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盘点2017年神经科学和神经病学的二十大重磅研究

已有 4174 次阅读 2018-1-4 17:52 |个人分类:神经科学临床和基础|系统分类:观点评述

1、研究发现人类胚胎发生和神经发生阶段的突变率高于成年时期。

Science. 2017Dec 7. pii: eaan8690. doi: 10.1126/science.aan8690. [Epub ahead of print]

Different mutational rates and mechanisms in humancells at pregastrulation and neurogenesis.

Abstract

Somatic mosaicism in the human brain may alterfunction of individual neurons. We analyzed genomes of single cells from theforebrains of three human fetuses (15 to 21 weeks post-conception) usingclonal cell populations. We detected 200-400 single nucleotidevariations (SNVs) per cell. SNV patterns resembled those found incancer cell genomes, indicating a role of background mutagenesis incancer. SNVs with a frequency of >2% in brain were shared with thespleen, revealing a pregastrulation origin. Wereconstructed cell lineages for the first five post-zygotic cleavagesand calculated a mutation rate of ~1.3 per division per cell. Later indevelopment, during neurogenesis, the mutation spectrum shifted towardoxidative damage and the mutation rate increased. Both neurogenesis and earlyembryogenesis exhibit drastically more mutagenesis than adulthood.

2、科学家勾画人类大脑基因表达图谱。

Science. 2017Nov 24;358(6366):1027-1032. doi: 10.1126/science.aan3456.

Molecular and cellular reorganization of neuralcircuits in the human lineage.

Abstract

To better understand the molecular and cellulardifferences in brain organization between human and nonhumanprimates, we performed transcriptome sequencing of 16 regions of adult human,chimpanzee, and macaque brains. Integration with humansingle-cell transcriptomic data revealed global, regional,and cell-type-specific species expression differences in genesrepresenting distinct functional categories. We validated and furthercharacterized the human specificity of genes enriched indistinct cell types through histological and functional analyses,including rare subpallial-derived interneurons expressing dopamine biosynthesisgenes enriched in the human striatum and absent in the nonhuman African apeneocortex. Our integrated analysis of the generated data revealed diversemolecular and cellular features of the phylogenetic reorganization of thehuman brain across multiple levels, with relevanceforbrain function and disease.

3、中枢神经系统胶质细胞-神经元间信号通路参与调控衰老过程

Nature. 2017 Nov 8;551(7679):198-203. doi:10.1038/nature24463.

Genetic variation in glia-neuron signalling modulatesageing rate.

Abstract

The rate of behavioural decline in the ageing populationis remarkably variable among individuals. Despite the considerable interest instudying natural variation in ageing rate to identify factors that controlhealthy ageing, no such factor has yet been found. Here we report a geneticbasis for variation in ageing rates in Caenorhabditis elegans. We find that C.elegans isolates show diverse lifespan and age-related declines in virility,pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-codinggene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and theneuropeptide receptor gene npr-28 influence the rate of age-related decline ofworm mating behaviour; these two genes might have been subjected to recentselective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which actsin serotonergic and dopaminergic neurons to accelerate behaviouraldeterioration. This signalling involves the SIR-2.1-dependent activation of themitochondrial unfolded protein response, a pathway that modulates ageing. Thus,natural variation in neuropeptide-mediated glia-neuron signalling modulates therate of ageing in C. elegans.

4、癫痫术后脑病理学检查揭示难治性癫痫最常见的病因

N EnglJ Med. 2017 Oct26;377(17):1648-1656. doi: 10.1056/NEJMoa1703784.

Histopathological Findings in Brain TissueObtained during Epilepsy Surgery.

Abstract

BACKGROUND:

Detailed neuropathological information on the structural brain lesions underlying seizures isvaluable for understanding drug-resistant focal epilepsy.

METHODS:

We report the diagnoses made on the basis of resected brain specimens from 9523 patients whounderwent epilepsy surgery for drug-resistant seizures in 36 centers from 12European countries over 25 years. Histopathological diagnoses were determinedthrough examination of the specimens in local hospitals (41%) or at the GermanNeuropathology Reference Center for Epilepsy Surgery (59%).

RESULTS:

The onset of seizures occurred before 18 years of age in 75.9% ofpatients overall, and 72.5% of the patients underwent surgery as adults. Themean duration of epilepsy before surgical resection was 20.1 years among adultsand 5.3 years among children. The temporal lobe was involved in 71.9% ofoperations. There were 36 histopathological diagnoses in seven major diseasecategories. The most common categories were hippocampal sclerosis, found in36.4% of the patients (88.7% of cases were in adults), tumors (mainlyganglioglioma) in 23.6%, and malformations of cortical development in 19.8%(focal cortical dysplasia was the most common type, 52.7% of cases of whichwere in children). No histopathological diagnosis could be established for 7.7%of the patients.

CONCLUSIONS:

In patients with drug-resistant focal epilepsy requiring surgery,hippocampal sclerosis was the most common histopathological diagnosis amongadults, and focal cortical dysplasia was the most common diagnosis amongchildren. Tumors were the second most common lesion in both groups. (Funded bythe European Union and others.).

5、研究发现了脑干限制性受体及其配体GDF15对体重的关键调控作用

Nature. 2017 Oct 12;550(7675):255-259. doi:10.1038/nature24042. Epub 2017 Sep 27.

Non-homeostatic body weight regulation through a brainstem-restrictedreceptor for GDF15.

Abstract

Under homeostatic conditions, animals use well-definedhypothalamic neural circuits to help maintain stable body weight, byintegrating metabolic and hormonal signals from the periphery to balance foodconsumption and energy expenditure. In stressed or disease conditions, however,animals use alternative neuronal pathways to adapt to the metabolic challengesof altered energy demand. Recent studies have identified brain areas outside the hypothalamus thatare activated under these 'non-homeostatic' conditions, but the molecular nature of the peripheral signals and brain-localizedreceptors that activate these circuits remains elusive. Here we identify glial cell-derivedneurotrophic factor (GDNF) receptor alpha-like (GFRAL) as abrainstem-restricted receptor for growth and differentiation factor 15 (GDF15).GDF15 regulates food intake, energy expenditure and body weight in response tometabolic and toxin-induced stresses; we show that Gfral knockout mice arehyperphagic under stressed conditions and are resistant to chemotherapy-inducedanorexia and body weight loss. GDF15 activates GFRAL-expressing neuronslocalized exclusively in the area postrema and nucleus tractus solitarius ofthe mouse brainstem. It then triggers the activation of neurons localizedwithin the parabrachial nucleus and central amygdala, which constitute part ofthe 'emergency circuit' that shapes feeding responses to stressful conditions.GDF15 levels increase in response to tissue stress and injury, and elevatedlevels are associated with body weight loss in numerous chronic human diseases.By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss,we identify a mechanistic basis for the non-homeostatic regulation of neuralcircuitry by a peripheral signal associated with tissue damage and stress.These findings provide opportunities to develop therapeutic agents for thetreatment of disorders with altered energy demand.

6.1、研究发现孕母免疫系统激活和后代大脑功能及行为异常相关,并揭示了其神经免疫机制基础。

Nature. 2017 Sep 28;549(7673):528-532. doi:10.1038/nature23910. Epub 2017 Sep 13.

Maternal gut bacteria promote neurodevelopmental abnormalities inmouse offspring.

Abstract

Maternal immune activation (MIA) contributes to behaviouralabnormalities associated with neurodevelopmental disorders in both primate androdent offspring. In humans, epidemiological studies suggest that exposure offetuses to maternal inflammation increases the likelihood of developing autismspectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by Thelper 17 (TH17) cells (CD4+ T helper effector cells involved inmultiple inflammatory conditions) induces behavioural and corticalabnormalities in the offspring exposed to MIA. However, it is unclear whetherother maternal factors are required to promote MIA-associated phenotypes.Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a inthe maternal circulation are not well understood. Here we show that MIAphenotypes in offspring require maternal intestinal bacteria that promote TH17 celldifferentiation.Pregnant mice that had been colonized with mouse commensal segmentedfilamentous bacteria or human commensal bacteria that induce intestinal TH17cells were more likely to produce offspring with MIA-associated abnormalities.We also show that small intestine dendritic cells from pregnant, but not fromnon-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells toproduce IL-17a upon exposure to MIA. Overall, our data suggest that defined gutcommensal bacteria with a propensity to induce TH17 cells mayincrease the risk of neurodevelopmental disorders in the offspring of pregnantmothers undergoing immune system activation owing to infections orautoinflammatory syndromes.

6.2、研究发现孕母免疫系统激活和后代大脑功能及行为异常相关,并找到了相关干预方法。

Nature. 2017 Sep 28;549(7673):482-487. doi:10.1038/nature23909. Epub 2017 Sep 13.

Reversing behavioural abnormalities in mice exposed to maternalinflammation.

Abstract

Viral infection during pregnancy is correlated with increasedfrequency of neurodevelopmental disorders, and this is studied in miceprenatally subjected to maternal immune activation (MIA). We previously showedthat maternal T helper 17 cells promote the development of cortical andbehavioural abnormalities in MIA-affected offspring. Here we show that corticalabnormalities are preferentially localized to a region encompassing thedysgranular zone of the primary somatosensory cortex (S1DZ). Moreover,activation of pyramidal neurons in this cortical region was sufficient toinduce MIA-associated behavioural phenotypes in wild-type animals, whereasreduction in neural activity rescued the behavioural abnormalities in MIA-affectedoffspring. Sociability and repetitive behavioural phenotypes could beselectively modulated according to the efferent targets of S1DZ. Our workidentifies a cortical region primarily, if not exclusively, centred on the S1DZas the major node of a neural network that mediates behavioural abnormalitiesobserved in offspring exposed to maternal inflammation.

7、研究发现不定带Lhx6阳性GABA能神经元具有睡眠促进作用。

Nature. 2017 Aug 31;548(7669):582-587. doi:10.1038/nature23663. Epub 2017 Aug 23.

Lhx6-positive GABA-releasing neurons of the zonaincerta promote sleep.

Abstract

Multiple populations of wake-promoting neurons have beencharacterized in mammals, but few sleep-promoting neurons have been identified.Wake-promoting cell types include hypocretin and GABA(γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, whichpromote the transition to wakefulness from non-rapid eye movement (NREM) andrapid eye movement (REM) sleep. Here we show that a subset of GABAergic neuronsin the mouse ventral zona incerta, which express the LIM homeodomain factorLhx6 and are activated by sleep pressure, both directly inhibit wake-activehypocretin and GABAergic cells in the lateral hypothalamus and receive inputsfrom multiple sleep-wake-regulating neurons. Conditional deletion of Lhx6 fromthe developing diencephalon leads to decreases in both NREM and REM sleep.Furthermore, selective activation and inhibition of Lhx6-positive neurons inthe ventral zona incerta bidirectionally regulate sleep time in adult mice, inpart through hypocretin-dependent mechanisms. These studies identify aGABAergic subpopulation of neurons in the ventral zona incerta that promotesleep.

8、研究发现哺乳动物环状RNA缺失可引起miRNA调控和大脑功能异常

Science. 2017Sep 22;357(6357). pii: eaam8526. doi: 10.1126/science.aam8526.Epub 2017 Aug 10.

Loss of a mammalian circular RNA locus causes miRNA deregulationand affects brain function.

Abstract

Hundreds of circular RNAs (circRNAs) are highly abundant in themammalian brain,often with conserved expression. Here we show that the circRNA Cdr1as ismassively bound by the microRNAs (miRNAs) miR-7 and miR-671 in human and mousebrains. When theCdr1as locuswas removed from the mouse genome, knockout animals displayed impairedsensorimotor gating-a deficit in the ability to filter out unnecessaryinformation-which is associated with neuropsychiatric disorders.Electrophysiological recordings revealed dysfunctional synaptic transmission.Expression of miR-7 and miR-671 was specifically and posttranscriptionallymisregulated in allbrain regions analyzed. Expression ofimmediate early genes such as Fos,a direct miR-7 target, was enhanced in Cdr1as-deficientbrains, providing a possible molecular link to the behavioral phenotype. Ourdata indicate an in vivo loss-of-function circRNA phenotype and suggest thatinteractions between Cdr1as and miRNAs are important for normal brain function.

9、研究首次勾画昆虫大脑学习和记忆的脑连接组图谱。

Nature. 2017 Aug 9;548(7666):175-182. doi:10.1038/nature23455.

The complete connectome of a learning and memory centre in aninsect brain.

Abstract

Associating stimuli with positive or negative reinforcement isessential for survival, but a complete wiring diagram of a higher-order circuitsupporting associative memory has not been previously available. Here wereconstruct one such circuit at synaptic resolution, the Drosophila larvalmushroom body. We find that most Kenyon cells integrate random combinations ofinputs but that a subset receives stereotyped inputs from single projectionneurons. This organization maximizes performance of a model output neuron on astimulus discrimination task. We also report a novel canonical circuit in eachmushroom body compartment with previously unidentified connections: reciprocalKenyon cell to modulatory neuron connections,modulatory neuron to output neuron connections, and a surprisingly high numberof recurrent connections between Kenyon cells. Stereotyped connections foundbetween output neurons could enhance the selection of learned behaviours. Thecomplete circuit map of the mushroom body should guide future functionalstudies of this learning and memory centre.

10、研究发现非侵袭性深部脑刺激技术助力神经科学研究和临床治疗。

Cell. 2017 Jun 1;169(6):1029-1041.e16.doi: 10.1016/j.cell.2017.05.024.

Noninvasive Deep Brain Stimulation viaTemporally Interfering Electric Fields.

Abstract

We report a noninvasive strategy forelectrically stimulating neurons at depth. By delivering to the brain multipleelectric fields at frequencies too high to recruit neural firing, but whichdiffer by a frequency within the dynamic range of neural firing, we canelectrically stimulate neurons throughout a region where interference betweenthe multiple fields results in a prominent electric field envelope modulated atthe difference frequency. We validated this temporal interference (TI) conceptvia modeling and physics experiments, and verified that neurons in the livingmouse brain could follow the electric field envelope. We demonstrate theutility of TI stimulation by stimulating neurons in the hippocampus of livingmice without recruiting neurons of the overlying cortex. Finally, we show thatby altering the currents delivered to a set of immobile electrodes, we cansteerably evoke different motor patterns in living mice.

11、研究发现人类脐带血血浆蛋白可以提高老年小鼠的海马功能。

Nature. 2017 Apr 27;544(7651):488-492.doi: 10.1038/nature22067. Epub 2017 Apr 19.

Human umbilical cord plasma proteinsrevitalize hippocampal function in aged mice.

Abstract

Ageing drives changes in neuronal andcognitive function, the decline of which is a major feature of manyneurological disorders. The hippocampus, a brain region subserving roles ofspatial and episodic memory and learning, is sensitive to the detrimentaleffects of ageing at morphological and molecular levels. With advancing age, synapsesin various hippocampal subfields exhibit impaired long-term potentiation, anelectrophysiological correlate of learning and memory. At the molecular level,immediate early genes are among the synaptic plasticity genes that are bothinduced by long-term potentiation and downregulated in the aged brain. Inaddition to revitalizing other aged tissues, exposure to factors in young bloodcounteracts age-related changes in these central nervous system parameters,although the identities of specific cognition-promoting factors or whether suchactivity exists in human plasma remains unknown. We hypothesized that plasma ofan early developmental stage, namely umbilical cord plasma, provides areservoir of such plasticity-promoting proteins. Here we show that human cordplasma treatment revitalizes the hippocampus and improves cognitive function inaged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-bornefactor enriched in human cord plasma, young mouse plasma, and young mousehippocampi, appears in the brain after systemic administration and increasessynaptic plasticity and hippocampal-dependent cognition in aged mice. Depletionexperiments in aged mice revealed TIMP2 to be necessary for the cognitivebenefits conferred by cord plasma. We find that systemic pools of TIMP2 arenecessary for spatial memory in young mice, while treatment of brain sliceswith TIMP2 antibody prevents long-term potentiation, arguing for previouslyunknown roles for TIMP2 in normal hippocampal function. Our findings revealthat human cord plasma contains plasticity-enhancing proteins of hightranslational value for targeting ageing- or disease-associated hippocampaldysfunction.

12、研究首次开发反义寡核苷酸药物用于治疗2型脊髓小脑共济失调

Nature. 2017 Apr 20;544(7650):362-366.doi: 10.1038/nature22044. Epub 2017 Apr 12.

Antisense oligonucleotide therapy forspinocerebellar ataxia type 2.

Abstract

There are no disease-modifying treatmentsfor adult human neurodegenerative diseases. Here we test RNA-targeted therapiesin two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomaldominant polyglutamine disease. Both models recreate the progressiveadult-onset dysfunction and degeneration of a neuronal network that are seen inpatients, including decreased firing frequency of cerebellar Purkinje cells anda decline in motor function. We developed a potential therapy directed at theATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The mostpromising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, whichresulted in delayed onset of the SCA2 phenotype. After delivery byintracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized toPurkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10weeks without microglial activation, and reduced the levels of cerebellar ATXN2.Treatment of symptomatic mice with ASO7 improved motor function compared tosaline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model,and in both mouse models it normalized protein levels of several SCA2-relatedproteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76and Fam107b. Notably, the firing frequency of Purkinje cells returned to normaleven when treatment was initiated more than 12 weeks after the onset of themotor phenotype in BAC-Q72 mice. These findings support ASOs as a promisingapproach for treating some human neurodegenerative diseases.

13、研究首次揭示记忆巩固的印记和环路基础。

Science. 2017 Apr 7;356(6333):73-78. doi:10.1126/science.aam6808.

Engrams and circuits crucial for systemsconsolidation of a memory.

Kitamura T1, Ogawa SK1, Roy DS1, OkuyamaT1, Morrissey MD1, Smith LM1, Redondo RL1,2, Tonegawa S3,2.

Author information

Abstract

Episodic memories initially require rapidsynaptic plasticity within the hippocampus for their formation and aregradually consolidated in neocortical networks for permanent storage. However,the engrams and circuits that support neocortical memory consolidation havethus far been unknown. We found that neocortical prefrontal memory engramcells, which are critical for remote contextual fear memory, were rapidlygenerated during initial learning through inputs from both the hippocampal-entorhinalcortex network and the basolateral amygdala. After their generation, theprefrontal engram cells, with support from hippocampal memory engram cells,became functionally mature with time. Whereas hippocampal engram cellsgradually became silent with time, engram cells in the basolateral amygdala,which were necessary for fear memory, were maintained. Our data provide newinsights into the functional reorganization of engrams and circuits underlyingsystems consolidation of memory.

14、研究表明重叠记忆神经元是记忆片段连接而非回想的基础。

Science. 2017 Jan 27;355(6323):398-403.doi: 10.1126/science.aal2690.

Overlapping memory trace indispensable forlinking, but not recalling, individual memories.

Abstract

Memories are not stored in isolation fromother memories but are integrated into associative networks. However, themechanisms underlying memory association remain elusive. Using twoamygdala-dependent behavioral paradigms-conditioned taste aversion (CTA) andauditory-cued fear conditioning (AFC)-in mice, we found that presenting theconditioned stimulus used for the CTA task triggered the conditioned responseof the AFC task after natural coreactivation of the memories. This wasaccompanied through an increase in the overlapping neuronal ensemble in thebasolateral amygdala. Silencing of the overlapping ensemble suppressed CTAretrieval-induced freezing. However, retrieval of the original CTA or AFC memorywas not affected. A small population of coshared neurons thus mediates the linkbetween memories. They are not necessary for recalling individual memories.

15、集中性语言训练对治疗卒中后慢性失语有效。

Lancet. 2017 Apr 15;389(10078):1528-1538. Intensivespeech and language therapy in patients with chronic aphasia after stroke: arandomised, open-label, blinded-endpoint, controlled trial in a health-caresetting.

Abstract

BACKGROUND:

Treatment guidelines for aphasia recommendintensive speech and language therapy for chronic (≥6 months) aphasia afterstroke, but large-scale, class 1 randomised controlled trials on treatmenteffectiveness are scarce. We aimed to examine whether 3 weeks of intensivespeech and language therapy under routine clinical conditions improved verbalcommunication in daily-life situations in people with chronic aphasia afterstroke.

METHODS:

In this multicentre, parallel group,superiority, open-label, blinded-endpoint, randomised controlled trial,patients aged 70 years or younger with aphasia after stroke lasting for 6months or more were recruited from 19 inpatient or outpatient rehabilitationcentres in Germany. An external biostatistician used a computer-generatedpermuted block randomisation method, stratified by treatment centre, torandomly assign participants to either 3 weeks or more of intensive speech andlanguage therapy (≥10 h per week) or 3 weeks deferral of intensive speech andlanguage therapy. The primary endpoint was between-group difference in thechange in verbal communication effectiveness in everyday life scenarios(Amsterdam-Nijmegen Everyday Language Test A-scale) from baseline toimmediately after 3 weeks of treatment or treatment deferral. All analyses weredone using the modified intention-to-treat population (those who received 1 dayor more of intensive treatment or treatment deferral). This study is registeredwith ClinicalTrials.gov, number NCT01540383.

FINDINGS:

We randomly assigned 158 patients betweenApril 1, 2012, and May 31, 2014. The modified intention-to-treat populationcomprised 156 patients (78 per group). Verbal communication was significantlyimproved from baseline to after intensive speech and language treatment (meandifference 2·61 points [SD 4·94]; 95% CI 1·49 to 3·72), but not from baselineto after treatment deferral (-0·03 points [4·04]; -0·94 to 0·88; between-groupdifference Cohen's d 0·58; p=0·0004). Eight patients had adverse events duringtherapy or treatment deferral (one car accident [in the control group], twocommon cold [one patient per group], three gastrointestinal or cardiac symptoms[all intervention group], two recurrent stroke [one in intervention groupbefore initiation of treatment, and one before group assignment had occurred]);all were unrelated to study participation.

INTERPRETATION:

3 weeks of intensive speech and languagetherapy significantly enhanced verbal communication in people aged 70 years oryounger with chronic aphasia after stroke, providing an effectiveevidence-based treatment approach in this population. Future studies shouldexamine the minimum treatment intensity required for meaningful treatmenteffects, and determine whether treatment effects cumulate over repeatedintervention periods.

FUNDING:

German Federal Ministry of Education andResearch and the German Society for Aphasia Research and Treatment.

16、自闭症高风险婴儿的早期大脑发育存在显著异常一项MRI研究成果。

Nature. 2017 Feb 15;542(7641):348-351.doi: 10.1038/nature21369. Early brain development in infants at high risk forautism spectrum disorder.

Abstract

Brain enlargement has been observed inchildren with autism spectrum disorder (ASD), but the timing of thisphenomenon, and the relationship between ASD and the appearance of behaviouralsymptoms, are unknown. Retrospective head circumference and longitudinal brainvolume studies of two-year olds followed up at four years of age have providedevidence that increased brain volume may emerge early in development. Studiesof infants at high familial risk of autism can provide insight into the earlydevelopment of autism and have shown that characteristic social deficits in ASDemerge during the latter part of the first and in the second year of life.These observations suggest that prospective brain-imaging studies of infants athigh familial risk of ASD might identify early postnatal changes in brainvolume that occur before an ASD diagnosis. In this prospective neuroimagingstudy of 106 infants at high familial risk of ASD and 42 low-risk infants, weshow that hyperexpansion of the cortical surface area between 6 and 12 monthsof age precedes brain volume overgrowth observed between 12 and 24 months in 15high-risk infants who were diagnosed with autism at 24 months. Brain volumeovergrowth was linked to the emergence and severity of autistic socialdeficits. A deep-learning algorithm that primarily uses surface areainformation from magnetic resonance imaging of the brain of 6-12-month-oldindividuals predicted the diagnosis of autism in individual high-risk childrenat 24 months (with a positive predictive value of 81% and a sensitivity of88%). These findings demonstrate that early brain changes occur during theperiod in which autistic behaviours are first emerging.

17、对侧第七颈神经移植治疗患侧上肢痉挛性瘫痪有效。

N Engl J Med. 2017 Dec 20. doi:10.1056/NEJMoa1615208. [Epub ahead of print]

Trial of Contralateral Seventh CervicalNerve Transfer for Spastic Arm Paralysis.

Abstract

Background Spastic limb paralysis due toinjury to a cerebral hemisphere can cause long-term disability. We investigatedthe effect of grafting the contralateral C7 nerve from the nonparalyzed side tothe paralyzed side in patients with spastic arm paralysis due to chroniccerebral injury. Methods We randomly assigned 36 patients who had hadunilateral arm paralysis for more than 5 years to undergo C7 nerve transferplus rehabilitation (18 patients) or to undergo rehabilitation alone (18patients). The primary outcome was the change from baseline to month 12 in thetotal score on the Fugl-Meyer upper-extremity scale (scores range from 0 to 66,with higher scores indicating better function). Results The mean increase in Fugl-Meyerscore in the paralyzed arm was 17.7 in the surgery group and 2.6 in the controlgroup (difference, 15.1; 95% confidence interval, 12.2 to 17.9; P<0.001).With regard to improvements in spasticity as measured on the Modified AshworthScale (an assessment of five joints, each scored from 0 to 5, with higherscores indicating more spasticity), the smallest between-group difference wasin the thumb, with 6, 9, and 3 patients in the surgery group having a 2-unitimprovement, a 1-unit improvement, or no change, respectively, as compared with1, 6, and 7 patients in the control group (P=0.02). Transcranial magneticstimulation and functional imaging showed connectivity between the ipsilateralhemisphere and the paralyzed arm. There were no significant differences frombaseline to month 12 in power, tactile threshold, or two-point discriminationin the hand on the side of the donor graft. Conclusions In this single-centertrial involving patients who had had unilateral arm paralysis due to chroniccerebral injury for more than 5 years, transfer of the C7 nerve from thenonparalyzed side to the side of the arm that was paralyzed was associated witha greater improvement in function and reduction of spasticity thanrehabilitation alone over a period of 12 months. Physiological connectivitydeveloped between the ipsilateral cerebral hemisphere and the paralyzed hand.(Funded by the National Natural Science Foundation of China and others; ChineseClinical Trial Registry number, 13004466 .).

18、微生物组对出生前和成年阶段的小胶质细胞产生重要的影响,且具有性别特异性。

Cell. 2017 Dec 21. pii:S0092-8674(17)31432-0. doi: 10.1016/j.cell.2017.11.042. [Epub ahead of print] MicrobiomeInfluences Prenatal and Adult Microglia in a Sex-Specific Manner.

Abstract

Microglia are embryonically seededmacrophages that contribute to brain development, homeostasis, and pathologies.It is thus essential to decipher how microglial properties are temporallyregulated by intrinsic and extrinsic factors, such as sexual identity and themicrobiome. Here, we found that microglia undergo differentiation phases,discernable by transcriptomic signatures and chromatin accessibilitylandscapes, which can diverge in adult males and females. Remarkably, theabsence of microbiome in germ-free mice had a time and sexually dimorphicimpact both prenatally and postnatally: microglia were more profoundlyperturbed in male embryos and female adults. Antibiotic treatment of adult micetriggered sexually biased microglial responses revealing both acute andlong-term effects of microbiota depletion. Finally, human fetal microgliaexhibited significant overlap with the murine transcriptomic signature. Ourstudy shows that microglia respond to environmental challenges in a sex- andtime-dependent manner from prenatal stages, with major implications for ourunderstanding of microglial contributions to health and disease.

19、衰老和神经变性与单个神经元的突变增加显著相关。

Science. 2017 Dec 7. pii: eaao4426. doi:10.1126/science.aao4426. [Epub ahead of print] Aging and neurodegeneration areassociated with increased mutations in single human neurons.

Abstract

It has long been hypothesized that agingand neurodegeneration are associated with somatic mutation in neurons; however,methodological hurdles have prevented testing this hypothesis directly. We usedsingle-cell whole-genome sequencing to perform genome-wide somaticsingle-nucleotide variant (sSNV) identification on DNA from 161 single neuronsfrom the prefrontal cortex and hippocampus of fifteen normal individuals (aged4 months to 82 years) as well as nine individuals affected by early-onsetneurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome andXeroderma pigmentosum). sSNVs increased approximately linearly with age in bothareas (with a higher rate in hippocampus) and were more abundant in neurodegenerativedisease. The accumulation of somatic mutations with age-which we termgenosenium-shows age-related, region-related, and disease-related molecularsignatures, and may be important in other human age-associated conditions.

20.1、脊肌萎缩症基因治疗临床实验成功。

N Engl J Med. 2017 Nov2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752. Nusinersen versus Sham Controlin Infantile-Onset Spinal Muscular Atrophy.

Abstract

BACKGROUND:

Spinal muscular atrophy is an autosomalrecessive neuromuscular disorder that is caused by an insufficient level ofsurvival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotidedrug that modifies pre-messenger RNA splicing of the SMN2 gene and thuspromotes increased production of full-length SMN protein.

METHODS:

We conducted a randomized, double-blind,sham-controlled, phase 3 efficacy and safety trial of nusinersen in infantswith spinal muscular atrophy. The primary end points were a motor-milestoneresponse (defined according to results on the Hammersmith Infant NeurologicalExamination) and event-free survival (time to death or the use of permanentassisted ventilation). Secondary end points included overall survival andsubgroup analyses of event-free survival according to disease duration atscreening. Only the first primary end point was tested in a prespecifiedinterim analysis. To control the overall type I error rate at 0.05, ahierarchical testing strategy was used for the second primary end point and thesecondary end points in the final analysis.

RESULTS:

In the interim analysis, a significantlyhigher percentage of infants in the nusinersen group than in the control grouphad a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%],P<0.001), and this result prompted early termination of the trial. In thefinal analysis, a significantly higher percentage of infants in the nusinersengroup than in the control group had a motor-milestone response (37 of 73infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival washigher in the nusinersen group than in the control group (hazard ratio fordeath or the use of permanent assisted ventilation, 0.53; P=0.005). Thelikelihood of overall survival was higher in the nusinersen group than in thecontrol group (hazard ratio for death, 0.37; P=0.004), and infants with ashorter disease duration at screening were more likely than those with a longerdisease duration to benefit from nusinersen. The incidence and severity ofadverse events were similar in the two groups.

CONCLUSIONS:

Among infants with spinal muscularatrophy, those who received nusinersen were more likely to be alive and haveimprovements in motor function than those in the control group. Early treatmentmay be necessary to maximize the benefit of the drug. (Funded by Biogen andIonis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

20.2N Engl JMed. 2017 Nov 2;377(18):1713-1722. doi: 10.1056/NEJMoa1706198. Single-DoseGene-Replacement Therapy for Spinal Muscular Atrophy.

Abstract

BACKGROUND:

Spinal muscular atrophy type 1 (SMA1) is aprogressive, monogenic motor neuron disease with an onset during infancy thatresults in failure to achieve motor milestones and in death or the need formechanical ventilation by 2 years of age. We studied functional replacement ofthe mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

METHODS:

Fifteen patients with SMA1 received asingle dose of intravenous adeno-associated virus serotype 9 carrying SMNcomplementary DNA encoding the missing SMN protein. Three of the patientsreceived a low dose (6.7×1013 vg per kilogram of body weight), and 12 receiveda high dose (2.0×1014 vg per kilogram). The primary outcome was safety. Thesecondary outcome was the time until death or the need for permanentventilatory assistance. In exploratory analyses, we compared scores on the CHOPINTEND (Children's Hospital of Philadelphia Infant Test of NeuromuscularDisorders) scale of motor function (ranging from 0 to 64, with higher scoresindicating better function) in the two cohorts and motor milestones in thehigh-dose cohort with scores in studies of the natural history of the disease(historical cohorts).

RESULTS:

As of the data cutoff on August 7, 2017,all 15 patients were alive and event-free at 20 months of age, as compared witha rate of survival of 8% in a historical cohort. In the high-dose cohort, arapid increase from baseline in the score on the CHOP INTEND scale followedgene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3months, as compared with a decline in this score in a historical cohort. Of the12 patients who had received the high dose, 11 sat unassisted, 9 rolled over,11 fed orally and could speak, and 2 walked independently. Elevated serumaminotransferase levels occurred in 4 patients and were attenuated byprednisolone.

CONCLUSIONS:

In patients with SMA1, a singleintravenous infusion of adeno-associated viral vector containing DNA coding forSMN resulted in longer survival, superior achievement of motor milestones, andbetter motor function than in historical cohorts. Further studies are necessaryto confirm the safety and efficacy of this gene therapy. (Funded by AveXis andothers; ClinicalTrials.gov number, NCT02122952 .).

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