Predicting brain-age from multimodal imaging data captures cognitive impairment.

The disparity between the chronological age of an individual and their brain-age measured based on biological information has the potential to offer clinically relevant biomarkers of neurological syndromes that emerge late in the lifespan. While prior brain-age prediction studies have relied exclusively on either structural or functional brain data, here we investigate how multimodal brain-imaging data improves age prediction. Using cortical anatomy and whole-brain functional connectivity on a large adult lifespan sample (N=2354, age 19-82), we found that multimodal data improves brain-based age prediction, resulting in a mean absolute prediction error of 4.29 years. Furthermore, we found that the discrepancy between predicted age and chronological age captures cognitive impairment. Importantly, the brain-age measure was robust to confounding effects: head motion did not drive brain-based age prediction and our models generalized reasonably to an independent dataset acquired at a different site (N=475). Generalization performance was increased by training models on a larger and more heterogeneous dataset. The robustness of multimodal brain-age prediction to confounds, generalizability across sites, and sensitivity to clinically-relevant impairments, suggests promising future application to the early prediction of neurocognitive disorders.

Sex and age interact in reading the mind in the eyes.

Social cognition includes understanding the mental states (thoughts, feelings, intentions, desires, and beliefs) of others - so-called 'theory of mind' or 'mindreading'. Recent studies have shown an impact of age and sex. Here, we applied the 'Reading the Mind in the Eyes' Test (RMET) that measures the ability to identify mental states from the eye region of the face. RMET accuracy was measured and analyzed in a large population-based sample (N = 1603) across the whole adult age-range from 19 to 79 years with effect size analyses (Hedges' g). Overall test performance was lower in older than younger women and men, whereas differences between women and men were almost negligible across the whole cohort. In a further analysis focusing on age-specific sex differences, RMET accuracy was higher for women below 45 years compared to men. This sex effect nearly vanished in older people above 45 years of age. Results were verified in a sub-cohort after excluding participants with neurological and psychiatric conditions, and with another cut-off, i.e. 50 years of age. In conclusion, results suggest that mindreading declines with age. Overall sex effects were small and results suggest that age-related hormonal and social factors may impact mental state perception. Future mega-analyses and longitudinal studies including hormonal and social measures are needed to validate the interaction between RMET performance, aging and sex.

Face Masks Protect From Infection but May Impair Social Cognition in Older Adults and People With Dementia.

The coronavirus disease 2019 (COVID-19) pandemic will have a high impact on older adults and people with Alzheimer's disease and other dementias. Social cognition enables the understanding of another individual's feelings, intentions, desires and mental states, which is particularly important during the COVID-19 pandemic. To prevent further spread of the disease face masks have been recommended. Although justified for prevention of this potentially devastating disease, they partly cover the face and hamper emotion recognition and probably mindreading. As social cognition is already affected by aging and dementia, strategies must be developed to cope with these profound changes of communication. Face masking even could accelerate cognitive decline in the long run. Further studies are of uppermost importance to address face masks' impact on social cognition in aging and dementia, for instance by longitudinally investigating decline before and in the pandemic, and to design compensatory strategies. These issues are also relevant for face masking in general, such as in medical surroundings-beyond the COVID-19 pandemic.

Reading cognition from the eyes: association of retinal nerve fibre layer thickness with cognitive performance in a population-based study.

With the eye as a window to the brain, non-invasive fast screening of retinal nerve fibre layer thickness poses the opportunity for early detection of cognitive decline leading to dementia. Our objective is to determine whether performance in various neurocognitive tests has an association with itemized retinal nerve fibre layer thickness. Detailed investigation of associations factored in sex and eye-side. The large population-based LIFE-Adult study (Leipzig Research Centre for Civilization Diseases) was conducted at Leipzig University, Germany from 2011 to 2014. Randomly selected participants (N = 10 000) were drawn from population registry in an age- and gender-stratified manner, focusing on 40-80 years. Cognitive function was examined with the CERAD-NP Plus test-battery (Consortium to Establish a Registry for Alzheimer's Disease), Stroop-Test, Reading the Mind in the Eyes-Test and Multiple-Choice Vocabulary Intelligence Test. Circumpapillary retinal nerve fibre layer thickness was measured with Optical Coherence Tomography. Subjects with reliable measurements (≥50 B-scan repetitions, signal-to-noise-ratio ≥20 dB, ≤5% missing A-scans) and without clinical eye pathology (sample A) and additional exclusion due to conditions of the central nervous system (sample B) were evaluated. The relationship between cognitive function and retinal nerve fibre layer thickness was investigated for six segments: temporal, temporal-superior, temporal-inferior, nasal, nasal-superior and nasal-inferior. For comparison with other studies, global mean is given. Brain-side projection analysis links results to the corresponding brain hemisphere. We analysed 11 124 eyes of 6471 subjects [55.5 years of age (19.1-79.8 years), 46.9% male]. Low cognitive performance was predominantly associated with thinner retinal nerve fibre layer thickness. Correlation analysis indicated emphasis on global and temporally located effects. Multivariable regression analysis with adjustments (age, sex and scan radius) presented individual results for each test, differentiating between sex and eye-side. For instance, verbal fluency tests and Trail Making Test-B show stronger association in females; Trail Making Test-A shows right-eye dominance. Findings in Trail-Making-Test-A projected to left brain hemisphere, and the ratio incongruent to neutral in the Stroop test projected to right brain-hemisphere. Separate assessment for sex and eye-side is presented for the first time in a population-based study. Location-specific sectorial retinal nerve fibre layer thickness was found to be an indicator for cognitive performance, giving an option for early detection of cognitive decline and the potential of early treatment. The eye as a window to the brain was studied with optical coherence tomography and connected to cognition. Girbardt et al. report that thinner retinal nerve fibre layer thickness was found to be a meaningful index for poorer cognitive performance which presents the potential for prediction of future cognitive decline.

Age- and Sex-Specific Standard Scores for the Reading the Mind in the Eyes Test.

The reliable, valid and economic assessment of social cognition is more relevant than ever in the field of clinical psychology. Theory of Mind is one of the most important socio-cognitive abilities but standardized assessment instruments for adults are rare. The Reading the Mind in the Eyes Test (RMET) is well-established and captures the ability to identify mental states from gaze. Here, we computed standard scores for the German version of the RMET derived from a large, community-dwelling sample of healthy adults (20-79 years). The standardization sample contains 966 healthy adult individuals of the population-based Leipzig Research Center for Civilization Diseases (LIFE) study. Before standardization, weighting factors were applied to match the current sample with distribution characteristics of the German population regarding age, sex, and education. RMET scores were translated into percentage ranks for men and women of five age groups (20-29, 30-39, 40-49, 50-59, 60+ years). Age-specific percentage ranks are provided for men and women. Independent of age, men present a larger variance in test scores compared to women. Within the specific age groups, women score higher and their scoring range is less variable. With increasing age, the scoring variance increases in both men and women. This is the first study providing age- and sex-specific RMET standard scores. Data was weighted to match German population characteristics, enabling the application of standard scores across German-speaking areas. Our results contribute to the standardized assessment of socio-cognitive abilities in clinical diagnostics.

Mindreading From the Eyes Declines With Aging - Evidence From 1,603 Subjects.

Social cognition, in particular mindreading, enables the understanding of another individual's feelings, intentions, desires, and mental states. The Reading the Mind in the Eyes Test (RMET) captures the ability to identify mental states from gaze. We investigated RMET accuracy in the context of age and cognition across the whole adult age-range (19-79 years) in a very large population-based sample (N = 1,603) with linear regression models accounting for cognitive abilities, neurological diseases, and psychiatric disorders. Higher age predicted lower RMET performance in women and men, suggesting difficulties to infer mental states from gaze at older age. Effects remained stable when taking other cognitive abilities and psychiatric disorders or neurological diseases into account. Our results show that RMET performance as a measure of social cognition declines with increasing age.

Lesion location matters: The relationships between white matter hyperintensities on cognition in the healthy elderly.

White matter hyperintensities (WMH) are associated with cognitive decline. We aimed to identify the spatial specificity of WMH impact on cognition in non-demented, healthy elderly. We quantified WMH volume among healthy participants of a community dwelling cohort ( n = 702, age range 60 - 82 years, mean age = 69.5 years, 46% female) and investigated the effects of WMH on cognition and behavior, specifically for executive function, memory, and motor speed performance. Lesion location influenced their effect on cognition and behavior: Frontal WMH in the proximity of the frontal ventricles mainly affected executive function and parieto-temporal WMH in the proximity of the posterior horns deteriorated memory, while WMH in the upper deep white matter-including the corticospinal tract-compromised motor speed performance. This study exposes the subtle and subclinical yet detrimental effects of WMH on cognition in healthy elderly, and strongly suggests a causal influence of WMH on cognition by demonstrating the spatial specificity of these effects.

Sex, Age, and Emotional Valence: Revealing Possible Biases in the 'Reading the Mind in the Eyes' Task.

The 'Reading the Mind in the Eyes' test (RMET) assesses a specific socio-cognitive ability, i.e., the ability to identify mental states from gaze. The development of this ability in a lifespan perspective is of special interest. Whereas former investigations were limited mainly to childhood and adolescence, the focus has been shifted towards aging, and psychiatric and neurodegenerative diseases recently. Although the RMET is frequently applied in developmental psychology and clinical settings, stimulus characteristics have never been investigated with respect to potential effects on test performance. Here, we analyzed the RMET stimulus set with a special focus on interrelations between sex, age and emotional valence. Forty-three persons rated age and emotional valence of the RMET picture set. Differences in emotional valence and age ratings between male and female items were analyzed. The linear relation between age and emotional valence was tested over all items, and separately for male and female items. Male items were rated older and more negative than female stimuli. Regarding male RMET items, age predicted emotional valence: older age was associated with negative emotions. Contrary, age and valence were not linearly related in female pictures. All ratings were independent of rater characteristics. Our results demonstrate a strong confound between sex, age, and emotional valence in the RMET. Male items presented a greater variability in age ratings compared to female items. Age and emotional valence were negatively associated among male items, but no significant association was found among female stimuli. As personal attributes impact social information processing, our results may add a new perspective on the interpretation of previous findings on interindividual differences in RMET accuracy, particularly in the field of developmental psychology, and age-associated neuropsychiatric diseases. A revision of the RMET might be afforded to overcome confounds identified here.

White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory.

Age-related white matter hyperintensities (WMH) are a manifestation of white matter damage seen on magnetic resonance imaging (MRI). They are related to vascular risk factors and cognitive impairment. This study investigated the cognitive profile at different stages of WMH in a large community-dwelling sample; 849 subjects aged 21 to 79 years were classified on the 4-stage Fazekas scale according to hyperintense lesions seen on individual T2-weighted fluid-attenuated inversion recovery MRI scans. The evaluation of cognitive functioning included seven domains of cognitive performance and five domains of subjective impairment, as proposed by the DSM-5. For the first time, the impact of age-related WMH on Theory of Mind was investigated. Differences between Fazekas groups were analyzed non-parametrically and effect sizes were computed. Effect sizes revealed a slight overall cognitive decline in Fazekas groups 1 and 2 relative to healthy subjects. Fazekas group 3 presented substantial decline in social cognition, attention and memory, although characterized by a high inter-individual variability. WMH groups reported subjective cognitive decline. We demonstrate that extensive WMH are associated with specific impairment in attention, memory, social cognition, and subjective cognitive performance. The detailed neuropsychological characterization of WMH offers new therapeutic possibilities for those affected by vascular cognitive decline.

A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests.

Behavioral variant frontotemporal dementia (bvFTD) is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011) and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET), Stroop task, Trail Making Test (TMT), Hamasch-Five-Point Test (H5PT), and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test's discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC). bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC) was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD)-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM)-5.