was significantly associated with each of the targeted risk factors. Specifically, slower Super G response time was associated with being an APOE ε4 carrier (odds ratio 0.12, 95% CI 0.02-0.44; P=.006), greater Super G time in target (TinT) was associated with being male (odds ratio 32.03, 95% CI 3.74-1192,61; P=.01), and lower Super G TinT was associated with greater age (β −3.97, 95% CI −6.64 to −1.30; P=.005). Furthermore, a sex-by-TinT interaction demonstrated a differential relationship between Super G TinT and verbal learning depending on sex (β_male:TinT 6.77, 95% CI 0.34-13.19; P=.04). Conclusions: This experiment demonstrated that this web-based game, Super G, has the potential to be a skill-based digital biomarker for screening of AD risk on a large scale with relatively limited resources.

Objective: On continuous recognition tasks, changing the context objects are embedded in impairs memory. Older adults are worse on pattern separation tasks requiring identification of similar objects compared to younger adults. However, how contexts impact pattern separation in aging is unclear. The apolipoprotein (APOE) ϵ4 allele may exacerbate possible age-related changes due to early, elevated neuropathology. The goal of this study is to determine how context and APOE status affect pattern separation among younger and older adults.Method: Older and younger ϵ4 carriers and noncarriers were given a continuous object recognition task. Participants indicated if objects on a Repeated White background, Repeated Scene, or a Novel Scene were old, similar, or new. The proportions of correct responses and the types of errors made were calculated.Results: Novel scenes lowered recognition scores compared to all other contexts for everyone. Younger adults outperformed older adults on identifying similar objects. Older adults misidentified similar objects as old more than new, and the repeated scene exacerbated this error. APOE status interacted with scene and age such that in repeated scenes, younger carriers produced less false alarms, and this trend switched for older adults where carriers made more false alarms.Conclusions: Context impacted recognition memory in the same way for both age groups. Older adults underutilized details and over relied on holistic information during pattern separation compared to younger adults. The triple interaction in false alarms may indicate an even greater reliance on holistic information among older adults with increased risk for Alzheimer’s disease.

Hispanics/Latinos are at an equal or a greater risk for Alzheimer's disease (AD), yet risk factors remain more poorly characterized as compared to non-Hispanic/Latino Whites. Among non-Hispanic/Latino White cohorts, the apolipoprotein E (APOE) ε4 allele is one of the strongest risk factors for AD with subtle declines in episodic memory and brain volumes detectable in the preclinical stages. We examined whether the APOE ε4 status had a differential impact on cognition and brain volumes among cognitively healthy and mild cognitively impaired Hispanics/Latinos (n = 86; ε4 n = 23) compared to a well-matched group of non-Hispanic/Latino Whites (n = 92; ε4 n = 29). Neither the APOE ε4 status nor the interaction between the ε4 status and ethnicity was associated with cognitive performance. The APOE ε4 status was associated with white matter and not with gray matter volumes. APOE ε4 carriers had a significantly smaller total brain white matter volumes, as well as smaller right middle temporal and left superior temporal volumes. The Hispanics/Latinos had significantly smaller left middle frontal gray matter volumes, yet marginally larger overall white matter volumes, than the non-Hispanic/Latino Whites. Exploratory analysis within the Hispanic/Latino sample found that those people whose primary language was Spanish had larger total brain white matter volumes compared primarily to the English speakers. Importantly, primary language differences only held for Hispanic/Latino ε4 carriers and did not differentiate Hispanic/Latino non-carriers, underscoring the need for further investigation into the impacts of language and acculturation on cognitive aging among the fastest growing ethnic minority group in the United States.

To identify individual differences and potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT, index of processing speed) and paired-associate learning (PAL, index of verbal episodic memory). svRT and PAL results were combined with 22 survey questions. Analysis of MindCrowd’s svRT data revealed education and reported stroke as potential modifiers of changes in processing speed and memory from younger to older ages ( n _total = 75,666, n _women = 47,700, n _men = 27,966; ages 18-85 years old, mean ( M ) _Age = 46.54, standard deviation (SD) _Age = 18.40). To complement this work, we evaluated complex recognition reaction time (cvrRT) in the UK Biobank cohort ( n _total = 158,249 n _women = 89,333 n _men = 68,916; ages 40-70 years old, M _Age = 55.81, SD _Age = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of the MindCrowd cohort. Labeled UKBb MindCrowd ( n _total = 39,795, n _women = 29,640, n _men = 10,155; ages 40-70 years old, M _Age = 56.59, SD _Age = 8.16), this subset was carefully selected to mirror the UK Biobank. An identical linear model (LM) was used to assess both cohorts. The LM revealed similarities between MindCrowd and the UK Biobank across most results, despite obvious cohort differences (e.g., US vs. the UK). Notable divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer’s disease (FHAD) was associated with longer RTs in only. (2) Compared to being a man with more education, being a woman was associated with longer cvrRT length differences observed from younger to older ages. Divergent results from UKBb MindCrowd include more education and reported smoking. More education was associated with shorter and smoking longer cvrRTs differences observed from younger to older ages. Collected with our prior work, MindCrowd is beginning to reveal the intricate network connecting processing speed, memory, and cognition to healthy and pathological brain aging.