Cumulative effects of subsequent concussions on the neural patterns of young rugby athletes: data from event-related potentials.

Our study aimed at detecting a potential cumulative effect of subsequent concussions on the neural activation patterns of young rugby athletes with or without concussion history. Event-related brain potential (ERP) data from 24 rugby players, 22-year-old on average, were retrospectively examined. All underwent a Sport Concussion Assessment Tool (SCAT2) during preseason and an on-site ERP task (P300) following a recent concussion event (<48 hours). Sixteen players suffered at least one concussion in the previous 3 years and eight were without self-reported past concussion. While no differences were reported between groups regarding symptom appraisal on the SCAT2 assessment, ERP revealed significantly decreased P3b amplitude and a trend for increased P3b latency in players who experienced prior concussions. Our data thus support the cumulative effect of concussions on neuroelectric events in young rugby players, highlighting the importance of managing player's concussion load to reduce the risk of long-term injuries.

Comparison of ultrasensitive and mass spectrometry quantification of blood-based amyloid biomarkers for Alzheimer's disease diagnosis in a memory clinic cohort.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with ß-amyloid pathology as a key underlying process. The relevance of cerebrospinal fluid (CSF) and brain imaging biomarkers is validated in clinical practice for early diagnosis. Yet, their cost and perceived invasiveness are a limitation for large-scale implementation. Based on positive amyloid profiles, blood-based biomarkers should allow to detect people at risk for AD and to monitor patients under therapeutics strategies. Thanks to the recent development of innovative proteomic tools, the sensibility and specificity of blood biomarkers have been considerably improved. However, their diagnosis and prognosis relevance for daily clinical practice is still incomplete. METHODS: The Plasmaboost study included 184 participants from the Montpellier's hospital NeuroCognition Biobank with AD (n = 73), mild cognitive impairments (MCI) (n = 32), subjective cognitive impairments (SCI) (n = 12), other neurodegenerative diseases (NDD) (n = 31), and other neurological disorders (OND) (n = 36). Dosage of ß-amyloid biomarkers was performed on plasma samples using immunoprecipitation-mass spectrometry (IPMS) developed by Shimadzu (IPMS-Shim Aß42, Aß40, APP669-711) and Simoa Human Neurology 3-PLEX A assay (Aß42, Aß40, t-tau). Links between those biomarkers and demographical and clinical data and CSF AD biomarkers were investigated. Performances of the two technologies to discriminate clinically or biologically based (using the AT(N) framework) diagnosis of AD were compared using receiver operating characteristic (ROC) analyses. RESULTS: The amyloid IPMS-Shim composite biomarker (combining APP669-711/Aß42 and Aß40/Aß42 ratios) discriminated AD from SCI (AUC: 0.91), OND (0.89), and NDD (0.81). The IPMS-Shim Aß42/40 ratio also discriminated AD from MCI (0.78). IPMS-Shim biomarkers have similar relevance to discriminate between amyloid-positive and amyloid-negative individuals (0.73 and 0.76 respectively) and A-T-N-/A+T+N+ profiles (0.83 and 0.85). Performances of the Simoa 3-PLEX Aß42/40 ratio were more modest. Pilot longitudinal analysis on the progression of plasma biomarkers indicates that IPMS-Shim can detect the decrease in plasma Aß42 that is specific to AD patients. CONCLUSIONS: Our study confirms the potential usefulness of amyloid plasma biomarkers, especially the IPMS-Shim technology, as a screening tool for early AD patients.

Effects of preventive interventions on neuroimaging biomarkers in subjects at-risk to develop Alzheimer's disease: A systematic review.

Alzheimer's Disease (AD) is a multifactorial and complex neurodegenerative disorder. Some modifiable risk factors have been associated with an increased risk of appearance of the disease and/or cognitive decline. Preventive clinical trials aiming at reducing one or combined risk factors have been implemented and their potential effects assessed on cognitive trajectories and on AD biomarkers. However, the effect of interventions on surrogate markers, in particular imaging biomarkers, remains poorly understood. We conducted a review of the literature and analyzed 43 interventional studies that included physical exercise, nutrition, cognitive training or multidomain interventions, and assessed various brain imaging biomarkers, to determine the effects of preventive interventions on imaging biomarkers for subjects at-risk to develop AD. Deciphering the global and regional brain effect of each and combined interventions will help to better understand the interplay relationship between multimodal interventions, cognition, surrogate brain markers, and to better design primary and secondary outcomes for future preventive clinical trials. Those studies were pondered using generally-admitted quality criteria to reveal that interventions may affect the brain of patients with cognitive impairment rather than those without cognitive impairment thus indicating that particular care should be taken when selecting individuals for interventions. Additionally, a majority of the studies concurred on the effect of the interventions and particularly onto the frontal brain areas.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.

Introduction: The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). Methods: To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. Results: No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. Discussion: These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

Htt is a repressor of Abl activity required for APP-induced axonal growth.

Huntington's disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer's disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αß neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αß neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.

miR-92a Suppresses Mushroom Body-Dependent Memory Consolidation in Drosophila.

MicroRNAs (miRNAs) fine tune gene expression to regulate many aspects of nervous system physiology. Here, we show that miR-92a suppresses memory consolidation that occurs in the αß and γ mushroom body neurons (MBns) of Drosophila, making miR-92a a memory suppressor miRNA. Bioinformatics analyses suggested that mRNAs encoding kinesin heavy chain 73 (KHC73), a protein that belongs to Kinesin-3 family of anterograde motor proteins, may be a functional target of miR-92a. Behavioral studies that employed expression of khc73 with and without its 3' untranslated region (UTR) containing miR-92a target sites, luciferase assays in HEK cells with reporters containing wild-type and mutant target sequences in the khc73 3'UTR, and immunohistochemistry experiments involving KHC73 expression with and without the wild-type khc73 3'UTR, all point to the conclusion that khc73 is a major target of miR-92a in its functional role as a miRNA memory suppressor gene.

MicroRNA function in Drosophila memory formation.

MicroRNAs (miRs) are small non-coding RNAs that regulate protein expression through post-transcriptional mechanisms. They participate in broad aspects of biology from the control of developmental processes to tumorigenesis. Recent studies in Drosophila show that they also regulate activity-dependent and sensory-specific protein expression and support olfactory memory formation. Among the hundreds of miRs described, several have been demonstrated to be required for normal learning, memory, or for the development of neuronal circuits that support memory formation. Fly models of human diseases offer promise of identifying miRs whose expression becomes dysregulated and part of the pathological state, providing models for understanding brain disorders and drug discovery.

Developmental inhibition of miR-iab8-3p disrupts mushroom body neuron structure and adult learning ability.

MicroRNAs are small non-coding RNAs that inhibit protein expression post-transcriptionally. They have been implicated in many different physiological processes, but little is known about their individual involvement in learning and memory. We recently identified several miRNAs that either increased or decreased intermediate-term memory when inhibited in the central nervous system, including miR-iab8-3p. We report here a new developmental role for this miRNA. Blocking the expression of miR-iab8-3p during the development of the organism leads to hypertrophy of individual mushroom body neuron soma, a reduction in the field size occupied by axonal projections, and adult intellectual disability. We further identified four potential mRNA targets of miR-iab8-3p whose inhibition modulates intermediate-term memory including ceramide phosphoethanolamine synthase, which may account for the behavioral effects produced by miR-iab8-3p inhibition. Our results offer important new information on a microRNA required for normal neurodevelopment and the capacity to learn and remember normally.

MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1.

MicroRNAs have been associated with many different biological functions, but little is known about their roles in conditioned behavior. We demonstrate that Drosophila miR-980 is a memory suppressor gene functioning in multiple regions of the adult brain. Memory acquisition and stability were both increased by miR-980 inhibition. Whole cell recordings and functional imaging experiments indicated that miR-980 regulates neuronal excitability. We identified the autism susceptibility gene, A2bp1, as an mRNA target for miR-980. A2bp1 levels varied inversely with miR-980 expression; memory performance was directly related to A2bp1 levels. In addition, A2bp1 knockdown reversed the memory gains produced by miR-980 inhibition, consistent with A2bp1 being a downstream target of miR-980 responsible for the memory phenotypes. Our results indicate that miR-980 represses A2bp1 expression to tune the excitable state of neurons, and the overall state of excitability translates to memory impairment or improvement.

microRNAs That Promote or Inhibit Memory Formation in Drosophila melanogaster.

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally. Prior studies have shown that they regulate numerous physiological processes critical for normal development, cellular growth control, and organismal behavior. Here, we systematically surveyed 134 different miRNAs for roles in olfactory learning and memory formation using "sponge" technology to titrate their activity broadly in the Drosophila melanogaster central nervous system. We identified at least five different miRNAs involved in memory formation or retention from this large screen, including miR-9c, miR-31a, miR-305, miR-974, and miR-980. Surprisingly, the titration of some miRNAs increased memory, while the titration of others decreased memory. We performed more detailed experiments on two miRNAs, miR-974 and miR-31a, by mapping their roles to subpopulations of brain neurons and testing the functional involvement in memory of potential mRNA targets through bioinformatics and a RNA interference knockdown approach. This screen offers an important first step toward the comprehensive identification of all miRNAs and their potential targets that serve in gene regulatory networks important for normal learning and memory.

Wnt signaling is required for long-term memory formation.

Wnt signaling regulates synaptic plasticity and neurogenesis in the adult nervous system, suggesting a potential role in behavioral processes. Here, we probed the requirement for Wnt signaling during olfactory memory formation in Drosophila using an inducible RNAi approach. Interfering with ß-catenin expression in adult mushroom body neurons specifically impaired long-term memory (LTM) without altering short-term memory. The impairment was reversible, being rescued by expression of a wild-type ß-catenin transgene, and correlated with disruption of a cellular LTM trace. Inhibition of wingless, a Wnt ligand, and arrow, a Wnt coreceptor, also impaired LTM. Wingless expression in wild-type flies was transiently elevated in the brain after LTM conditioning. Thus, inhibiting three key components of the Wnt signaling pathway in adult mushroom bodies impairs LTM, indicating that this pathway mechanistically underlies this specific form of memory.

Olfactory learning in Drosophila.

Studies of olfactory learning in Drosophila have provided key insights into the brain mechanisms underlying learning and memory. One type of olfactory learning, olfactory classical conditioning, consists of learning the contingency between an odor with an aversive or appetitive stimulus. This conditioning requires the activity of molecules that can integrate the two types of sensory information, the odorant as the conditioned stimulus and the aversive or appetitive stimulus as the unconditioned stimulus, in brain regions where the neural pathways for the two stimuli intersect. Compelling data indicate that a particular form of adenylyl cyclase functions as a molecular integrator of the sensory information in the mushroom body neurons. The neuronal pathway carrying the olfactory information from the antennal lobes to the mushroom body is well described. Accumulating data now show that some dopaminergic neurons provide information about aversive stimuli and octopaminergic neurons about appetitive stimuli to the mushroom body neurons. Inhibitory inputs from the GABAergic system appear to gate olfactory information to the mushroom bodies and thus control the ability to learn about odors. Emerging data obtained by functional imaging procedures indicate that distinct memory traces form in different brain regions and correlate with different phases of memory. The results from these and other experiments also indicate that cross talk between mushroom bodies and several other brain regions is critical for memory formation.

Expression of Zif268 in the granule cell layer of the adult mouse olfactory bulb is modulated by experience.

Behavioral and physiological evidence indicates that odor processing in the main olfactory bulb is influenced by olfactory experience. At the cellular level, changes in inhibitory influence exerted by granular interneurons may contribute to restructuring odor representations. To assess experience-dependent modulation in the responsiveness of granule cells, we measured the level and spatial distribution of odor-induced expression of the immediate-early gene Zif268 in the granule cell layer of adult mice submitted or not to olfactory discrimination conditioning. We first show that stimulation by the reinforced odorant in conditioned animals did not induce any increase in Zif268 expression in contrast to stimulation with an unfamiliar odorant which induced an odor-specific three-fold increase in Zif268 expression. The same lack of Zif268 induction was observed in animals exposed to odorants without learning, indicating that familiarity to the odorant with or without conditioning similarly reduced responsiveness of granule cells to odorant stimulation. Second, conditioning induced a spatial reorganization of Zif268-positive cells leading to higher contrast and significant enlargement of their distribution pattern. The latter effect was also present in animals exposed to the odorants without conditioning but was significantly weaker. Taken together, these data indicate that distinct populations of granule cells are solicited by odorant processing, depending on its familiarity or behavioral significance. Finally, we report that the expression pattern of Zif268 in the granule cell layer is constrained by anteroposterior and dorsolateral gradients in cell density, pointing to anatomical and possibly functional disparity within the layer.

A computer-assisted odorized hole-board for testing olfactory perception in mice.

The present paper describes a behavioral setup, designed and built in our laboratory, allowing the systematic and automatic recording of performances in a large number of olfactory behavioral tests. This computerized monitoring system has the capability of measuring different aspects of olfactory function in mice using different paradigms including threshold evaluation, generalization tasks, habituation/dishabituation, olfactory associative learning, short-term olfactory memory with or without a spatial component, and olfactory preferences. In this paper, we first describe the hole-board apparatus and its software and then give the experimental results obtained using this system. We demonstrate that one single, easy-to-run experimental setup is a powerful tool for the study of olfactory behavior in mice that has many advantages and broad applications.