Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.Peer Reviewe

Corrigendum: Valenced action/inhibition learning in humans is modulated by a genetic variant linked to dopamine D2 receptor expression

Motivational salience plays an important role in shaping human behavior, but recent studies demonstrate that human performance is not uniformly improved by motivation. Instead, action has been shown to dominate valence in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward, but the neural mechanism behind this behavioral specificity is yet unclear. In all mammals, including humans, the monoamine neurotransmitter dopamine is particularly important in the neural manifestation of appetitively motivated behavior, and the human dopamine system is subject to considerable genetic variability. The well-studied TaqIA restriction fragment length polymorphism (rs1800497) has previously been shown to affect striatal dopamine metabolism. In this study we investigated a potential effect of this genetic variation on motivated action/inhibition learning. Two independent cohorts consisting of 87 and 95 healthy participants, respectively, were tested using the previously described valenced go/no-go learning paradigm in which participants learned the reward-associated no-go condition significantly worse than all other conditions. This effect was modulated by the TaqIA polymorphism, with carriers of the A1 allele showing a diminished learning-related performance enhancement in the rewarded no-go condition compared to the A2 homozygotes. This result highlights a modulatory role for genetic variability of the dopaminergic system in individual learning differences of action-valence interaction

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

BACKGROUND AND OBJECTIVES: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. METHODS: We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. RESULTS: In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. DISCUSSION: Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803–814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust agegroup-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging

Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.

Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Systemaattinen kirjallisuuskatsaus urheilumenestyksen ennustekijöiden mitattavuudesta nuorilla urheilijoilla

Tämän opinnäytetyön tarkoituksena oli luoda Langinkosken peruskoulun urheiluluokalle testipatteristo, jonka avulla voidaan arvioida potentiaalisten nuorten urheilijoiden kehittymistä tulevaisuuden menestyviksi urheilijoiksi. Testipatteriston tavoitteena on mitata tiettyjä fyysisen suorituskyvyn ennustekijöitä, joiden katsotaan olevan oleellisia myöhemmän urheilumenestyksen kannalta. Systemaattiseen kirjallisuuskatsaukseen sisältyi 33 hyväksyttyä alkuperäistutkimusta. Alkuperäistutkimuksia etsittiin seuraavista tietokannoista: Google Scholar, ProQuest Central, PubMed, ScienceDirect ja SPORTDiscus. Alkuperäistutkimuksista saadut tulokset käsiteltiin sisällönanalyysimenetelmää apuna käyttäen. Tulokset käsiteltiin ensin lajikohtaiseen taitoon ja tekniikkaan sekä suorituksen osoittajiin vaikuttavien tekijöiden osalta. Näin saatiin selville itse urheilusuoritukseen vaikuttavia tekijöitä ja niiden mahdollista ennusteellista arvoa. Tämän jälkeen esiteltiin eri fyysisiin suorituskykyominaisuuksiin vaikuttavat tekijät, joissa huomioitiin myös niiden mahdollinen ennustearvo. Varsinaista merkittävää ennustekijää näistä suorituskykyominaisuuksista ei pystytty osoittamaan, koska tulokset antoivat ristiriitaista tietoa tutkittavasta aiheesta. Kasvulla, kypsyydellä, iällä, relatiivisella ikävaikutuksella ja harjoitushistorialla osoitettiin olevan merkitystä eri fyysisiin suorituskykyominaisuuksiin, joten niiden vaihtelevan ja muuttuvan luonteen takia nuorten potentiaalisten urheilijoiden tulevaisuuden urheilumenestyksen ennustettavuutta ei voida pelkkien fyysisten suorituskykytestien avulla mitata ja arvioida. Ainoa selkeä ennustearvo havaittiin tutkittaessa nuoria tyttövoimistelijoita, joiden menestys motorisissa taidoissa ja koordinaatiossa korreloi merkittävästi kilpailumenestykseen kahden vuoden päästä. Luotettavaa ja ennustearvoa sisältävää testipatteristoa nuorten potentiaalisten urheilijoiden tunnistamis- ja valintaohjelmiin ei voida luoda tämän systemaattisen kirjallisuuskatsauksen tulosten perusteella. Kustannustehokas ja käytännöllinen testipatteristoehdotus kuitenkin muotoiltiin tuloksiin perustuen ehdottaen motorisen taidon sekä myös aerobisen kestävyyden mittaamista nuorilta potentiaalisilta urheilijoilta.The purpose of this thesis was to create a test battery for selecting athletic students to a sports class in Langinkosken peruskoulu “elementary school”. The test battery was aimed to evaluate the potential of becoming a top-level athlete by measuring certain physical performance characteristics that are thought to be relevant for future success in sports. This systematic literature review contains 33 articles. Five databases were searched: Google Scholar, ProQuest Central, PubMed, ScienceDirect and SPORTDiscus. Content analysis was used for data extraction and synthesis. First, the results were discussed for the effects of the physical performance characteristics on the performance indicators and sport-specific skills. They revealed the possible predictability of these certain characteristics on future success in sports by taking into account the sports performances themselves. After that, the physical performance characteristics were discussed separately, and the impact of such factors as growth and maturation was taken into account. The results were conflicting indicating that there is not a proper physical performance characteristic to be demonstrated for predicting future success in sports. Because of the varying nature of certain components affecting the physical performance characteristics (ie. growth, maturation and relative age effect), the talent identification and selection programs are troublesome for predicting future success in young athletes. Only one study concluded that there is predictive value in young gymnasts performing motor skill test and competition success two years later. The motor skill test results correlated with the competition performance two years later. Based on the results of this systematic literature review, it is not possible to construct a test battery that is reliable and have predictive value for future success in sports. However, a cost-effective and practical test battery proposal was formulated for testing motor skills and also aerobic capacity in potential young athletes

Age-related differences in fMRI subsequent memory effects are directly linked to local grey matter volume differences

Episodic memory performance declines with increasing age, and older adults typically show reduced activation of inferior temporo-parietal cortices in functional magnetic resonance imaging (fMRI) studies of episodic memory formation. Given the age-related cortical volume loss, it is conceivable that age-related reduction of memory-related fMRI activity may be partially attributable to reduced grey matter volume (GMV). We performed a voxel-wise multimodal neuroimaging analysis of fMRI correlates of successful memory encoding, using regional GMV as covariate. In a large cohort of healthy adults (106 young, 111 older), older adults showed reduced GMV across the entire neocortex and reduced encoding-related activation of inferior temporal and parieto-occipital cortices compared to young adults. Importantly, these reduced fMRI activations during successful encoding could in part be attributed to lower regional GMV. Our results highlight the importance of controlling for structural MRI differences in fMRI studies in older adults but also demonstrate that age-related differences in memory-related fMRI activity cannot be attributed to structural variability alone