已有 1303 次阅读 2020-11-28 09:34 |个人分类:神经科学临床和基础|系统分类:科研笔记



Importance:There are limitations in current diagnostic testing approaches forAlzheimer disease (AD).

Objective:To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnosticbiomarker for AD.

Design,setting, and participants: Three cross-sectional cohorts: an Arizona-basedneuropathology cohort (cohort 1), including 34 participants with AD and 47without AD (dates of enrollment, May 2007-January 2019); the SwedishBioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n= 301) and clinically diagnosed patients with mild cognitive impairment (MCI)(n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99)(April 2017-September 2019); and a Colombian autosomal-dominant AD kindred(cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutationnoncarriers (December 2013-February 2017).

Exposures:Plasma P-tau217.

Mainoutcomes and measures: Primary outcome was the discriminative accuracy ofplasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondaryoutcome was the association with tau pathology (determined using neuropathologyor positron emission tomography [PET]).

Results:Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% incohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217differentiated neuropathologically defined AD from non-AD (area under the curve[AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy thanplasma P-tau181 and neurofilament light chain (NfL) (AUC range,0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 incohort 2 for clinical AD dementia vs other neurodegenerative diseases(AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasmaP-tau181plasma NfL, and MRI measures (AUC range, 0.50-0.81; P <.001) but not significantly different compared with cerebrospinal fluid(CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P >.15). In cohort 3, plasma P-tau217 levels were significantly greater amongPSEN1 mutation carriers, compared with noncarriers, from approximately 25 yearsand older, which is 20 years prior to estimated onset of MCI among mutationcarriers. Plasma P-tau217 levels correlated with tau tangles inparticipants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ= 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96])with significantly higher accuracy than plasma P-tau181, plasma NfL, CSFP-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P <.05), but its performance was not significantly different compared with CSFP-tau217 (AUC, 0.96; P = .22).

Conclusionsand relevance: Among 1402 participants from 3 selected cohorts, plasmaP-tau217 discriminated AD from other neurodegenerative diseases, withsignificantly higher accuracy than established plasma- and MRI-basedbiomarkers, and its performance was not significantly different from key CSF-or PET-based measures. Further research is needed to optimize the assay,validate the findings in unselected and diverse populations, and determine itspotential role in clinical care.

参考文献:DiscriminativeAccuracy of Plasma Phospho-tau217 for Alzheimer Disease vs OtherNeurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781.


突破二:Lancet Neurol + Nature medicine—科学家发现血液P-tau181AD的诊断生物标志物


Background:CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer'sdisease pathology, but the invasiveness, high cost, and poor availability ofthese detection methods restrict their widespread use as clinical diagnostictools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highlyspecific biomarker for Alzheimer's disease pathology. We aimed to assesswhether blood p-tau181 could be used as a biomarker for Alzheimer's disease andfor prediction of cognitive decline and hippocampal atrophy.

Methods:We developed and validated an ultrasensitive blood immunoassay for p-tau181.Assay performance was evaluated in four clinic-based prospective cohorts. Thediscovery cohort comprised patients with Alzheimer's disease and age-matchedcontrols. Two validation cohorts (TRIAD and BioFINDER-2) included cognitivelyunimpaired older adults (mean age 63-69 years), participants with mildcognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia.In addition, TRIAD included healthy young adults (mean age 23 years) andBioFINDER-2 included patients with other neurodegenerative disorders. Theprimary care cohort, which recruited participants in Montreal, Canada,comprised control participants from the community without a diagnosis of aneurological condition and patients referred from primary care physicians ofthe Canadian National Health Service for specialist care. Concentrations ofplasma p-tau181 were compared with established CSF and PET biomarkers and longitudinalmeasurements using Spearman correlation, area under the curve (AUC), and linearregression analyses.

Findings:We studied 37 individuals in the discovery cohort, 226 in the first validationcohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 inthe primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181showed gradual increases along the Alzheimer's disease continuum, from thelowest concentrations in amyloid β-negative young adults and cognitivelyunimpaired older adults, through higher concentrations in the amyloidβ-positive cognitively unimpaired older adults and MCI groups, to the highestconcentrations in the amyloid β-positive MCI and Alzheimer's disease groups(p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181distinguished Alzheimer's disease dementia from amyloid β-negative young adults(AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% acrosscohorts), as well as other neurodegenerative disorders, including frontotemporaldementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%),progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), andParkinson's disease or multiple systems atrophy (AUC=81·90%). Plasmap-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% acrosscohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In theprimary care cohort, plasma p-tau181 discriminated Alzheimer's disease fromyoung adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%),but not from MCI (AUC=55·00%).

Interpretation:Blood p-tau181 can predict tau and amyloid β pathologies, differentiateAlzheimer's disease from other neurodegenerative disorders, and identifyAlzheimer's disease across the clinical continuum. Blood p-tau181 could be usedas a simple, accessible, and scalable test for screening and diagnosis ofAlzheimer's disease.


Plasmaphosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease(AD), but its usefulness for differential diagnosis and prognosis is unclear.We studied plasma P-tau181 in three cohorts, with a total of 589 individuals,including cognitively unimpaired participants and patients with mild cognitiveimpairment (MCI), AD dementia and non-AD neurodegenerative diseases. PlasmaP-tau181 was increased in preclinical AD and further increased at the MCI anddementia stages. It correlated with CSF P-tau181 and predicted positive Taupositron emission tomography (PET) scans (area under the curve (AUC) =0.87-0.91 for different brain regions)Plasma P-tau181 differentiatedAD dementia from non-AD neurodegenerative diseases with an accuracy similar tothat of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected ADneuropathology in an autopsy-confirmed cohort. High plasma P-tau181 wasassociated with subsequent development of AD dementia in cognitively unimpairedand MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnosticand prognostic biomarker of AD, which may be useful in clinical practice andtrials.


Withthe potential development of new disease-modifying Alzheimer's disease (AD)therapies, simple, widely available screening tests are needed to identifywhich individuals, who are experiencing symptoms of cognitive or behavioraldecline, should be further evaluated for initiation of treatment. A blood-basedtest for AD would be a less invasive and less expensive screening tool than thecurrently approved cerebrospinal fluid or amyloid β positron emissiontomography (PET) diagnostic tests. We examined whether plasma tauphosphorylated at residue 181 (pTau181) could differentiate between clinicallydiagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. PlasmapTau181 concentrations were increased by 3.5-fold in AD compared to controlsand differentiated AD from both clinically diagnosed (receiver operatingcharacteristic area under the curve of 0.894) and autopsy-confirmedfrontotemporal lobar degeneration (area under the curve of 0.878). PlasmapTau181 identified individuals who were amyloid β-PET-positive regardless ofclinical diagnosis and correlated with cortical tau protein deposition measuredby 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for taupathology associated with AD.

参考文献:Bloodphosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnosticperformance and prediction modelling study using data from four prospectivecohorts. Lancet Neurol. 2020 May;19(5):422-433.

参考文献:PlasmaP-tau181 in Alzheimer's disease: relationship to other biomarkers, differentialdiagnosis, neuropathology and longitudinal progression to Alzheimer's dementia.Nat Med. 2020 Mar;26(3):379-386.

参考文献:Diagnosticvalue of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporallobar degeneration. Nat Med. 2020 Mar;26(3):387-397.


突破三:Nat Med —科学家揭示tau蛋白位点特异性磷酸化的动态演变规律


Developmentof tau-based therapies for Alzheimer's disease requires an understanding of thetiming of disease-related changes in tau. We quantified the phosphorylationstate at multiple sites of the tau protein in cerebrospinal fluid markersacross four decades of disease progression in dominantly inherited Alzheimer'sdisease. We identified a pattern of tau staging where site-specificphosphorylation changes occur at different periods of disease progression andfollow distinct trajectories over time. These tau phosphorylation state changesare uniquely associated with structural, metabolic, neurodegenerative andclinical markers of disease, and some (p-tau217 and p-tau181) begin with theinitial increases in aggregate amyloid-β as early as two decades before thedevelopment of aggregated tau pathologyOthers (p-tau205 and t-tau)increase with atrophy and hypometabolism closer to symptom onset. Thesefindings provide insights into the pathways linking tau, amyloid-β andneurodegeneration, and may facilitate clinical trials of tau-based treatments.

参考文献:Asoluble phosphorylated tau signature links tau, amyloid and the evolution ofstages of dominantly inherited Alzheimer's disease. Nat Med. 2020Mar;26(3):398-407.


突破四:Lancet Neurol —科学家揭示血浆NflAD活动性神经变性的标志物


Background:Neurofilament light chain (NfL) is a promising biomarker of active axonalinjury and neuronal degeneration. We aimed to characterise cross-sectional andlongitudinal plasma NfL measurements and determine the age at which NfLconcentrations begin to differentiate between carriers of the presenilin 1(PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombianautosomal dominant Alzheimer's disease kindred.

Methods:In this cross-sectional and longitudinal cohort study, members of the familialAlzheimer's disease Colombian kindred aged 8-75 years with no otherneurological or health conditions were recruited from the Alzheimer'sPrevention Initiative Registry at the University of Antioquia (Medellín,Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single moleculearray immunoassay and log-transformed data to examine the relationship between plasmaNfL concentrations and age, and establish the earliest age at which NfLconcentrations begin to diverge between mutation carriers and non-carriers.

Findings:We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074non-carriers with baseline assessments; of these participants, longitudinalmeasures (with a mean follow-up of 6 years) were available for 242 mutationcarriers and 262 non-carriers. Plasma NfL measurements increased with age inboth groups (p<0·0001), and began to differentiate carriers fromnon-carriers when aged 22 years (22 years before the estimated median age atmild cognitive impairment onset of 44 years), although the ability of plasmaNfL to discriminate between carriers and non-carriers only reached highsensitivity close to the age of clinical onset.

Interpretation:Our findings further support the promise of plasma NfL as a biomarker of activeneurodegeneration in the detection and tracking of Alzheimer's disease and theevaluation of disease-modifying therapies.

参考文献:Plasmaneurofilament light chain in the presenilin 1 E280A autosomal dominantAlzheimer's disease kindred: a cross-sectional and longitudinal cohort study. LancetNeurol. 2020 Jun;19(6):513-521.




Alzheimer'sdisease (AD) causes unrelenting, progressive cognitive impairments, but itscourse is heterogeneous, with a broad range of rates of cognitive decline1. Thespread of tau aggregates (neurofibrillary tangles) across the cerebral cortexparallels symptom severity2,3. We hypothesized that the kinetics of tau spreadmay vary if the properties of the propagating tau proteins vary acrossindividuals. We carried out biochemical, biophysical, MS and both cell- andanimal-based-bioactivity assays to characterize tau in 32 patients with AD. Wefound striking patient-to-patient heterogeneity in the hyperphosphorylatedspecies of soluble, oligomeric, seed-competent tau. Tau seeding activitycorrelates with the aggressiveness of the clinical disease, and somepost-translational modification (PTM) sites appear to be associated with bothenhanced seeding activity and worse clinical outcomes, whereas others are not.These data suggest that different individuals with 'typical' AD may havedistinct biochemical features of tau. These data are consistent with thepossibility that individuals with AD, much like people with cancer, may havemultiple molecular drivers of an otherwise common phenotype, and emphasize thepotential for personalized therapeutic approaches for slowing clinicalprogression of AD.

参考文献:Taumolecular diversity contributes to clinical heterogeneity in Alzheimer'sdisease. Nat Med. 2020 Aug;26(8):1256-1263.


突破六:Lancet Neurol—荟萃分析揭示高血压患者降低血压可降低痴呆和AD的发生风险


Background:Dementia is a major health concern for which prevention and treatmentstrategies remain elusive. Lowering high blood pressure with specificantihypertensive medications (AHMs) could reduce the burden of disease. Weinvestigated whether specific AHM classes reduced the risk for dementia.

Methods:We did a meta-analysis of individual participant data from eligibleobservational studies published between Jan 1, 1980, and Jan 1, 2019. Cohortswere eligible for inclusion if they prospectively recruited community-dwellingadults; included more than 2000 participants; collected data for dementiaevents over at least 5 years; had measured blood pressure and verified use ofAHMs; included in-person exams, supplemented with additional data, to capture dementiaevents; and had followed up cases for mortality. We assessed the association ofincident dementia and clinical Alzheimer's disease with use of five AHMclasses, within strata of baseline high (systolic blood pressure [SBP] 140 mmHg or diastolic blood pressure [DBP] 90mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. Weused a propensity score to control for confounding factors related to theprobability of receiving AHM. Study-specific effect estimates were pooled usingrandom-effects meta-analyses.

Results:Six prospective community-based studies (n=31 090 well phenotyped dementia-freeadults older than 55 years) with median follow-ups across cohorts of 7-22 yearswere eligible for analysis. There were 3728 incident cases of dementia and 1741incident Alzheimer's disease diagnoses. In the high blood pressure stratum(n=15 537), those using any AHM had a reduced risk for developing dementia(hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer'sdisease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM.We did not find any significant differences between one drug class versus allothers on risk of dementia. In the normal blood pressure stratum (n=15 553),there was no association between AHM use and incident dementia or Alzheimer'sdisease.

Interpretation:Over a long period of observation, no evidence was found that a specific AHMdrug class was more effective than others in lowering risk of dementia. Amongpeople with hypertensive levels of blood pressure, use of any AHM with efficacyto lower blood pressure might reduce the risk for dementia. These findingssuggest future clinical guidelines for hypertension management should alsoconsider the beneficial effect of AHM on the risk for dementia.

参考文献:Antihypertensivemedications and risk for incident dementia and Alzheimer's disease: ameta-analysis of individual participant data from prospective cohort studies. LancetNeurol. 2020 Jan;19(1):61-70.


突破七:Lancet Neurol—RCT研究发现将血压降低到120mmHg,相比于140mmHg,不能提高记忆力和认知处理速度两个亚认知模块。


Background:Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showedthat intensive control of systolic blood pressure significantly reduced theoccurrence of mild cognitive impairment, but not probable dementia. Weinvestigated the effects of intensive lowering of systolic blood pressure on specificcognitive functions in a preplanned substudy of participants from SPRINT.

Methods:SPRINT was an open-label, multicentre, randomised controlled trial undertakenat 102 sites, including academic medical centres, Veterans Affairs medicalcentres, hospitals, and independent clinics, in the USA and Puerto Rico.Participants were adults aged 50 years or older with systolic blood pressurehigher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participantswere randomly assigned (1:1) to a systolic blood pressure goal of less than 120mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment).All major classes of antihypertensive agents were included. A subgroup ofrandomly assigned participants including, but not limited to, participantsenrolled in an MRI substudy was then selected for a concurrent substudy ofcognitive function (target 2800 participants). Each individual was assessedwith a screening cognitive test battery and an extended cognitive test batteryat baseline and biennially during the planned 4-year follow-up. The primaryoutcomes for this substudy were standardised composite scores for memory(Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediaterecall], and Hopkins Verbal Learning Test-Revised [delayed recall]) andprocessing speed (Trail Making Test and Digit Symbol Coding). SPRINT wasregistered with, NCT01206062.

Findings:From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolledin the substudy (1448 received intensive treatment and 1473 received standardtreatment). SPRINT was terminated early due to benefit observed in the primaryoutcome (composite of cardiovascular events). After a median follow-up of 4·1years (IQR 3·7-5·8), there was no between-group difference in memory, withan annual decline in mean standardised domain score of -0·005 (95% CI-0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to0·005) in the standard treatment group (between-group difference -0·004, 95% CI-0·012 to 0·004; p=0·33). Mean standardised processing speed domain scoresdeclined more in the intensive treatment group (between-group difference-0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025(-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to0·009) for the standard treatment group.

Interpretation:Intensive treatment to lower systolic blood pressure did not result in aclinically relevant difference compared with standard treatment in memory orprocessing speed in a subgroup of participants from SPRINT. The effect of bloodpressure lowering might not be evident in specific domains of cognitivefunction, but instead distributed across multiple domains.

参考文献:Effectsof intensive versus standard blood pressure control on domain-specificcognitive function: a substudy of the SPRINT randomised controlled trial. LancetNeurol. 2020 Nov;19(11):899-907.




Importance:The benefit of blood pressure lowering for the prevention of dementia orcognitive impairment is unclear.

Objective:To determine the association of blood pressure lowering with dementia orcognitive impairment.

Datasources and study selection: Search of PubMed, EMBASE, and CENTRAL forrandomized clinical trials published from database inception through December31, 2019, that evaluated the association of blood pressure lowering on cognitiveoutcomes. The control groups consisted of either placebo, alternativeantihypertensive agents, or higher blood pressure targets.

Dataextraction and synthesis: Data were screened and extracted independently by 2authors. Random-effects meta-analysis models were used to report pooledtreatment effects and CIs.

Mainoutcomes and measures: The primary outcome was dementia or cognitiveimpairment. The secondary outcomes were cognitive decline and changes incognitive test scores.

Results:Fourteen randomized clinical trials were eligible for inclusion (96 158participants), of which 12 reported the incidence of dementia (or composite ofdementia and cognitive impairment [3 trials]) on follow-up and were included inthe primary meta-analysis, 8 reported cognitive decline, and 8 reported changesin cognitive test scores. The mean (SD) age of trial participants was 69 (5.4)years and 40 617 (42.2%) were women. The mean systolic baseline blood pressurewas 154 (14.9) mm Hg and the mean diastolic blood pressure was 83.3 (9.9) mmHg. The mean duration of follow-up was 49.2 months. Blood pressure loweringwith antihypertensive agents compared with control was significantly associatedwith a reduced risk of dementia or cognitive impairment (12 trials; 92 135 participants)(7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years; odds ratio[OR], 0.93 [95% CI, 0.88-0.98]; absolute risk reduction, 0.39% [95% CI,0.09%-0.68%]; I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% ofparticipants over a mean trial follow-up of 4.1 years; OR, 0.93 [95% CI,0.88-0.99]; absolute risk reduction, 0.71% [95% CI, 0.19%-1.2%]; I2 = 36.1%).Blood pressure lowering was not significantly associated with a change incognitive test scores.

Conclusionsand relevance: In this meta-analysis of randomized clinical trials, bloodpressure lowering with antihypertensive agents compared with control wassignificantly associated with a lower risk of incident dementia or cognitiveimpairment.

参考文献:Associationof Blood Pressure Lowering With Incident Dementia or Cognitive Impairment: ASystematic Review and Meta-analysis. JAMA. 2020 May 19;323(19):1934-1944.




Background:Alzheimer's disease and its complications are the leading cause of deathin adults with Down syndrome. Studies have assessed Alzheimer's disease inindividuals with Down syndrome, but the natural history of biomarker changes inDown syndrome has not been established. We characterised the order andtiming of changes in biomarkers of Alzheimer's disease in a population ofadults with Down syndrome.

Methods:We did a dual-centre cross-sectional study of adults with Down syndrome recruitedthrough a population-based health plan in Barcelona (Spain) and throughservices for people with intellectual disabilities in Cambridge (UK). Cognitiveimpairment in participants with Down syndrome was classified with the CambridgeCognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Onlyparticipants with mild or moderate disability were included who had at leastone of the following Alzheimer's disease measures: apolipoprotein E allelecarrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 andtheir ratio (Aβ1-42/1-40), total tau protein, and neurofilament light chain(NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinalfluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET withamyloid tracers, and MRI. Cognitively healthy euploid controls aged up to75 years who had no biomarker abnormalities were recruited from the Sant PauInitiative on Neurodegeneration. We used a first-order locally estimatedscatterplot smoothing curve to determine the order and age at onset of thebiomarker changes, and the lowest ages at the divergence with 95% CIs are alsoreported where appropriate.

Findings:Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009,and Dec 31, 2014 (Cambridge), we included 388 participants with Downsyndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease,and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls.CSF Aβ1-42/1-40 and plasma NFL values changed in individuals with Down syndromeas early as the third decade of life, and amyloid PET uptake changedin the fourth decade18F-fluorodeoxyglucose PET and CSF p-tau changesoccurred later in the fourth decade of life, followed by hippocampal atrophyand changes in cognition in the fifth decade of life. ProdromalAlzheimer's disease was diagnosed at a median age of 50·2 years (IQR47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2).Symptomatic Alzheimer's disease prevalence increased with age in individualswith Down syndrome, reaching 90-100% in the seventh decade of life.

Interpretation:Alzheimer's disease in individuals with Down syndrome has a long preclinicalphase in which biomarkers follow a predictable order of changes over more thantwo decades. The similarities with sporadic and autosomal dominantAlzheimer's disease and the prevalence of Down syndrome make this population asuitable target for Alzheimer's disease preventive treatments.

参考文献:Clinicaland biomarker changes of Alzheimer's disease in adults with Down syndrome: across-sectional study. Lancet. 2020 Jun 27;395(10242):1988-1997.


突破十:Lancet Neurol— GLP1受体激动剂度拉糖肽Dulaglutide可改善2型糖尿病患者的认知功能损害


Background:Diabetes is an independent risk factor for cognitive impairment. We aimed toinvestigate the association between the glucagon-like peptide-1 (GLP-1)receptor agonist dulaglutide and cognitive impairment as an exploratoryanalysis within the Researching Cardiovascular Events With a Weekly Incretin inDiabetes (REWIND) trial.

Methods:REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in24 countries. We included men and women (aged 50 years) with either established ornewly diagnosed type 2 diabetes and additional cardiovascular risk factors,glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oralglucose-lowering drugs with or without basal insulin, and a body-mass index ofat least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneousinjections once a week of either dulaglutide (1·5 mg) or an equal volume ofmatching placebo. Randomisation was done using a computer-generated code withstratification by site. Participants and all study personnel were masked totreatment allocation until the database was locked. Participants were followedup at least every 6 months for the composite primary outcome of stroke,myocardial infarction, or death from cardiovascular or unknown causes.Cognitive function was assessed at baseline and during follow-up using the MontrealCognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). Wepresent here the exploratory primary cognitive outcome, which was the firstoccurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more belowthe baseline mean score in the participant's country. All analyses were doneusing an intention-to-treat approach. The REWIND trial is registered, NCT01394952.

Findings:Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomlyassigned to either dulaglutide (n=4949) or placebo (n=4952). During medianfollow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline andone or more follow-up MoCA or DSST scores, of whom 4456 were assigneddulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI0·85-1·02; p=0·11). After post-hoc adjustment for individual standardisedbaseline scores, the hazard of substantive cognitive impairment was reducedby 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018).

Interpretation:Long-term treatment with dulaglutide might reduce cognitive impairment inpeople with type 2 diabetes. Further studies of this drug focused on brainhealth and cognitive function are clearly indicated.

参考文献:Effectof dulaglutide on cognitive impairment in type 2 diabetes: an exploratoryanalysis of the REWIND trial. Lancet Neurol. 2020 Jul;19(7):582-590.





1. 年终盘点:2020年阿尔茨海默病十大研究突破(附语音解读)


1. 年终盘点:2019年帕金森病十大基础研究进展

2. 年终盘点:2019年帕金森病十大临床研究进展

3. 年终盘点:2019年阿尔茨海默病十大基础研究进展

4. 年终盘点:2019年阿尔茨海默病十大临床研究进展

5. 年终盘点:2019年神经科学领域十大基础研究进展

6. 年终盘点:2019年抑郁症领域十大基础研究进展(一半来自中国)

7. 年终盘点:2019年脑血管病领域十大基础研究进展

8. 年终盘点:2019年神经炎症领域十大基础研究进展

9. 年终盘点:2019年神经活动记录十大基础研究进展

10. 年终盘点:2019年ALS/FTD十大基础研究进展

11. 年终盘点:2019年医学和生物学领域深度学习和神经网络十大基础研究进展

12. 年终盘点:2019年神经内科十大临床研究突破

13. 年终盘点:2019年疼痛防治和痛觉机制十大研究突破

14. 年终盘点:2019年睡眠和失眠领域十大研究突破


16. 年终盘点:2019年大脑学习和记忆的十大研究突破

17. 年终盘点:2019年衰老和长寿十大研究突破

18. 年终盘点:2019年自闭症十大研究突破




3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症(ALS)十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破







6、神经科学临床和基础Movement disorders亚群;








14、神经科学临床和基础Neural Development亚群;


16、神经科学临床和基础Neural circuits亚群;











27、神经科学临床和基础Learning & Memory亚群;





32、神经科学Autism & ADHD研究群;




36、神经科学Non-human primate研究群;



























1. 意识研究:意识的本质、组成、运行机制及其物质载体;不同意识层次的操控和干预,意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控:记忆的形成和消退机制,记忆的人为移植和记忆的人为消除等;

3. 痴呆研究:阿尔茨海默病的机制和治疗研究,血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究:喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究:性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究,包括脑卒中、脊髓损伤机制研究,神经干细胞移植研究,新型神经修复技术,神经康复技术。

13. 精神类疾病的机制和干预研究:自闭症、精分、抑郁症、智能障碍、药物成瘾等;

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究,包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术:光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究,包括脑机接口、神经刺激芯片、记忆存储芯片,意识存储芯片,人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术:包括任何机械肢体的人类移植,大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术:高分辨率成像技术、大型电极微阵列技术等。











该博文允许注册用户评论 请点击登录 评论 (0 个评论)


Archiver|手机版|科学网 ( 京ICP备07017567号-12 )

GMT+8, 2022-1-17 09:07

Powered by

Copyright © 2007- 中国科学报社