Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes.

BACKGROUND: Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. METHODS: Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. RESULTS: Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. CONCLUSIONS: There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

Associations of genetic liability for Alzheimer's disease with cognition and eye movements in a large, population-based cohort study.

To identify cognitive measures that may be particularly sensitive to early cognitive decline in preclinical Alzheimer's disease (AD), we investigated the relation between genetic risk for AD and cognitive task performance in a large population-based cohort study. We measured performance on memory, processing speed, executive function, crystallized intelligence and eye movement tasks in 5182 participants of the Rhineland Study, aged 30 to 95 years. We quantified genetic risk for AD by creating three weighted polygenic risk scores (PRS) based on the genome-wide significant single-nucleotide polymorphisms coming from three different genetic association studies. We assessed the relation of AD PRS with cognitive performance using generalized linear models. Three PRS were associated with lower performance on the Corsi forward task, and two PRS were associated with a lower probability of correcting antisaccade errors, but none of these associations remained significant after correction for multiple testing. Associations between age and trail-making test A (TMT-A) performance were modified by AD genetic risk, with individuals at high genetic risk showing the strongest association. We conclude that no single measure of our cognitive test battery robustly captures genetic liability for AD as quantified by current PRS. However, Corsi forward performance and the probability of correcting antisaccade errors may represent promising candidates whose ability to capture genetic liability for AD should be investigated further. Additionally, our finding on TMT-A performance suggests that processing speed represents a sensitive marker of AD genetic risk in old age and supports the processing speed theory of age-related cognitive decline.

The Associations of Hearing Sensitivity and Different Cognitive Functions with Perception of Speech-in-Noise.

OBJECTIVES: Impaired speech-in-noise perception affects individuals' daily lives and is a frequent symptom of age-related hearing loss, which is a common disabling condition and a health concern in aging populations. The relative impact of hearing sensitivity loss and different cognitive functions on speech-in-noise perception is not well understood. We aimed to assess to what extent hearing sensitivity and different cognitive functions were associated with sentence-in-noise performance across the adult lifespan. DESIGN: This study is based on data of 2585 participants of the Rhineland Study, which is a German community-based cohort study of persons of age 30 years and older. We assessed speech-in-noise with a sentence-in-noise test (Göttinger Satztest), hearing sensitivity thresholds (air conduction pure-tone audiometry [PTA] average of 0.5, 1, 2, and 4 kHz), and the following cognitive domains: crystallized intelligence (German Mehrfachwahl-Wortschatz-Intelligenztest, MWT-B), executive functioning (Trail Making Test B, TMT), working memory (Digit Span forward, DS), and long-term memory (Verbal Learning and Memory Test delayed recall; VLMT). We examined the association between hearing sensitivity and cognitive functions with sentence-in-noise perception using a multivariable linear regression model adjusted for age, sex, and multiple potential confounders. RESULTS: Better hearing sensitivity was associated with better speech-in-noise perception (0.25 signal noise ratio [SNR] dB HL decrease per 5 dB HL decrease in PTA; 95% confidence interval [CI]: 0.20 to 0.25; p < 0.001). Better cognitive performance was also associated with better speech-in-noise perception, but to a lesser extent. Crystallized intelligence (MWT-B) showed an effect size of -0.10 SNR dB HL decrease per SD (95% CI: -0.14 to -0.06; p < 0.001), executive functioning (TMT) of -0.08 SNR dB HL decrease per SD (95% CI: -0.13 to -0.03; p = 0.002), working memory (DS) of -0.04 SNR dB HL decrease per SD (95% CI: -0.08 to -0.003; p = 0.03), and long-term memory (VLMT) of -0.03 SNR dB HL decrease per SD (95% CI: -0.07 to 0.01; p = 0.12). The standardized effect of hearing sensitivity (ß = 0.34) on speech-in-noise perception was four to five times larger than the effects of crystallized intelligence (ß = -0.08) and executive functioning (ß = -0.06). CONCLUSIONS: Hearing sensitivity was the strongest determinant of sentence-in-noise perception in adults above the age of 30. We determined the relative effect of different cognitive functions on sentence-in-noise perception. Crystallized intelligence and executive functions showed stronger associations while working and long-term memory functions had much smaller independent effects. Our results contribute to the understanding of determinants of speech-in-noise perception in aging adults.

Ten German versions of Rey's auditory verbal learning test: Age and sex effects in 4,000 adults of the Rhineland Study.

INTRODUCTION: Detecting early pathological cognitive decline is critical for dementia and aging-related research and clinical diagnostics. Rey's Auditory Verbal Learning Test (AVLT) is commonly used to measure episodic verbal memory. The test requires participants to learn a list of 15 words over several trials. Since multiple testing is often required to detect cognitive decline, but repeating the same test can bias results, we developed 10 German AVLT word lists. METHOD: We randomly assigned the lists to 4,000 participants (aged 30-94 years) from a population-based cohort to test their comparability, as well as aging effects and sex differences. RESULTS: Nine lists were highly comparable, with only one being slightly more difficult. Recall performance decreased on average by 0.6-1.1 words per trial per decade of age. Perseveration errors decreased with increasing age. Women remembered on average between 0.8 and 1.5 words per trial more than men, regardless of age. Women also outperformed men in the sum of Trials 1-5, learning over trials, retroactive inhibition, and false-positive and interference errors. Proactive inhibition remained stable across age and was unaffected by sex. CONCLUSION: This German AVLT version presents comparable lists including detailed age and sex references and therefore allows test repetition excluding training effects. These versions are a valuable resource for research and clinical application.

Perceived stress but not hair cortisol concentration is related to adult cognitive performance.

Chronic stress detrimentally affects cognition but evidence from population-based studies is scarce and largely based on one-dimensional stress assessments. In this study, we aimed to investigate associations of subjective and psychological chronic stress measures with cognition in a population-based sample of adults aged 30-95 years from the Rhineland Study. Participants completed the Perceived Stress Scale (subjective measure) and a cognitive test battery (N = 1766). Hair cortisol concentration (physiological measure) was assessed by liquid chromatography tandem mass spectrometry in 1098 participants. Cross-sectional associations between the two measures of chronic stress and cognition were investigated using multivariable linear regression models. Subjective and physiological measures of chronic stress were not associated with each other (B = 0.005 [95 %CI = -0.005 - 0.015]). Participants with higher perceived stress and specifically lower perceived self-efficacy performed worse in all cognitive domains (effect sizes ranged from ß = -0.129 [95 %CI = -0.177 - -0.080] to -0.054 [95 %CI = -0.099 - -0.009]; and from ß = 0.052 [95 %CI = 0.005 - 0.098] to 0.120 [95 %CI = 0.072 - 0.167], respectively). Relationships between subjective chronic stress measures and executive functioning were stronger in men compared to women (interaction ß = -0.144 [95 %CI = -0.221 - -0.067]). Relationships between perceived stress and working memory, and between perceived self-efficacy and executive functioning, processing speed, verbal episodic and working memory, increased with older age. Hair cortisol concentration was not associated with performance in any cognitive domain. Our results suggest that subjective and physiological measures capture different aspects of chronic stress in the general population.

A Functional MRI Paradigm for Efficient Mapping of Memory Encoding Across Sensory Conditions.

We introduce a new and time-efficient memory-encoding paradigm for functional magnetic resonance imaging (fMRI). This paradigm is optimized for mapping multiple contrasts using a mixed design, using auditory (environmental/vocal) and visual (scene/face) stimuli. We demonstrate that the paradigm evokes robust neuronal activity in typical sensory and memory networks. We were able to detect auditory and visual sensory-specific encoding activities in auditory and visual cortices. Also, we detected stimulus-selective activation in environmental-, voice-, scene-, and face-selective brain regions (parahippocampal place and fusiform face area). A subsequent recognition task allowed the detection of sensory-specific encoding success activity (ESA) in both auditory and visual cortices, as well as sensory-unspecific positive ESA in the hippocampus. Further, sensory-unspecific negative ESA was observed in the precuneus. Among others, the parallel mixed design enabled sustained and transient activity comparison in contrast to rest blocks. Sustained and transient activations showed great overlap in most sensory brain regions, whereas several regions, typically associated with the default-mode network, showed transient rather than sustained deactivation. We also show that the use of a parallel mixed model had relatively little influence on positive or negative ESA. Together, these results demonstrate a feasible, versatile, and brief memory-encoding task, which includes multiple sensory stimuli to guarantee a comprehensive measurement. This task is especially suitable for large-scale clinical or population studies, which aim to test task-evoked sensory-specific and sensory-unspecific memory-encoding performance as well as broad sensory activity across the life span within a very limited time frame.

Less head motion during MRI under task than resting-state conditions.

Head motion reduces data quality of neuroimaging data. In three functional magnetic resonance imaging (MRI) experiments we demonstrate that people make less head movements under task than resting-state conditions. In Experiment 1, we observed less head motion during a memory encoding task than during the resting-state condition. In Experiment 2, using publicly shared data from the UCLA Consortium for Neuropsychiatric Phenomics LA5c Study, we again found less head motion during several active task conditions than during a resting-state condition, although some task conditions also showed comparable motion. In the healthy controls, we found more head motion in men than in women and more motion with increasing age. When comparing clinical groups, we found that patients with a clinical diagnosis of bipolar disorder, or schizophrenia, move more compared to healthy controls or patients with ADHD. Both these experiments had a fixed acquisition order across participants, and we could not rule out that a first or last scan during a session might be particularly prone to more head motion. Therefore, we conducted Experiment 3, in which we collected several task and resting-state fMRI runs with an acquisition order counter-balanced. The results of Experiment 3 show again less head motion during several task conditions than during rest. Together these experiments demonstrate that small head motions occur during MRI even with careful instruction to remain still and fixation with foam pillows, but that head motion is lower when participants are engaged in a cognitive task. These finding may inform the choice of functional runs when studying difficult-to-scan populations, such as children or certain patient populations. Our findings also indicate that differences in head motion complicate direct comparisons of measures of functional neuronal networks between task and resting-state fMRI because of potential differences in data quality. In practice, a task to reduce head motion might be especially useful when acquiring structural MRI data such as T1/T2-weighted and diffusion MRI in research and clinical settings.