Maximizing utility of neuropsychological measures in sex-specific predictive models of incident Alzheimer's disease in the Framingham Heart Study.

INTRODUCTION: Sex differences in neuropsychological (NP) test performance might have important implications for the diagnosis of Alzheimer's disease (AD). This study investigates sex differences in neuropsychological performance among individuals without dementia at baseline. METHODS: Neuropsychological assessment data, both standard test scores and process coded responses, from Framingham Heart Study participants were analyzed for sex differences using regression model and Cox proportional hazards model. Optimal NP profiles were identified by machine learning methods for men and women. RESULTS: Sex differences were observed in both summary scores and composite process scores of NP tests in terms of adjusted means and their associations with AD incidence. The optimal NP profiles for men and women have 10 and 8 measures, respectively, and achieve 0.76 mean area under the curve for AD prediction. DISCUSSION: These results suggest that NP tests can be leveraged for developing more sensitive, sex-specific indices for the diagnosis of AD.

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience.

BACKGROUND: Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio-cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience. METHODS: We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from (1) literature searches, (2) policy documents and reports by the European Commission and national funding agencies, (3) web-based searches, (4) "Web of Science", and (5) searches of project databases of funding agencies. An informative / non-systematic search was performed for sections on policies and funding, education, basic research, while a systematic literature and database review was conducted forquantitative analysis of research output and funded projects in terms of sex and gender analysis. RESULTS: Our mapping shows that there is a growing interest and attention towards sex and gender consideration in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities. DISCUSSION: We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

Towards AI-driven longevity research: An overview.

While in the past technology has mostly been utilized to store information about the structural configuration of proteins and molecules for research and medical purposes, Artificial Intelligence is nowadays able to learn from the existing data how to predict and model properties and interactions, revealing important knowledge about complex biological processes, such as aging. Modern technologies, moreover, can rely on a broader set of information, including those derived from the next-generation sequencing (e.g., proteomics, lipidomics, and other omics), to understand the interactions between human body and the external environment. This is especially relevant as external factors have been shown to have a key role in aging. As the field of computational systems biology keeps improving and new biomarkers of aging are being developed, artificial intelligence promises to become a major ally of aging research.

Cellular form of prion protein inhibits Reelin-mediated shedding of Caspr from the neuronal cell surface to potentiate Caspr-mediated inhibition of neurite outgrowth.

Extension of axonal and dendritic processes in the CNS is tightly regulated by outgrowth-promoting and -inhibitory cues to assure precision of synaptic connections. We identify a novel role for contactin-associated protein (Caspr) as an inhibitory cue that reduces neurite outgrowth from CNS neurons. We show that proteolysis of Caspr at the cell surface is regulated by the cellular form of prion protein (PrP), which directly binds to Caspr. PrP inhibits Reelin-mediated shedding of Caspr from the cell surface, thereby increasing surface levels of Caspr and potentiating the inhibitory effect of Caspr on neurite outgrowth. PrP deficiency results in reduced levels of Caspr at the cell surface, enhanced neurite outgrowth in vitro, and more efficient regeneration of axons in vivo following spinal cord injury. Thus, we reveal a previously unrecognized role for Caspr and PrP in inhibitory modulation of neurite outgrowth in CNS neurons, which is counterbalanced by the proteolytic activity of Reelin.

Differentiation of postnatal cerebellar glial progenitors is controlled by Bmi1 through BMP pathway inhibition.

Bmi1 is a polycomb group (Pc-G) protein involved in heritable gene repression, maintenance of cell identity, and proliferation. During the development of the central nervous system, Bmi1 is crucial for self-renewal of neural stem cells and for proliferation of neuronal (granule cell) progenitors of the cerebellum. Here, we use loss of function mouse models and in vitro assays--granule cell cultures and glial-neuronal co-cultures--to show that Bmi1 plays a crucial role in specification of glial progenitors during postnatal cerebellar development. Moreover, we demonstrate in in vitro assays that Bmi1 exerts this novel function through repression of BMP pathway and that this is independent of its known role in mediating the cellular response to Shh signaling. Thus modulation of Bmi1 expression in glial progenitors may represent a key event in determining the differentiation potential of these cells.

Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth.

In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor.

Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system.

Schizophrenia is characterized by positive, negative, and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-d-aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor's pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. More recently, the selective glycine reuptake inhibitor bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders.