Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

The effect of visual perspective on episodic memory in aging: A virtual reality study.

The possibility of flexibly retrieving our memories using a first-person or a third-person perspective (1PP or 3PP) has been extensively investigated in episodic memory research. Here, we used a Virtual Reality-based paradigm to manipulate the visual perspective used during the encoding stage to investigate age-related differences in the formation of memories experienced from 1PP vs. 3PP. 32 young adults and 32 seniors participated in the study. Participants navigated through two virtual cities to encode complex real-life virtual events, from either a 1PP (as if from their egocentric viewpoint) or a 3PP, while actively controlling an avatar. While recognition accuracy was higher in young adults after encoding in 1PP compared to 3PP, there was no benefit in memory formation in 1PP for older adults. These findings are discussed in terms of both age-related changes in episodic memory functioning and self-referencing processes.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study.

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

INTRODUCTION: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. METHODS: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. RESULTS: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. DISCUSSION: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Older People's Health-Related Behaviors: Evidence from Three Cohorts of the Lc65+ Study.

Baby-boomers might be more health-conscious than earlier birth cohorts, but limited evidence has been produced so far. To investigate such changes, this study compared health-related behaviors at age 65 to 70 among three successive five-year birth cohorts (pre-war: born 1934-1938; war: born 1939-1943 and baby-boom: born 1944-1948) representative of the community-dwelling population. Information about alcohol use, smoking, physical activity, and nutrition was compared across the three cohorts (n = 4,270 participants) using Chi-squared test. Alcohol and the mean nutritional intake score did not vary across cohorts, whereas the consumption of nonalcoholic drinks increased significantly from pre-war to war and to baby-boom cohort (p<.001). Other differences across cohorts were observed only in women: the proportion of women who never or rarely engaged in sports decreased from 52.9% in the pre-war cohort to around 43% in subsequent cohorts (p<.001), while the proportion of women who had never smoked was higher in the pre-war cohort (56.1%) than in the war and the baby-boom cohorts (49.8% and 46.8%, respectively, p<.001). Overall, these results show some positive changes in older persons' health behaviors over time. Nevertheless, considerable room remains for improving lifestyles through public health interventions.

[Cognitive fitness to drive : feedback at Leenaards Memory Centre]. / Aptitude cognitive à la conduite automobile : retour d'expérience du Centre Leenaards de la Mémoire.

Cognitive impairment can interfere with the fitness to drive. An increase in requests to assess this aspect is observed at Leenaards Memory Centre. Changes in the law could be an explanatory factor. The views formulated in 2019 are mainly unfavorable because all the patients present cognitive disorders, generally attributed to Alzheimer's disease or a related disorder, but never linked with aging only. Moreover, unfavorable views are frequently expressed before the age of 75. Therefore, each patient is unique, and each decision is based neither on the patient's age or his diagnosis, but rather on his cognitive profile. In this article we discuss the reasons for an unfavorable view and discuss them in the context of the tasks of our centre.

Les troubles cognitifs peuvent interférer avec l'aptitude à la conduite automobile. Une hausse des demandes d'évaluation ciblée sur cet aspect est observée au Centre Leenaards de la Mémoire. Les modifications de la loi pourraient être un facteur explicatif. Les avis formulés en 2019 sont majoritairement défavorables chez les patients présentant des troubles cognitifs dus à une maladie d'Alzheimer ou une pathologie apparentée, mais jamais en lien avec le vieillissement seul. Les avis défavorables sont fréquents avant l'âge de 75 ans. Chaque situation est donc unique et chaque décision prise se base non pas sur l'âge du patient, ni sur le diagnostic étiologique, mais sur le profil cognitif. Nous abordons dans cet article les raisons d'un avis défavorable et les discutons dans le contexte des missions de notre centre.

[The Swiss Brain Health Registry : a national infrastructure for Alzheimer's research]. / Le Registre suisse pour la santé du cerveau - Une infrastructure nationale pour la recherche sur la maladie d'Alzheimer.

The Memory Centres of several Swiss hospitals have set up a national online registry for Alzheimer's research, called www.BHR-suisse.org. This type of registry already exists in the United States (www.brainhealthregistry.org/) and the Netherlands (https://hersenonderzoek.nl/). It contributes, as do these initiating sites, to the creation of a global database of research partnersb who wish to contribute by participating in studies on neurodegenerative diseases and more particularly on Alzheimer's disease. By registering, they provide a certain amount of information and become potential research partners. Researchers can then select a panel of volunteers according to the selection and exclusion criteria of their studies, contact them and include them in their studies.

Les centres de la mémoire de plusieurs hôpitaux suisses ont créé un Registre national suisse en ligne pour la recherche sur Alzheimer, intitulé www.bhr-suisse.org. Ce type de registre existe déjà aux États-Unis (www.brainhealthregistry.org/) et aux Pays-Bas (hersenonderzoek.nl/). Il contribue, au même titre que ces sites initiateurs, à constituer une base de données globale de partenaires de recherchea qui souhaitent apporter leur contribution en participant à des études sur les maladies neurodégénératives et, plus particulièrement, sur la maladie d'Alzheimer. En s'inscrivant, ces derniers apportent un certain nombre d'informations et deviennent de potentiels partenaires de recherche. Les chercheurs peuvent ensuite sélectionner un panel suivant les critères de sélection et d'exclusion de leurs études, contacter les volontaires et les intégrer dans ces études.

[Recent Advances in Neurology]. / Neurologie.

Significant developments were published in 2020 in the field of blood biomarkers in Alzheimer's disease. Several studies helped to define more accurately the management of status epilepticus and of epilepsy in women of childbearing age. The new Swiss guidelines for the pre-hospital management of acute stroke were issued, as are new targets for stroke prevention. Numerous advances concerning the management of NMO-SD (NeuroMyelitis Optica Spectrum Disorder) were published. Different neurological presentations linked to the COVID-19 pandemic were described (central and peripheral). Several studies confirmed the effectiveness of new migraine treatments (including anti-CGRP). New pharmacological therapies are available for Parkinson's disease.

L'année 2020 a vu d'importantes avancées dans le domaine des biomarqueurs sanguins pour le diagnostic biologique de la maladie d'Alzheimer. Plusieurs études permettent de mieux définir la prise en charge de l'épilepsie chez la femme en âge de procréer et de l'état de mal épileptique. Les nouvelles recommandations suisses pour la prise en charge préhospitalière de l'AVC aigu sont en cours de publication, tout comme de nouvelles cibles pour leur prévention secondaire. De nombreuses avancées concernant la prise en charge des Neuromyelitis Optica Spectrum Disorder ont été publiées. Divers tableaux neurologiques (centraux et périphériques) liés à la pandémie de Covid-19 ont été décrits. Plusieurs études ont permis de confirmer l'efficacité des nouveaux traitements de la migraine (notamment les anti-Calcitonin Gene-Related Peptide). Enfin, de nouvelles thérapies pharmacologiques sont disponibles pour la maladie de Parkinson.

A nation-wide initiative for brain imaging and clinical phenotype data federation in Swiss university memory centres.

PURPOSE OF REVIEW: The goal of our nation-wide initiative is to provide clinicians intuitive and robust tools for accurate diagnosis, therapy monitoring and prognosis of cognitive decline that is based on large-scale multidomain data. RECENT FINDINGS: We describe a federation framework that allows for statistical analysis of aggregated brain imaging and clinical phenotyping data across memory clinics in Switzerland. The adaptation and deployment of readily available data capturing and federation modules is paralleled by developments in ontology, quality and regulatory control of brain imaging data. Our initiative incentivizes data sharing through the common resource in a way that provides individual researcher with access to large-scale data that surpasses the data acquisition capacity of a single centre. Clinicians benefit from fine-grained epidemiological characterization of own data compared with the rest additional to intuitive tools allowing for computer-based diagnosis of dementia. Finally, our concept aims at closing the loop between group-level results based on aggregate data and individual diagnosis by providing disease models, that is, classifiers for neurocognitive disorders that will enable the computer-based diagnosis of individual patients. SUMMARY: The obtained results will inform recommendations on best clinical practice in all relevant fields focusing on standardization and interoperability of acquired data, privacy protection framework and ethical consideration in the context of evolutive pathology.