Mayo normative studies: regression-based normative data for ages 30-91 years with a focus on the Boston Naming Test, Trail Making Test and Category Fluency.

OBJECTIVE: Normative neuropsychological data are essential for interpretation of test performance in the context of demographic factors. The Mayo Normative Studies (MNS) aim to provide updated normative data for neuropsychological measures administered in the Mayo Clinic Study of Aging (MCSA), a population-based study of aging that randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. We examined demographic effects on neuropsychological measures and validated the regression-based norms in comparison to existing normative data developed in a similar sample. METHOD: The MNS includes cognitively unimpaired adults ≥30 years of age (n = 4,428) participating in the MCSA. Multivariable linear regressions were used to determine demographic effects on test performance. Regression-based normative formulas were developed by first converting raw scores to normalized scaled scores and then regressing on age, age2, sex, and education. Total and sex-stratified base rates of low scores (T < 40) were examined in an older adult validation sample and compared with Mayo's Older Americans Normative Studies (MOANS) norms. RESULTS: Independent linear regressions revealed variable patterns of linear and/or quadratic effects of age (r2 = 6-27% variance explained), sex (0-13%), and education (2-10%) across measures. MNS norms improved base rates of low performance in the older adult validation sample overall and in sex-specific patterns relative to MOANS. CONCLUSIONS: Our results demonstrate the need for updated norms that consider complex demographic associations on test performance and that specifically exclude participants with mild cognitive impairment from the normative sample.

Stricker Learning Span criterion validity: a remote self-administered multi-device compatible digital word list memory measure shows similar ability to differentiate amyloid and tau PET-defined biomarker groups as in-person Auditory Verbal Learning Test.

OBJECTIVE: The Stricker Learning Span (SLS) is a computer-adaptive digital word list memory test specifically designed for remote assessment and self-administration on a web-based multi-device platform (Mayo Test Drive). We aimed to establish criterion validity of the SLS by comparing its ability to differentiate biomarker-defined groups to the person-administered Rey's Auditory Verbal Learning Test (AVLT). METHOD: Participants (N = 353; mean age = 71, SD = 11; 93% cognitively unimpaired [CU]) completed the AVLT during an in-person visit, the SLS remotely (within 3 months) and had brain amyloid and tau PET scans available (within 3 years). Overlapping groups were formed for 1) those on the Alzheimer's disease (AD) continuum (amyloid PET positive, A+, n = 125) or not (A-, n = 228), and those with biological AD (amyloid and tau PET positive, A+T+, n = 55) vs no evidence of AD pathology (A-T-, n = 195). Analyses were repeated among CU participants only. RESULTS: The SLS and AVLT showed similar ability to differentiate biomarker-defined groups when comparing AUROCs (p's > .05). In logistic regression models, SLS contributed significantly to predicting biomarker group beyond age, education, and sex, including when limited to CU participants. Medium (A- vs A+) to large (A-T- vs A+T+) unadjusted effect sizes were observed for both SLS and AVLT. Learning and delay variables were similar in terms of ability to separate biomarker groups. CONCLUSIONS: Remotely administered SLS performed similarly to in-person-administered AVLT in its ability to separate biomarker-defined groups, providing evidence of criterion validity. Results suggest the SLS may be sensitive to detecting subtle objective cognitive decline in preclinical AD.

Sex-specific differences in neuropsychological profiles of mild cognitive impairment in a hospital-based clinical sample.

OBJECTIVE: Mild cognitive impairment (MCI) is an etiologically nonspecific diagnosis including a broad spectrum of cognitive decline between normal aging and dementia. Several large-scale cohort studies have found sex effects on neuropsychological test performance in MCI. The primary aim of the current project was to examine sex differences in neuropsychological profiles in a clinically diagnosed MCI sample using clinical and research diagnostic criteria. METHOD: The current study includes archival data from 349 patients (age M = 74.7; SD = 7.7) who underwent an outpatient neuropsychological evaluation and were diagnosed with MCI. Raw scores were converted to z-scores using normative datasets. Sex differences in neurocognitive profiles including severity, domain-specific composites (memory, executive functioning/information processing speed, and language), and modality-specific learning curves (verbal, visual) were examined using Analysis of Variance, Chi-square analyses, and linear mixed models. Post hoc analyses examined whether sex effects were uniform across age and education brackets. RESULTS: Females exhibit worse non-memory domain and test-specific cognitive performances compared to males with otherwise comparable categorical MCI criteria and global cognition measured via screening and composite scores. Analysis of learning curves showed additional sex-specific advantages (visual Males>Females; verbal Females >Males) not captured by MCI subtypes. CONCLUSIONS: Our results highlight sex differences in a clinical sample with MCI. The emphasis of verbal memory in the diagnosis of MCI may result in diagnosis at more advanced stages for females. Additional investigation is needed to determine whether these profiles confer greater risk for progressing to dementia or are confounded by other factors (e.g., delayed referral, medical comorbidities).

Mayo-PACC: A parsimonious preclinical Alzheimer's disease cognitive composite comprised of public-domain measures to facilitate clinical translation.

INTRODUCTION: We aimed to define a Mayo Preclinical Alzheimer's disease Cognitive Composite (Mayo-PACC) that prioritizes parsimony and use of public domain measures to facilitate clinical translation. METHODS: Cognitively unimpaired participants aged 65 to 85 at baseline with amyloid PET imaging were included, yielding 428 amyloid negative (A-) and 186 amyloid positive (A+) individuals with 7 years mean follow-up. Sensitivity to amyloid-related cognitive decline was examined using slope estimates derived from linear mixed models (difference in annualized change across A+ and A- groups). We compared differences in rates of change between Mayo-PACC and other composites (A+ > A- indicating more significant decline in A+). RESULTS: All composites showed sensitivity to amyloid-related longitudinal cognitive decline (A+ > A- annualized change p < 0.05). Comparisons revealed that Mayo-PACC (AVLT sum of trials 1-5+6+delay, Trails B, animal fluency) showed comparable longitudinal sensitivity to other composites. DISCUSSION: Mayo-PACC performs similarly to other composites and can be directly translated to the clinic.

A Lifespan Model of Interference Resolution and Inhibitory Control: Risk for Depression and Changes with Illness Progression.

The cognitive processes involved in inhibitory control accuracy (IC) and interference resolution speed (IR) or broadly - inhibition - are discussed in this review, and both are described within the context of a lifespan model of mood disorders. Inhibitory control (IC) is a binary outcome (success or no for response selection and inhibition of unwanted responses) for any given event that is influenced to an extent by IR. IR refers to the process of inhibition, which can be manipulated by task design in earlier and later stages through use of distractors and timing, and manipulation of individual differences in response proclivity. We describe the development of these two processes across the lifespan, noting factors that influence this development (e.g., environment, adversity and stress) as well as inherent difficulties in assessing IC/IR prior to adulthood (e.g., cross-informant reports). We use mood disorders as an illustrative example of how this multidimensional construct can be informative to state, trait, vulnerability and neuroprogression of disease. We present aggregated data across numerous studies and methodologies to examine the lifelong development and degradation of this subconstruct of executive function, particularly in mood disorders. We highlight the challenges in identifying and measuring IC/IR in late life, including specificity to complex, comorbid disease processes. Finally, we discuss some potential avenues for treatment and accommodation of these difficulties across the lifespan, including newer treatments using cognitive remediation training and neuromodulation.

Cardiovascular disease risk factors, tract-based structural connectomics, and cognition in older adults.

Cardiovascular disease risk factors (CVD-RFs) are associated with decreased gray and white matter integrity and cognitive impairment in older adults. Less is known regarding the interplay between CVD-RFs, brain structural connectome integrity, and cognition. We examined whether CVD-RFs were associated with measures of tract-based structural connectivity in 94 non-demented/non-depressed older adults and if alterations in connectivity mediated associations between CVD-RFs and cognition. Participants (age = 68.2 years; 52.1% female; 46.8% Black) underwent CVD-RF assessment, MRI, and cognitive evaluation. Framingham 10-year stroke risk (FSRP-10) quantified CVD-RFs. Graph theory analysis integrated T1-derived gray matter regions of interest (ROIs; 23 a-priori ROIs associated with CVD-RFs and dementia), and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for local efficiency and nodal strength. A principal component analysis resulted in three rotated factor scores reflecting executive function (EF; FAS, Trail Making Test (TMT) B-A, Letter-Number Sequencing, Matrix Reasoning); attention/information processing (AIP; TMT-A, TMT-Motor, Digit Symbol); and memory (CVLT-II Trials 1-5 Total, Delayed Free Recall, Recognition Discriminability). Linear regressions between FSRP-10 and connectome ROIs adjusting for word reading, intracranial volume, and white matter hyperintensities revealed negative associations with nodal strength in eight ROIs (p-values<.05) and negative associations with efficiency in two ROIs, and a positive association in one ROI (p-values<.05). There was mediation of bilateral hippocampal strength on FSRP-10 and AIP, and left rostral middle frontal gyrus strength on FSRP-10 and AIP and EF. Stroke risk plays differential roles in connectivity and cognition, suggesting the importance of multi-modal neuroimaging biomarkers in understanding age-related CVD-RF burden and brain-behavior.

Investigating the separate and interactive associations of trauma and depression on brain structure: implications for cognition and aging.

OBJECTIVE: Trauma and depression are associated with brain structural alterations; their combined effects on these outcomes are unclear. We previously reported a negative effect of trauma, independent of depression, on verbal learning and memory; less is known about underlying structural associates. We investigated separate and interactive associations of trauma and depression on brain structure. METHODS: Adults aged 30-89 (N = 203) evaluated for depression (D+) and trauma history (T+) using structured clinical interviews were divided into 53 D+T+, 42 D+T-, 50 D-T+, and 58 D-T-. Multivariable linear regressions examined the separate and interactive associations of depression and trauma with prefrontal and temporal lobe cortical thickness composites and hippocampal volumes adjusting for age, sex, predicted verbal IQ, comorbid anxiety, and vascular risk. Significant results informed analyses of tract-based structural connectomic measures of efficiency and centrality. RESULTS: Trauma, independent of depression, was associated with greater left prefrontal cortex (PFC) thickness, in particular the medial orbitofrontal cortex and pars orbitalis. A trauma × depression interaction was observed for the right PFC in age-stratified analyses: Older D + T+ had reduced PFC thickness compared with older D - T+ individuals. Regardless of age, trauma was associated with more left medial orbitofrontal cortex efficiency and less pars orbitalis centrality. In the T+ group, left pars orbitalis cortical thickness and centrality negatively correlated with verbal learning. CONCLUSIONS: Trauma, independent of depression, associated with altered PFC characteristics, morphologically and in terms of structural network communication and influence. Additionally, findings suggest that there may be a combined effect of trauma and depression in older adults. Copyright © 2017 John Wiley & Sons, Ltd.

A novel computer adaptive word list memory test optimized for remote assessment: Psychometric properties and associations with neurodegenerative biomarkers in older women without dementia.

Introduction: This study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use. Methods: Women enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e-mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in-person neuropsychological tests (n = 96, ages 55-79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer's disease (n = 47). Results: SLS performance significantly correlated with the Auditory Verbal Learning Test and measures of neurodegeneration (temporal meta-regions of interest and entorhinal cortical thickness, adjusting for age and education). Test-retest reliabilities across two sessions were 0.71-0.76 (two-way mixed intraclass correlation coefficients). Discussion: The SLS is a valid and reliable self-administered memory test that shows promise for remote assessment of aging and neurodegenerative disorders.

Associations of the Mediterranean diet with cognitive and neuroimaging phenotypes of dementia in healthy older adults.

Background: Accumulating evidence suggests that higher Mediterranean diet (MedDiet) adherence is associated with higher global cognitive performance and brain structural integrity as well as decreased risk of Alzheimer disease (AD) and vascular dementia (VaD). Objectives: We directly examined cross-sectional associations between the MedDiet and cognitive and neuroimaging phenotypes associated with AD and VaD (separately) in a cohort of nondemented, nondepressed older adults. Methods: Community-dwelling older adults (n = 82; aged ∼68.8 y; 50% female, 50% minority) underwent dietary (Block Food Frequency Questionnaire 2005) and neuropsychological assessments and neuroimaging. MedDiet scores were quantified with the use of published criteria, and participants were divided into High and Low (median split) adherence groups. We focused our neuropsychological investigation on cognitive phenotypes primarily associated with AD [i.e., learning and memory (L&M)] and VaD (i.e., information processing and executive functioning). AD neuroimaging phenotypes consisted of hippocampal and dentate gyrus volumes quantified using T1-weighted images and the FreeSurfer 6.0 segmentation pipeline (http://surfer.nmr.mgh.harvard.edu). The VaD neuroimaging phenotype consisted of total white matter hyperintensity (WMH) volumes quantified using combined T1-weighted and T2-fluid-attenuated inversion recovery images. Neuroimaging metrics were adjusted for total intracranial volume. Separate multivariable linear regression models controlling for age, sex, education, body mass index, and caloric intake examined the associations between MedDiet groups (High compared with Low) and cognitive and neuroimaging outcomes. Results: When compared with the Low MedDiet group, the High MedDiet group was associated with better L&M performance and larger dentate gyri. MedDiet adherence was not associated with information processing, executive functioning, or WMH. Conclusion: Results highlight the association between increasing MedDiet adherence and specific cognitive and neuroimaging phenotypes that, when altered, are associated with AD.