Neuroscience

Neural repair: Tagging mRNA drives regeneration

Nature Rev. Neurosc. - 8 February 2018 - 12:00am

Neural repair: Tagging mRNA drives regeneration

Neural repair: Tagging mRNA drives regeneration, Published online: 08 February 2018; doi:10.1038/nrn.2018.14

A dynamic mRNA modification promotes axon regeneration in injured peripheral sensory neurons.
Categories: Neuroscience

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

Nature Rev. Neurosc. - 8 February 2018 - 12:00am

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential, Published online: 08 February 2018; doi:10.1038/nrn.2018.2

The changes in spinal cord excitability proposed to drive neuropathic pain have been linked to alterations in microglial function. Inoue and Tsuda describe our current understanding of the molecular mechanisms involved and consider implications for therapeutic approaches to chronic pain.
Categories: Neuroscience

High complement levels in astrocyte-derived exosomes of Alzheimer's disease

Annals of Neurology - 6 February 2018 - 4:50pm
Abstract

Objective: Astrocytes fulfill neuronal trophic roles normally, but are transformed in Alzheimer's disease (AD) into A1-type reactive astrocytes that may destroy neurons through unknown mechanisms. Methods: To investigate astrocyte inflammatory mechanisms, astrocyte-derived exosomes (ADEs) were isolated immunochemically from plasmas of AD patients and matched controls for ELISA quantification of complement proteins. Results: ADE levels of C1q, C4b, C3d, factor B, factor D, Bb, C3b and C5b-C9 terminal complement complex (TCC), but not mannose-binding lectin (MBL), normalized by the CD81 exosome marker were significantly higher for AD patients (n=28) than age- and gender-matched controls (all p<0.0001). ADE normalized levels of IL-6, TNF-α and IL-1β were significantly higher for AD patients than controls, but there was greater overlap between the two groups than for complement proteins. Mean ADE levels of complement proteins for AD patients in a longitudinal study were significantly higher (n=16, p<0.0001) at the AD2 stage of moderate dementia than at the AD1 preclinical stage five to 12 years earlier, which were the same as for controls. ADE levels of complement regulatory proteins CD59, CD46, decay-accelerating factor (DAF) and complement receptor type 1 (CR1), but not factor I, were significantly lower for AD patients than controls (p<0.0001 for CD59 and DAF), were diminished by the AD1 stage and were further decreased at the AD2 stage. Interpretation: ADE complement effector proteins in AD are produced by dysregulated systems, attain higher levels than in controls, and may potentially damage neurons in the late inflammatory phase of AD. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

N-methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications

Annals of Neurology - 6 February 2018 - 4:50pm
Abstract

Introduction

N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is mediated by IgG-autoantibodies directed against the NR1-subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown.

Methods

Clinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from ten patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these ten patients, and two available ovarian teratomas, were stimulated with combinations of immune factors, and tested for secretion of total IgG and NR1-antibodies.

Results

In addition to disease-defining NR1-IgG, serum NR1-IgM were found in 6/10 patients. NR1-IgM levels were typically highest around disease onset, and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody-secreting cells in vitro and, in 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p<0.0001) and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1-IgG in culture.

Interpretation

Persistent serum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest ongoing germinal center-reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

Annals of Neurology - 5 February 2018 - 5:30pm
Abstract

Objective: Huntington's disease (HD) gene-carriers can be identified prior to clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real-life clinical diagnosis in HD.

Method: A multivariate machine learning approach was applied to resting-state and structural MRI scans from 19 pre-manifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years post-scanning) and 21 healthy controls. A classification model was developed using cross-group comparisons between preHD and controls, and within the preHD group in relation to “estimated” and “actual” proximity to disease onset. Imaging measures were modelled individually, and combined, and permutation modelling robustly tested classification accuracy.

Results: Classification performance for preHDs vs. controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy including those who were not expected to manifest in that timescale based on the currently adopted statistical models.

Interpretation: We propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of Huntington's disease, with implications for prognostication and preclinical trials. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Orthostatic Heart Rate Changes in Patients with Autonomic Failure caused by Neurodegenerative Synucleinopathies

Annals of Neurology - 5 February 2018 - 4:50pm
ABSTRACT

Objective: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.

Methods: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation.

Results: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p<0.0001] but only one third of the increase in HR than those with non-neurogenic OH (8±8 vs. 25±11 bpm, p<0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic vs. non-neurogenic OH (AUC=0.96, p<0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p=0.0003), but there was considerable overlap with patients with Lewy body disorders.

Interpretation: A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg is diagnostic of neurogenic OH. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes

Nature Neuroscience - 5 February 2018 - 12:00am

Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes

Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes, Published online: 05 February 2018; doi:10.1038/s41593-018-0075-7

Direct neuronal conversion of skin fibroblasts from individuals with Huntington’s disease (HD) generates a population of medium spiny neurons that recapitulate hallmarks of HD, including aggregation of mutant huntingtin protein, DNA damage and spontaneous cell death.
Categories: Neuroscience

Studying individual differences in human adolescent brain development

Nature Neuroscience - 5 February 2018 - 12:00am

Studying individual differences in human adolescent brain development

Studying individual differences in human adolescent brain development, Published online: 05 February 2018; doi:10.1038/s41593-018-0078-4

Research in adolescent neurocognitive development has focussed largely on averages, but there is substantial individual variation in development. This Perspective proposes that the field should move towards studying individual differences.
Categories: Neuroscience

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear

Nature Neuroscience - 5 February 2018 - 12:00am

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear, Published online: 05 February 2018; doi:10.1038/s41593-018-0073-9

Neurons in the ventral hippocampus project to parvalbumin inhibitory interneurons in the infralimbic (IL) region of medial prefrontal cortex. Activation of this projection produces feed-forward inhibition of IL and causes relapse of extinguished fear.
Categories: Neuroscience

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals

Nature Neuroscience - 5 February 2018 - 12:00am

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals, Published online: 05 February 2018; doi:10.1038/s41593-018-0070-z

Using longitudinal multimodal imaging data collected in healthy older individuals, Jacobs et al. provide in vivo evidence in humans that amyloid deposition facilitates tau spread along connected pathways and memory decline.
Categories: Neuroscience

Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness

Nature Neuroscience - 5 February 2018 - 12:00am

Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness

Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness, Published online: 05 February 2018; doi:10.1038/s41593-018-0074-8

The authors show that Mrgprs, vagal sensory neuron-expressing GPCRs, mediate bronchoconstriction and hyperresponsiveness, both of which are hallmark features of asthma. The results reveal novel potential neural mechanisms underlying asthma.
Categories: Neuroscience

Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease

Nature Neuroscience - 5 February 2018 - 12:00am

Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease

Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease, Published online: 05 February 2018; doi:10.1038/s41593-018-0080-x

The key driver of early-stage Alzheimer’s pathophysiology remains controversial. Styr and Slutsky propose that failures in firing homeostasis and imbalance between stability and plasticity represent the driving force of early disease progression.
Categories: Neuroscience

CRISPR interference-based specific and efficient gene inactivation in the brain

Nature Neuroscience - 5 February 2018 - 12:00am

CRISPR interference-based specific and efficient gene inactivation in the brain

CRISPR interference-based specific and efficient gene inactivation in the brain, Published online: 05 February 2018; doi:10.1038/s41593-018-0077-5

CRISPR interference-based gene silencing was adopted to achieve highly efficient multiple and conditional gene knockdown in the mouse brain with negligible off-target effects, providing a rapid gene interrogation tool in the mammalian brain.
Categories: Neuroscience

Activation of pial and dural macrophages and dendritic cells by CSD (67 chrs)

Annals of Neurology - 3 February 2018 - 12:00am
Abstract

Objective:

Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when.

Methods:

Investigating cellular events in the meninges shortly after CSD, we used in-vivo 2-photon imaging to identify changes in macrophages and dendritic cells (DC) that reside in the pia, arachnoid, and dura, and their anatomical relationship to TRPV1 axons.

Results:

We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DC stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid and dural DC 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DC can appear in close proximity to TRPV1-positive axons.

Interpretation:

The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20-30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DC in the SAS and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and dendritic cells support a role for these immune cells in the modulation of head pain. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage

Annals of Neurology - 2 February 2018 - 11:57pm
Abstract

Objective:

Information about Rivaroxaban plasma levels (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.

Methods:

In a multicenter registry-based study (Novel-Oral-Anticoagulants-In-Stroke-Patients collaboration;NOACISP;ClinicalTrials.gov:NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS-patients had RivLev≤100ng/ml, indicating possible eligibility for thrombolysis and how many ICH-patients had RivLev≥75ng/ml, possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation; regression models) and studied the sensitivity and specificity of INR-thresholds to substitute RivLevs using cross tables and ROC curves.

Results:

Among 241 patients (median age 80 years[IQR73-84], median time-from-onset-to-admission 2 hours[IQR1-4.5hours], median RivLev 89ng/ml[31-194]), 190 had AIS and 51 had ICH. RivLev were similar in AIS-patients (82ng/ml[IQR30-202] and ICH-patients (102ng/ml[IQR 51-165]; p=0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS- and 34/51 (66.7%) ICH-patients. Among AIS-patients, 108/190 (56.8%) had RivLev≤100ng/ml. In ICH-patients 33/51(64.7%) had RivLev≥75ng/ml. RivLev were associated with rivaroxaban dosage, inversely with renal function and time-since-last-intake (each p<.05). INR≤1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev≤100ng/ml. INR≥1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev≥75ng/ml.

Interpretation:

RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under Rivaroxaban had RivLev low enough to consider thrombolysis. In ICH-patients, 2/3 had RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR-thresholds perform poor to inform treatment decisions in individual patients. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Sleep and Cognitive Decline: A Prospective Non-demented Elderly Cohort Study

Annals of Neurology - 2 February 2018 - 11:56pm
Abstract

Objective: To investigate sleep disturbances that induce cognitive changes over four years in non-demented elderlies.

Methods: Data were acquired from a nationwide, population-based, prospective cohort of Korean elderlies (2,238 normal cognition [NC] and 655 mild cognitive impairment [MCI]). At baseline and 4-year follow up assessments, sleep-related parameters (mid-sleep time, sleep duration, latency, subjective quality, efficiency and daytime dysfunction) and cognitive status were measured using Pittsburgh Sleep Quality Index and Consortium to Establish a Registry for Alzheimer's Disease Assessment, respectively. We used logistic regression models adjusted for covariates including age, sex, education, apolipoprotein E genotype, Geriatric Depression Scale, Cumulative Illness Rating Scale, and physical activity.

Results: In participants with NC, long sleep latency (> 30 min), long sleep duration (≥ 7.95 hr), and late mid-sleep time (after 3:00AM) at baseline were related to the risk of cognitive decline at 4-year follow-up assessment; odds ratio (OR) was 1.40 for long sleep latency, 1.67 for long sleep duration, and 0.61 for late mid-sleep time. These relationships remained significant when these variables maintained their status throughout the follow-up period. Newly developed long sleep latency also doubled the risk of cognitive decline. In those with MCI, however, only long sleep latency reduced the chance of reversion to NC (OR = 0.69).

Interpretation: As early markers of cognitive decline, long sleep latency can be used for elderlies with NC or MCI, while long sleep duration and relatively early sleep time might be used for cognitively normal elderlies only. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Mutations in MICAL-1 cause autosomal dominant lateral temporal epilepsy

Annals of Neurology - 2 February 2018 - 11:56pm
Abstract

Objective: Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder.

Methods: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single nucleotide polymorphism-array linkage analysis.

Results: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain, and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics.

Interpretation: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Increase of HCN current in the aberrant excitability of spinal muscular atrophy

Annals of Neurology - 2 February 2018 - 11:56pm
Abstract

Objective

The pathophysiology of spinal muscular atrophy (SMA) is still unclear.

Methods

The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, Western blotting and whole-cell patch-clamp recording were used for the identified hypothesis.

Results

The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold relationship was reproducible in a mouse model of mild SMA and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and Western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in the SMA mice, and voltage-clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA.

Interpretation

This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN-target for SMA therapy. This article is protected by copyright. All rights reserved.

Categories: Neuroscience

Cortical Perception

Annals of Neurology - 2 February 2018 - 11:55pm
Categories: Neuroscience

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