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Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended onZ-DNA binding protein 1(Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) againstZbp1ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibitZbp1could become a novel therapeutic strategy.

N 6 -methyladenosine (m 6 A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m 6 A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m 6 A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m 6 A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer’s disease (AD) patients showed decreased m 6 A RNA methylation in AD patients. m 6 A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 ( CAMKII ) and AMPA-selective glutamate receptor 1 ( Glua1 ). We used proximity ligation assays to show that reduced m 6 A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m 6 A levels impaired synaptic function. Our results suggest that m 6 A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.

Over the last few years, extracellular vesicles (EVs) have received increasing attention as potential non-invasive diagnostic and therapeutic biomarkers for various diseases. The interest in EVs is related to their structure and content, as well as to their changing cargo in response to different stimuli. One of the potential areas of use of EVs as biomarkers is the central nervous system (CNS), in particular the brain, because EVs can cross the blood–brain barrier, exist also in peripheral tissues and have a diverse cargo. Thus, they may represent “liquid biopsies” of the CNS that can reflect brain pathophysiology without the need for invasive surgical procedures. Overall, few studies to date have examined EVs in neuropsychiatric disorders, and the present evidence appears to lack reproducibility. This situation might be due to a variety of technical obstacles related to working with EVs, such as the use of different isolation strategies, which results in non-uniform vesicular and molecular outputs. Multi-omics approaches and improvements in the standardization of isolation procedures will allow highly pure EV fractions to be obtained in which the molecular cargo, particularly microRNAs and proteins, can be identified and accurately quantified. Eventually, these advances will enable researchers to decipher disease-relevant molecular signatures of the brain-derived EVs involved in synaptic plasticity, neuronal development, neuro-immune communication, and other related pathways. This narrative review summarizes the findings of studies on EVs in major psychiatric disorders, particularly in the field of biomarkers, and discusses the respective therapeutic potential of EVs.

N6-methyladenosine (m6A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes and memory function. However, the precise role of m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo a massive decrease across mouse brain regions as a consequence of aging. In addition, Alzheimer's disease in humans correlates with decreased N6-methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). We furthermore show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that m6A-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases.Significance statementThe addition of N6-methyladenosine (m6A) to RNA plays a role in various cellular processes and its de-regulation has been linked to several devastating diseases. The precise role of m6A RNA-methylation in the adult brain is, however, not well understood. In our study, we describe the genome-wide m6A epi-transcriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m6A transcripts are conserved. These transcripts are linked to the regulation of synaptic processes and are localized to synapses. In the diseases brain we detect RNA hypomethylation across multiple transcripts in all investigated brain regions and across species. At the mechanistic level we find that reduced m6A levels specifically impairs synaptic protein-synthesis.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Much like other psychiatric diseases, BD suffers from the chronic lack of reliable biomarkers and innovative pharmacological interventions. Better characterization of clinical profiles, experimental medicine, genomic data mining, and the utilization of experimental models, including stem cell and genetically modified mice, are suggested ways forward. Environment, including early childhood experiences, has been documented to modulate the risk for the development of psychiatric disorders via epigenetic mechanisms. Key epigenetic regulators, microRNAs (miRNAs, miRs), govern normal neuronal functioning and show altered expression in diverse brain pathologies. We observed significant alterations of exosomal miR-29c levels in prefrontal cortex (Brodmann area 9, BA9) of BD patients. We also demonstrated that exosomes extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, we hypothesized that increased miR-149 expression in BA24-derived exosomes may be consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with familial BD. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. These findings support neuron-glia interaction as a possible target mechanism in BD, implicated by others in neuroimaging, postmortem, and in vivo studies of the pathological changes mediated by glial cells.

2072 Background: Meningioma is the most common CNS tumor, yet there is no effective therapy for relapsed/refractory meningioma after surgery and radiation therapy. Although most meningiomas follow a relatively benign course, some have a more aggressive course with rapid tumor growth, brain invasion, higher recurrence rates or extracranial metastasis. Prostate-specific membrane antigen (PSMA) is a transmembrane peptidase upregulated on endothelial cells of malignant solid tumors including glioblastoma and metastatic brain tumors, but not in normal vasculature. PSMA has been investigated as a therapeutic target and as a molecular imaging marker to monitor response to treatment and evaluate disease activity in PSMA-avid tumors. PSMA expression however has not been studied in meningioma. Methods: Archival tumor specimens (96 tumor samples: 58 WHO grade 1, 35 WHO grade 2, 3 WHO grade 3) from 69 patients were stained for H&E, PSMA and CD31 and slides were scanned (Leica Aperio AT2 whole slide image scanner). 37 of these samples were recurrent tumors and 13 had prior radiation therapy (intensity-modulated, Gamma knife, craniospinal). 21 of the 69 patients had paired samples of initial and recurrent tumors. QuPath was utilized as open access solution to machine learning generating raw data for PSMA, CD31, PSMA/CD31 ratio and PSMA/vasculature ratio. Paired t-test, unpaired t-test and ROC curves were used for statistical analysis. Results: PSMA expression was seen in all of the study samples. PSMA expression (p = 0.0147) was lower in grade 1 compared to grade 2 and 3 tumors, but not different among histologic subtypes. PSMA/vasculature ratio (p = 0.0015) was lower in grade 1 compared to grade 2 and 3 tumors. PSMA expression (p = 0.002) and PSMA/vasculature ratio (p = 0.0015) were higher in recurrent compared to non-recurrent tumors. PSMA expression (p = 0.0442) was higher in recurrent compared to initial tumors among paired samples. When comparing initial tumors of paired samples to non-recurrent tumors, ROC curves demonstrated CD31 expression (AUC:0.7278; p = 0.0008), PSMA/CD31 ratio (AUC:0.7843; p = < 0.0001) and PSMA/vasculature ratio (AUC:0.6256; p = 0.0328) to be predictors of tumor recurrence. Tumors with prior radiation therapy had higher PSMA/vascular ratio (p = 0.0439) compared to those without. Conclusions: PSMA is expressed in tumor vasculature of meningioma of any grade, increases at recurrence and persists with prior radiation therapy. Since it is present in meningioma of different grades and throughout the course of the disease, it could potentially be utilized as consistent diagnostic biomarker, relevant factor for risk of recurrence stratification and novel therapeutic target for these tumors.

Cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD)—deposition of beta amyloid (Aβ) within the walls of cerebral blood vessels—typically accompanies Aβ buildup in brain parenchyma and causes abnormalities in vessel structure and function. We recently demonstrated that the immunoreactivity of activin receptor-like kinase 1 (ALK1), the type I receptor for circulating BMP9/BMP10 (bone morphogenetic protein) signaling proteins, is reduced in advanced, but not early stages of AD in CA3 pyramidal neurons. Here we characterize vascular expression of ALK1 in the context of progressive AD pathology accompanied by amyloid angiopathy in postmortem hippocampi using immunohistochemical methods. Hippocampal arteriolar wall ALK1 signal intensity was 35% lower in AD patients (Braak and Braak Stages IV and V [BBIV-V]; clinical dementia rating [CDR1-2]) as compared with subjects with early AD pathologic changes but either cognitively intact or with minimal cognitive impairment (BBIII; CDR0-0.5). The intensity of Aβ signal in arteriolar walls was similar in all analyzed cases. These data suggest that, as demonstrated previously for specific neuronal populations, ALK1 expression in blood vessels is also vulnerable to the AD pathophysiologic process, perhaps related to CAA. However, cortical arterioles may remain responsive to the ALK1 ligands, such as BMP9 and BMP10 in early and moderate AD.

Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer’s disease (AD). In this study we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with Alzheimer’s disease.

None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD., peer-reviewed

Alzheimer’s disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD., Rebecca Canter et al. use the SWITCH technique for immunolabeling whole brain to show that core regions of the Papez memory circuit are susceptible to Aβ accumulation in mice. They find that Aβ accumulation in the mammillary body is linked to neuronal hyper-excitability and amyloid deposition can be reduced using a pharmacogenetics approach.

This case of a radiation-naive patient with pilocytic astrocytoma highlights how deletions of CDKN2A (cyclin-dependent kinase Inhibitor 2A) and PTEN (phosphatase and tensin homolog) portended a poor clinical outcome. Pilocytic astrocytomas are grade 1 tumors usually occurring in children and young adults with KIAA1549-BRAF fusion defining the majority of pilocytic astrocytomas. The presence of CDKN2A and PTEN loss may be associated with aggressive biology in pilocytic astrocytoma and further studies should include comprehensive genomics in a larger series of adult pilocytic astrocytoma to evaluate this previously unreported finding. Providers need to be aware of this possibility given the potential for poor outcomes.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder causing huge emotional and economic burden to our societies. An effective therapy has not been implicated yet, which is in part also due to the fact that pathological changes occur years before clinical symptoms manifest. Thus, there is a great need for the development of a translatable biomarker. Recent evidence highlights microRNAs as candidate biomarkers. In this study, we use next-generation sequencing to study the small noncoding RNAome (sncRNAome) in exosomes derived from human cerebrospinal fluid (CSF). We show that the sncRNAome from CSF-derived exosomes is dominated not only by microRNAs (miRNAs) but also by PIWI-interacting RNAs (piRNAs). We define a combined signature consisting of three miRNAs and three piRNAs that are suitable to detect AD with an AUC of 0.83 in a replication cohort and furthermore predict the conversion of mild–cognitive impaired (MCI) patients to AD dementia with an AUC of 0.86 for the piRNA signature. When combining the smallRNA signature with pTau and Aβ 42/40 ratio the AUC reaches 0.98. Our study reports a novel exosomal small noncoding RNA signature to detect AD pathology and provides the first evidence that in addition to miRNAs, piRNAs should also be considered as a candidate biomarker for AD.

The neurological damage of Alzheimer’s disease (AD) is thought to be irreversible upon onset of dementia-like symptoms, as it takes years to decades for occult pathologic changes to become symptomatic. It is thus necessary to identify individuals at risk for the development of the disease before symptoms manifest in order to provide early intervention. Surrogate markers are critical for early disease detection, stratification of patients in clinical trials, prediction of disease progression, evaluation of response to treatment, and also insight into pathomechanisms. Here, we review the evidence for a number of microRNAs that may serve as biomarkers with possible mechanistic insights into the AD pathophysiologic processes, years before the clinical manifestation of the disease.

Genome-wide association studies have established BIN1 (Bridging Integrator 1) as the most significant late-onset Alzheimer disease (AD) susceptibility locus after APOE . We analyzed BIN1 protein expression using automated immunohistochemistry on the hippocampal CA1 region in 19 patients with either no, mild, or moderate-to-marked AD pathology, who had been assessed by Clinical Dementia Rating and CERAD scores. We also examined the amygdala, prefrontal, temporal, and occipital regions in a subset of these patients. In non-demented controls without AD pathology, BIN1 protein was expressed in white matter, glia, particularly oligodendrocytes, and in the neuropil in which the BIN1 signal decorated axons. With increasing severity of AD, BIN1 in the CA1 region showed: 1) sustained expression in glial cells, 2) decreased areas of neuropil expression, and 3) increased cytoplasmic neuronal expression that did not correlate with neurofibrillary tangle load. In patients with AD, both the prefrontal cortex and CA1 showed a decrease in BIN1-immunoreactive (BIN1-ir) neuropil areas and increases in numbers of BIN1-ir neurons. The numbers of CA1 BIN1-ir pyramidal neurons correlated with hippocampal CERAD neuritic plaque scores; BIN1 neuropil signal was absent in neuritic plaques. Our data provide novel insight into the relationship between BIN1 protein expression and the progression of AD-associated pathology and its diagnostic hallmarks.

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia. Beca Ramón y Cajal GAIN- Agencia Gallega de Innovación

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Alzheimer’s disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (Aβ) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of Aβ deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to Aβ accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early Aβ aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt Aβ burden. Finally, we confirm Aβ in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to Aβ deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.Author ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.RGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.HC built the custom microscope.RGC, L-HT, KC, ID wrote the manuscript.

Background Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Alzheimer's disease (AD) is the most common form of dementia in the elderly but effective therapeutic strategies to treat AD are not yet available. This is also due to the fact that the pathological mechanisms that drive the pathogenesis of sporadic AD are still not sufficiently understood and may differ on the individual level. Several risk factors such as altered insulin-like peptide (ILP) signaling have been linked to AD and modulating the ILP system has been discussed as a potential therapeutic avenue. Here we show that insulin-like growth factor binding protein 7 (IGFBP7), a protein that attenuates the function of ILPs, is up-regulated in the brains of AD patients and in a mouse model for AD via a process that involves altered DNA-methylation and coincides with decreased ILP signaling. Mimicking the AD-situation in wild type mice, by increasing hippocampal IGFBP7 levels leads to impaired memory consolidation. Consistently, inhibiting IGFBP7 function in mice that develop AD-like memory impairment reinstates associative learning behavior. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as a biomarker for AD. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of AD patients.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesicles (EVs) extracted from prefrontal cortex (Brodmann area 9, BA9) of BD patients. In this study, we show that EVs extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, increased miR-149 expression in BA24-derived EVs is consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with either familial BD or familial major depressive disorder. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. Finally, we report altered expression of both miR-149 and miR-29c in EVs extracted from brains of Flinders Sensitive Line rats, a well-validated animal model exhibiting depressive-like behaviors and glial (astrocytic) dysfunction. These findings warrant future investigations into the potential of using EV miRNA signatures as biomarkers to further enhance the biological definition of BD. © 2017 Wiley Periodicals, Inc.

Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies., peer-reviewed

MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR-34c could be a suitable therapy.

Intramedullary primary central nervous system lymphoma (PCNSL) is a rare central nervous system (CNS) malignancy affecting mostly the brain, but it may also involve the leptomeninges, eyes, and spinal cord. A 71-year-old woman presented with back pain and progressive unilateral lower extremity weakness owing to an intramedullary primary histiocytic sarcoma of the spine, a rare PCNSL subtype. To the authors' knowledge, this is the first case of an intramedullary PCNSL caused by histiocytic sarcoma.

We examined the protein expression of novel genome-wide association studies (GWAS) identified risk alleles implicated in Alzheimer's disease (AD) and low hippocampal volume using postmortem hippoca...

Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis.

Presentation of Case First Admission A 52-year-old right-handed woman was admitted to the neurologic clinic because of ataxia and fatigue. The patient had been well until four months earlier, when she had had a “sinus infection” characterized by green nasal discharge. Radiographs of the paranasal sinuses were reported to be unremarkable. At about the same time, while she was performing aerobic exercises, there was a sudden sensation of “tilting,” without diplopia; on walking shortly thereafter, she felt that she was veering to the left. She had an accompanying band of pain around the top of her head. These symptoms persisted, . . .

Background and Aims: In the prenatal and postnatal period, the human cortex undergoes different phases of development. The question therefore was, which phases of growth characterize pyramidal and nonpyramidal neurons in the human prefrontal cortex. Results and Conclusions: The major neuronal outgrowth occurs mainly in the first 2 postnatal years, both for pyramidal and nonpyramidal cells. The mature level of outgrowth is reached at about 3–4 years. The neurochemical specification, however, is then still not at the mature level. The mature distribution of neuropeptide Y, calbindin and parvalbumin immunoreactive nonpyramidal neurons is observed in early puberty.

INTRODUCTION: Clinical genomics platforms identify targetable alterations for precision medicine in pediatric neuro-oncology, allowing both the genomic profiling of tumors to inform clinical care and facilitating the potential discovery of novel driver alterations. METHODS: We applied two clinical genomic platforms (OncoPanel and OncoCopy) to profile pediatric brain tumors in a clinical setting. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer causing genes, was used to assess single nucleotide variants and rearrangements/indels. OncoCopy, a high-resolution genome-wide array comparative genomic hybridization (aCGH) assay, was used to evaluate copy number alterations and refine rearrangement breakpoints. RESULTS: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes including 117 analyzed by OncoPanel, 146 by OncoCopy, and 60 evaluated using both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. EWSRa rearrangements were observed unexpectedly in two patients; one with a Atypical Teratoid Rhabdoid Tumor with loss of INI-1 (SMARCB1), and the second in an ependymoma. Whole Genome Sequencing of the rhabdoid tumor confirmed a rearrangement involving EWSR1 and PLAGL1.CONCLUSIONS: The combined deployment of OncoPanel and OncoCopy multiplex genomic assays can identify clinically relevant genomic alterations in pediatric brain tumors and facilitate the discovery of novel driver alterations. *equal contribution

Ganglioglioma is a rare central nervous system neoplasm representing 0.4% to 1.7% of all brain tumors and most frequently occurs in the pediatric population with an incidence of 7.6%. These tumors are usually slow-growing and well-circumscribed solid or cystic lesions. Gangliogliomatosis infrequently occurs in the frontal lobe, pineal gland, basal ganglia, hypothalamus, and optic chiasm, with very few reports of brainstem ganglioglioma. We report a case of a 35-year-old female who initially presented with headache, vertigo, ataxia, saccadic dysfunction, dysarthria, and dysmetria for several years due to an unknown etiology. Her brain imaging showed multiple lesions in the pons and the cerebellum with cystic changes and size reduction and enlargement over the next few years while her neurological symptoms continued to worsen. The patient received courses of steroid treatment that improved her neurological symptoms, suggesting an inflammatory component of her disease. Extensive workup for an inflammatory or infectious etiology was unfruitful and two brain biopsies were inconclusive. A third biopsy showed atypical glial nuclei, binucleated cells, and Rosenthal fibers and the presence of BRAF V600E mutation was detected. The diagnosis of gangliogliomatosis was consequently established. This case illustrates that gangliogliomatosis may present with the waxing-and-waning neurological signs and symptoms. It can masquerade inflammatory processes in the central nervous system on brain imaging and deserves careful consideration in the diagnosis of patients with an indolent course of neurological deterioration.

The biological markers for schizophrenia (SZ) and bipolar disorder (BD) would represent a precious tool in evaluating the risk for the development of these common neuropsychiatric diseases and, possibly, in the prevention of either disease episodes and/or treatment efficiency monitoring. Since both SZ and BD are diseases with a significant genetic component, the research over the last decades has focused on the genes with altered function in the central nervous system (CNS) of individuals suffering from these illnesses. Recently, however, small non-coding RNA molecules (microRNAs, miRNAs, miRs) were shown to regulate the expression of human CNS genes involved in cell processes and functions negatively affected in neuropsychiatric disorders, including synaptic development and maturation, learning and memory. Differentially expressed sets of miRNAs have been reported in the tissues of SZ and BD patients in comparison to controls suggesting the emergence of a novel class of potential biomarkers. Here we review the reports on the changes in miRNA expression in postmortem brain tissue and peripheral blood in SZ and BD. We also evaluate the potential of miRNA packaged in exosomes, signaling vesicles released by neurons and glia, to contribute to the disaggregation of the molecular machinery underlying mental disorders and provide clinically useful biomarkers.

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer’s disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology., National Institutes of Health (U.S.) (Grant R01 NS051874), National Institutes of Health (U.S.) (Grant F31GM80055-03), Howard Hughes Medical Institute

Case presentationA 42-year-old man presented with a 9-month history ofprogressive numbness and paresthesias involving theupper limbs. His symptoms started at the fourth and fifthdigits of both arms, and ascended to involve the elbows.Within several weeks, the lower limbs became involvedwith the numbness and pain starting at the toes andprogressing up to mid thorax. He had no bowel or bladderinvolvement. His examination showed no stigmata ofsystemic disease. He had minimal weakness at hip flex-ion, upper motor neuron signs in all limbs, decreasedsensation in C8 distribution bilaterally, and a sensorylevel at T4 sparing proprioception. Magnetic resonanceimaging (MRI) of the spinal cord 6 and 9 months(September 2006, December 2006) after symptom onsetrevealed T2 prolongation and cord edema (Fig. 1a, c)with an 8 mm enhancing intramedullary lesion at the C5-6 (Fig. 1b, d). The possibility of demyelinating diseasewas considered. Thoracic and brain MRI where unre-markable. Further workup included cerebrospinal fluid(CSF) which revealed leukocytosis of 13 with 88% lym-phocytic predominance, protein of 310 mg/dl, normalglucose and two oligoclonal bands not present in a cor-responding serum sample. The patient continued todevelop progressive neurological deficits that did notrespond to treatment with 5 days of 1 g intravenousMethylprednisolone. Repeated CSF exam showed persis-tence of protein elevation (289 mg/dl), normalization ofleukocytosis and absence of oligoclonal bands. Bothexaminations showed normal cytology. Anti nuclearantibodies (ANA), Lyme serology, angiotensin convertingenzyme (ACE), HTLV-1 serology, B12 level, anti-neutr-ophilic cytoplasmic antibodies (ANCA) were all normal.CT scans of the chest, abdomen and pelvis excludedoccult malignancy and lymphadenopathy. Magnetic reso-nance angiography (MRA) and spinal angiogram showednormal cerebral and spinal vasculature. Repeated spineMRI (February 2007, July 2007) showed mildly increas-ing edema at the site of cervical spinal cord lesion, butstable lesion size and unchanged enhancement pattern.Differential diagnosis included a neoplastic process due tothe persistent duration of enhancement, the elevated pro-tein in the CSF, and absence of clinical or radiographicimprovement after treatment with intravenous steroids.As the etiology of the lesion was not clear preopera-tively, i.e. intramedullary neoplasm or ischemia fromstenosis, the patient underwent C4-T1 decompression,posterior spinal fusion, posterior laminectomy, and intra-dural subtotal mass resection. Intraoperatively the surfaceof the cord and the vasculature looked normal. The cord

The subplate and marginal zone are prominent transient zones of the developing cerebral wall and contain a variety of neuropeptide Y-immunoreactive (NPY-ir) cells. This study investigates morphological maturation as well as regression and/or transformation of NPY-ir neurons in the transient compartments and the cortical plate of the human frontal cortex. The most prominent NPY-ir neuronal population is that of NPY-ir subplate neurons. They exhibited features of all subplate neuronal types reported in Golgi-impregnated sections, with the exception of the pyramidal type. The NPY-ir subplate neurons were the largest of all NPY-ir neurons, but their size regressed rather sharply between 1 month after birth and 2 years. In the NPY-ir subplate neurons and in the NPY-ir Cajal-Retzius cells of the marginal zone, signs of degeneration were observed between 36 postovulatory weeks and about 9 months after birth. Only a few subpial granular layer cells were NPY positive, and they exhibited degeneration-like features, such as cytoplasmic vacuolization, as early as 23 postovulatory weeks. However, NPY-ir neurons continued to be present in the adult counterparts of the subplate and marginal zone, i.e., gyral white matter and layer I, respectively. Across cortical layers II-VI, NPY-ir neurons had the hallmarks of all aspinous short-axon types, with the exception of the neurogliaform and the chandelier neuronal types. Some signs of degeneration were also observed among a few cortical NPY-ir neurons around birth. Unlike the NPY-ir subplate neurons, the general development of cortical NPY-ir neurons did not show an obvious decline in neuronal size and was similar to the pattern in Golgi-staining. J. Comp. Neurol. 379:523–540, 1997. © 1997 Wiley-Liss, Inc.

The protein p35 is a regulatory subunit of cyclin-dependent kinase 5. It has no recognized homology to cyclins but binds to and activates cyclin-dependent kinase 5 directly in the absence of other protein molecules. Cyclin-dependent kinase 5 was initially isolated by homology to the key cell cycle regulator cdc2 kinase and later identified as a neuronal kinase that phosphorylates histone H1, tau or neurofilaments. This kinase is localized in axons of the developing and mature nervous system. To understand the role of p35 as a regulator of cyclin-dependent kinase 5 activity in the CNS, we examined the pattern of expression of p35 mRNA in the nervous system of embryonic, early postnatal and adult mice. In separate experiments, we also examined the spatial distribution of cyclin-dependent kinase 5 mRNA and the activity of cyclin-dependent kinase 5/p35 kinase complex. Postmitotic cells express p35 mRNA immediately after they leave the zones of cell proliferation. It is also expressed in developing axonal tracts in the brain. Cyclin-dependent kinase 5 mRNA is present in postmitotic and in proliferative cells throughout the embryonic central nervous system. During early postnatal period signal for p35 mRNA declines while that for cyclin-dependent kinase 5 mRNA increases throughout the brain. In the adult brain although both p35 and cyclin-dependent kinase 5 mRNAs are expressed at relatively high levels in certain structures associated with the limbic system, considerable differences exist in the patterns of their distribution in other parts of the brain. These data suggest that the p35/cyclin-dependent kinase 5 complex may be associated with early events of neuronal development such as neuronal migration and axonal growth while in the limbic system of the mature brain it may be associated with the maintenance of neuronal plasticity.

Brain reserve refers to the ability of the brain to tolerate pathological changes such as those seen in AD before manifesting clinical signs and symptoms [1-3]. Neurotrophic factors (NTFs), most notably Brain Derived Neurotrophic Factor (BDNF) and its receptor Tyrosine kinase B (TrkB), regulate synaptic plasticity and functional efficiency in adulthood [4-6] and thus may influence brain reserve. BDNF/TrkB signaling affects memory formation and retention [7,8], determines neurite length [9,10], and governs regeneration upon neuronal injury [11,12] by modifying neuronal cytoskeleton. Abnormalities in the neuronal cytoskeleton are well documented in AD. However, how these abnormalities affect AD progression remains unclear. In Drosophila, neurodegeneration stems directly from mutations in alpha and beta subunits of the actin capping protein (CP), demonstrating that a mutation in a gene encoding an actin cytoskeleton regulator can lead to demise of neurons [13]. Further, a causative role for actin cytoskeleton abnormalities in neurotoxicity has been documented in a Drosophila tauopathy model [14].

Hiccups are reflexive involuntary contractions of the respiatory muscles followed very early by sudden closure of the lottis. While common in the fetal stages of life they are usually enign, short-lived, self-limited and very commonly overlooked in dults. Rarely, hiccups can indicate significant neurologic disease 1]. Here, we present a case of a patient presenting with 3 years f intractable hiccups and a single medullary cavernous malforation whose symptoms resolved after resection of the lesion. We hen discuss the available literature for medullary cavernomas preenting with hiccups and how surgical resection relieves symptoms ikely by compromising the vagal activity.

We review here a computational model of neocortical histogenesis based upon experiments in the developing cerebral wall of the mouse. Though based upon experiments in mouse, commonalities of developmental history and structure of neocortex across mammalian species suggest that the principles which support this model will be generally applicable to neocortical evolution and development across species. In its scope the model spans the successive histogenetic events: cell proliferation, cell migration, and the positioning of cell somata in neocortical layers following migration. Neurons are produced in a pseudostratified epithelium (PVE) which lines the ventricular cavaties of the embryonic cerebrum. The parameters which determine the rate and total number of neurons produced in the PVE are (1) the size of the founder population, (2) the number of integer cell cycles executed by the founder population and its progeny in the course of the neuronogenetic interval, (3) the growth fraction, and (4) the fraction of cells which exits the cycle (Q fraction) with each integer cycle. There is a systematic relationship between the integer cycle of origin and the sequence of cell migration, position in the cortex, and the extent to which a set of postmigratory neurons will be diluted in the cortex by the combined effects of tissue growth and cell death. Variation across species in the number of integer cell cycles as a function of the rate of progression of Q may be expected to modulate profoundly the total numbers of neurons that are produced but not the relative proportions of neurons assigned to the major neocortical layers.

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein β2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease [superscript 1]. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge [superscript 2]. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade., Stanley Medical Research Institute, National Institute of Neurological Disorders and Stroke (U.S.) (RO1NS078839), Swiss National Science Foundation, Bard Richmond (Fellowship), Simons Foundation, Theodor und Ida Herzog-Egli Foundation

Central neurocytomas (CN) are benign central nervous system (CNS) tumors of neuroglial origin that represent 0.25 to 0.5% of all intracranial tumors in adults and an even smaller proportion of pediatric CNS tumors. These tumors characteristically occur in the subependymal layer of the lateral ventricle near the foramen of Monro and appear as sharply demarcated, solitary lesions. Surgical resection is considered curative, as the reported recurrence rate is less than 5% for patients with localized disease. In this report, we describe the case of a three-year-old boy with a diffuse CN with craniospinal dissemination identified at the time of diagnosis. Given the extensive nature of the disease, surgical resection was not indicated and he underwent a chemotherapeutic regimen of vincristine and carboplatin. At 18 months followup, the patient has completed 6 of 8 total cycles of vincristine and carboplatin and serial imaging shows stable disease within the craniospinal axis.