2018年阿尔茨海默病的十大临床研究进展

2018年阿尔茨海默病的十大临床研究进展

一.     AD新疗法：年轻血浆治疗AD安全可行，疗效值得期待。

摘要：

IMPORTANCE:

Young mouse plasma restores memory in agedmice, but, to our knowledge, the effects are unknown in patients with Alzheimerdisease (AD).

OBJECTIVE:

To assess the safety, tolerability, andfeasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18to 30 years in patients with AD.

DESIGN, SETTING, AND PARTICIPANTS:

The Plasma for Alzheimer SymptomAmelioration (PLASMA) study randomized 9 patients under a double-blindcrossover protocol to receive 4 once-weekly infusions of either 1 unit(approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed bya 6-week washout and crossover to 4 once-weekly infusions of an alternatetreatment. Patients and informants were masked to treatment and subjectivemeasurements. After an open-label amendment, 9 patients received 4 weekly yFFPinfusions only and their subjective measurements were unmasked. Patients wereenrolled solely at Stanford University, a tertiary academic medical center,from September 2014 to December 2016, when enrollment reached its target.Eighteen consecutive patients with probable mild to moderate AD dementia, aMini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50to 90 years were enrolled. Thirty-one patients were screened and 13 wereexcluded: 11 failed the inclusion criteria and 2 declined to participate.

INTERVENTIONS:

One unit of yFFP from male donors/placeboinfused once weekly for 4 weeks.

MAIN OUTCOME AND MEASURES:

The primary outcomes were the safety,tolerability, and feasibility of 4 weekly yFFP infusions. Safety end pointanalyses included all patients who received the study drug/placebo.

RESULTS:

There was no difference in the age (mean[SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental StateExamination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) andopen-label groups (n = 9). There were no related serious adverse events. Onepatient discontinued participation because of urticaria and another because ofan unrelated stroke. There was no statistically significant difference betweenthe plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverseevents, which were mild to moderate in severity. The most common adverse eventsin the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]),sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3[16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range,87%-100%) and adherence, accounting for a reduction in the total visitrequirement due to early patient discontinuation, was 96% (interquartile range,89%-100%).

CONCLUSIONS AND RELEVANCE:

The yFFP treatment was safe, welltolerated, and feasible. The study's limitations were the small sample size,short duration, and change in study design. The results warrant furtherexploration in larger, double-blinded placebo-controlled clinical trials.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT02256306.

参考文献：Safety,Tolerability, and Feasibility of Young Plasma Infusion in the Plasma forAlzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol.2018 Oct 29.

 

二.     AD转变预测新标志：flutemetamol- PET可有效预测MCI向AD的转变。

摘要：

IMPORTANCE:

Patients with amnestic mild cognitiveimpairment (aMCI) may progress to clinical Alzheimer disease (AD), remainstable, or revert to normal. Earlier progression to AD among patients who wereβ-amyloid positive vs those who were β-amyloid negative has been previouslyobserved. Current research now accepts that a combination of biomarkers couldprovide greater refinement in the assessment of risk for clinical progression.

OBJECTIVE:

To evaluate the ability of flutemetamol F18 and other biomarkers to assess the risk of progression from aMCI to probableAD.

DESIGN, SETTING, AND PARTICIPANTS:

In this multicenter cohort study, fromNovember 11, 2009, to January 16, 2014, patients with aMCI underwent positronemission tomography (PET) at baseline followed by local clinical assessmentsevery 6 months for up to 3 years. Patients with aMCI (365 screened; 232 wereeligible) were recruited from 28 clinical centers in Europe and the UnitedStates. Physicians remained strictly blinded to the results of PET, and thestandard of truth was an independent clinical adjudication committee thatconfirmed or refuted local assessments. Flutemetamol F 18-labeled PET scanswere read centrally as either negative or positive by 5 blinded readers with noknowledge of clinical status. Statistical analysis was conducted from February19, 2014, to January 26, 2018.

INTERVENTIONS:

Flutemetamol F 18-labeled PET at baselinefollowed by up to 6 clinical visits every 6 months, as well as magneticresonance imaging and multiple cognitive measures.

MAIN OUTCOMES AND MEASURES:

Time from PET to probable AD or lastfollow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age,hippocampal volume, and aMCI stage were entered into Cox proportional hazardslogistic regression analyses to identify variables associated with progressionto probable AD.

RESULTS:

Of 232 patients with aMCI (118 women and114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive resultsdetected on PET scan. By 36 months, the rates of progression to probable ADwere 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients withpositive results detected on PET scan, and 22.8% (29 of 127) for patients withnegative results detected on PET scan. Hazard ratios for association withprogression were 2.51 (95% CI, 1.57-3.99; P < .001) for="" a="" positive="" β-amyloidscan="" alone="" (primary="" outcome="" measure),="" 5.60="" (95%="" ci,="" 3.14-9.98;="">< .001)with additional="" low="" hippocampal="" volume,="" and="" 8.45="" (95%="" ci,="">< .001) when="" poorer="" cognitive="" status="" was="" added="" to="" the="">

CONCLUSIONS AND RELEVANCE:

A combination of positive results of flutemetamolF 18-labeled PET, low hippocampal volume, and cognitive status correspondedwith a high probability of risk of progression from aMCI to probable AD within36 months.

参考文献：Useof Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkersto Assess Risk of Clinical Progression in Patients With Amnestic Mild CognitiveImpairment. JAMA Neurol. 2018 Sep 1;75(9):1114-1123.

 

三.     看眼识AD：视网膜视神经层变薄和AD发生风险增加相关。

摘要：

IMPORTANCE:

Retinal structures may serve as a biomarkerfor dementia, but longitudinal studies examining this link are lacking.

OBJECTIVE:

To investigate the association of innerretinal layer thickness with prevalent and incident dementia in a generalpopulation of Dutch adults.

DESIGN, SETTING, AND PARTICIPANTS:

From September 2007 to June 2012,participants from the prospective population-based Rotterdam Study who were 45years and older and had gradable retinal optical coherence tomography imagesand at baseline were free from stroke, Parkinson disease, multiple sclerosis,glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic discpathology were included. They were followed up until January 1, 2015, for theonset of dementia.

EXPOSURES:

Inner retinal layer thicknesses (ie,retinal nerve fiber layer [RNFL]) and ganglion cell-inner plexiform layer(GC-IPL) thicknesses measured on optical coherence tomography images.

MAIN OUTCOMES AND MEASURES:

Odds ratios and hazard ratios for incidentdementia per SD decrease in retinal layer thickness adjusted for age, sex,education, and cardiovascular risk factors.

RESULTS:

Of 5065 individuals eligible for opticalcoherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years,1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41(1.2%) already had dementia. Thinner GC-IPL was associated with prevalentdementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). Noassociation was found of RNFL with prevalent dementia. During 14 674person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%)developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL atbaseline was associated with an increased risk of developing dementia (hazardratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar forAlzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association wasfound between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95%CI, 0.90-1.43]).

CONCLUSIONS AND RELEVANCE:

Thinner RNFL is associated with anincreased risk of dementia, including Alzheimer disease, suggesting thatretinal neurodegeneration may serve as a preclinical biomarker for dementia.

参考文献：Associationof Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: APopulation-Based Study.  JAMA Neurol.2018 Oct 1;75(10):1256-1263.

 

四.     AD成像新技术：SV2A-PET可用于AD患者大脑的突触密度成像。

摘要：

IMPORTANCE:

Synaptic loss is well established as themajor structural correlate of cognitive impairment in Alzheimer disease (AD).The ability to measure synaptic density in vivo could accelerate thedevelopment of disease-modifying treatments for AD. Synaptic vesicleglycoprotein 2A is an essential vesicle membrane protein expressed in virtuallyall synapses and could serve as a suitable target for synaptic density.

OBJECTIVE:

To compare hippocampal synaptic vesicleglycoprotein 2A (SV2A) binding in participants with AD and cognitively normalparticipants using positron emission tomographic (PET) imaging.

DESIGN, SETTING, AND PARTICIPANTS:

This cross-sectional study recruited 10participants with AD and 11 participants who were cognitively normal betweenNovember 2015 and June 2017. We hypothesized a reduction in hippocampal SV2Abinding in AD, based on the early degeneration of entorhinal cortical cellprojections to the hippocampus (via the perforant path) and hippocampal SV2Areductions that had been observed in postmortem studies. Participants underwenthigh-resolution PET scanning with((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one),a compound more commonly known as 11C-UCB-J, for SV2A. They also underwenthigh-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B(11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive andneurologic evaluation.

MAIN OUTCOMES AND MEASURES:

Outcomes were 11C-UCB-J-specific binding(binding potential [BPND]) via PET imaging in brain regions of interest inparticipants with AD and participants who were cognitively normal.

RESULTS:

Ten participants with AD (5 male and 5female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) werecompared with 11 participants who were cognitively normal (5 male and 6 female;mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participantswith AD spanned the disease stages from amnestic mild cognitive impairment(n = 5) to mild dementia (n = 5). Participants with AD had significantreduction in hippocampal SV2A specific binding (41%) compared with cognitivelynormal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normalparticipants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50];P = .005). These reductions remained significant after correction for atrophy(ie, partial volume correction; participants who were cognitively normal: mean[SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). HippocampalSV2A-specific binding BPND was correlated with a composite episodic memoryscore in the overall sample (R = 0.56; P = .01).

CONCLUSIONS AND RELEVANCE:

To our knowledge, this is the first studyto investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. Thisapproach may provide a direct measure of synaptic density, and it thereforeholds promise as an in vivo biomarker for AD and as an outcome measure fortrials of disease-modifying therapies, particularly those targeted at thepreservation and restoration of synapses.

参考文献：AssessingSynaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2APositron Emission Tomographic Imaging.  JAMANeurol. 2018 Oct 1;75(10):1215-1224.

 

 

五.     AD的复杂性：只有2/3的AD可归结于常见的神经病理改变。

摘要：

Abstract

OBJECTIVE:

The degree to which Alzheimer's versusother neuropathologies contribute to the risk of Alzheimer's dementia isunknown. We examined the risk of Alzheimer's dementia attributable to pathologicAD and 8 other neuropathologies.

METHODS:

Participants (n = 1,161) came from 2clinical-pathological studies of aging. Multivariable logistic regressionmodels examined associations of 8 neuropathological indices with Alzheimer'sdementia and quantified the percentage of cases attributable to each.Furthermore, because some dementia cases are not driven by commonneuropathologies, we re-estimated the attributable risks after empiricallyadjusting for such cases.

RESULTS:

Of 1,161 persons, 512 (44.1%) hadAlzheimer's dementia at time of death. With the exception of microinfarcts, allneuropathological indices were independently associated with greater odds ofAlzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases wereattributable to pathological AD. Separately, 8.9% were attributable tomacroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis,11.7% to transactive response DNA-binding protein 43, 8.1% to cerebral amyloidangiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of83.3% of cases were attributable to all 8 indices combined. However, afterfurther adjustment for cases driven by other factors, a total of 67.5% of caseswere attributable to all 8 neuropathologic indices combined.

INTERPRETATION:

Pathological AD accounts for a considerablepercentage of Alzheimer's dementia cases, but multiple other neuropathologiesalso contribute. In total, just over two-thirds of Alzheimer's dementia casesare attributable to common age-related neuropathologies, suggesting that otherdisease and resilience factors are important.

参考文献：Attributablerisk of Alzheimer's dementia attributed to age-related neuropathologies. AnnNeurol. 2018 Nov 12. doi: 10.1002/ana.25380.

 

 

六.     睡多了患痴呆：白天过度嗜睡增加大脑Aβ沉积。

IMPORTANCE: Aging is associated with excessive daytimesleepiness (EDS), which has been linked to cognitive decline in the elderly.However, whether EDS is associated with the pathologic processes of Alzheimerdisease remains unclear.

OBJECTIVE:

To investigate whether EDS at baseline isassociated with a longitudinal increase in regional β-amyloid (Aβ) accumulationin a cohort of elderly individuals without dementia.

DESIGN, SETTING, AND PARTICIPANTS:

This prospective analysis includedparticipants enrolled in the Mayo Clinic Study of Aging, a longitudinalpopulation-based study in Olmsted County, Minnesota. Of 2900 participants, 2172(74.9%) agreed to undergo carbon 11-labeled Pittsburgh compound B positronemission tomography (PiB-PET). We included 283 participants 70 years or olderwithout dementia who completed surveys assessing sleepiness at baseline and hadat least 2 consecutive PiB-PET scans from January 1, 2009, through July 31,2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder.

MAIN OUTCOMES AND MEASURES:

Excessive daytime sleepiness was defined asan Epworth Sleepiness Scale score of at least 10. The difference in Aβ levelsbetween the 2 consecutive scans (ΔPiB) in Aβ-susceptible regions (prefrontal,anterior cingulate, posterior cingulate-precuneus, and parietal) wasdetermined. Multiple linear regression models were fit to explore associationsbetween baseline EDS and ΔPiB while adjusting for baseline age, sex, presenceof the apolipoprotein E ε4 allele, educational level, baseline PiB uptake,global PiB positivity (standardized uptake value ratio ≥1.4),physical activity, cardiovascular comorbidities (obesity, hypertension,hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptomsduring sleep, depression, and interval between scans.

RESULTS:

Of the initial 283 participants, mean (SD)age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women.Sixty-three participants (22.3%) had EDS. Baseline EDS was significantlyassociated with increased regional Aβ accumulation in the anterior cingulate (Bcoefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posteriorcingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), andparietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions.Association of EDS with longitudinal Aβ accumulation was stronger inparticipants with baseline global PiB positivity in the anterior cingulate (Bcoefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (Bcoefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions.

CONCLUSIONS AND RELEVANCE:

Baseline EDS was associated with increasedlongitudinal Aβ accumulation in elderly persons without dementia, suggestingthat those with EDS may be more vulnerable to pathologic changes associatedwith Alzheimer disease. Further work is needed to elucidate whether EDS is aclinical marker of greater sleep instability, synaptic or network overload, orneurodegeneration of wakefulness-promoting centers. Early identification ofpatients with EDS and treatment of underlying sleep disorders could reduce Aβaccumulation in this vulnerable group.

参考文献： Associationof Excessive Daytime Sleepiness With Longitudinal β-Amyloid Accumulation inElderly Persons Without Dementia. JAMA Neurol. 2018 Jun 1;75(6):672-680.

 

七.     AD治疗新发现：即使高强度的运动也无法改善痴呆患者的认知功能。

摘要：

OBJECTIVE:

To estimate the effect of a moderate tohigh intensity aerobic and strength exercise training programme on cognitiveimpairment and other outcomes in people with mild to moderate dementia.

DESIGN:

Multicentre, pragmatic, investigatormasked, randomised controlled trial.

SETTING:

National Health Service primary care,community and memory services, dementia research registers, and voluntarysector providers in 15 English regions.

PARTICIPANTS:

494 people with dementia: 329 were assignedto an aerobic and strength exercise programme and 165 were assigned to usualcare. Random allocation was 2:1 in favour of the exercise arm.

INTERVENTIONS:

Usual care plus four months of supervisedexercise and support for ongoing physical activity, or usual care only.Interventions were delivered in community gym facilities and NHS premises.

MAIN OUTCOME MEASURES:

The primary outcome was score on theAlzheimer's disease assessment scale-cognitive subscale (ADAS-cog) at 12months. Secondary outcomes included activities of daily living,neuropsychiatric symptoms, health related quality of life, and carer quality oflife and burden. Physical fitness (including the six minute walk test) wasmeasured in the exercise arm during the intervention.

RESULTS:

The average age of participants was 77 (SD7.9) years and 301/494 (61%) were men. By 12 months the mean ADAS-cog score hadincreased to 25.2 (SD 12.3) in the exercise arm and 23.8 (SD 10.4) in the usualcare arm (adjusted between group difference -1.4, 95% confidence interval -2.6to -0.2, P=0.03). This indicates greater cognitive impairment in the exercisegroup, although the average difference is small and clinical relevanceuncertain. No differences were found in secondary outcomes or preplannedsubgroup analyses by dementia type (Alzheimer's disease or other), severity ofcognitive impairment, sex, and mobility. Compliance with exercise was good.Over 65% of participants (214/329) attended more than three quarters of scheduledsessions. Six minute walking distance improved over six weeks (mean change 18.1m, 95% confidence interval 11.6 m to 24.6 m).

CONCLUSION:

A moderate to high intensity aerobic andstrength exercise training programme does not slow cognitive impairment inpeople with mild to moderate dementia. The exercise training programme improvedphysical fitness, but there were no noticeable improvements in other clinicaloutcomes.

TRIAL REGISTRATION:

Current Controlled Trials ISRCTN10416500.

参考文献：DementiaAnd Physical Activity (DAPA) trial of moderate to high intensity exercisetraining for people with dementia: randomised controlled trial. BMJ. 2018 May16;361:k1675.

 

八.     BACE1抑制剂再受挫：BACE1抑制剂Verubecestat治疗轻中度AD失败。

摘要：

BACKGROUND:

Alzheimer's disease is characterized by thedeposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from thesequential cleavage of amyloid precursor protein by β-site amyloid precursorprotein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is anoral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid ofpatients with Alzheimer's disease.

METHODS:

We conducted a randomized, double-blind,placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mgand 40 mg per day, as compared with placebo, in patients who had a clinicaldiagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes werethe change from baseline to week 78 in the score on the cognitive subscale ofthe Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70,with higher scores indicating worse dementia) and in the score on theAlzheimer's Disease Cooperative Study Activities of Daily Living Inventoryscale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worsefunction).

RESULTS:

A total of 1958 patients underwentrandomization; 653 were randomly assigned to receive verubecestat at a dose of12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mgper day (the 40-mg group), and 653 to receive matching placebo. The trial wasterminated early for futility 50 months after onset, which was within 5 monthsbefore its scheduled completion, and after enrollment of the planned 1958patients was complete. The estimated mean change from baseline to week 78 inthe ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7in the placebo group (P=0.63 for the comparison between the 12-mg group and theplacebo group and P=0.46 for the comparison between the 40-mg group and theplacebo group). The estimated mean change from baseline to week 78 in theADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9in the placebo group (P=0.49 for the comparison between the 12-mg group and theplacebo group and P=0.32 for the comparison between the 40-mg group and theplacebo group). Adverse events, including rash, falls and injuries, sleepdisturbance, suicidal ideation, weight loss, and hair-color change, were morecommon in the verubecestat groups than in the placebo group.

CONCLUSIONS:

Verubecestat did not reduce cognitive orfunctional decline in patients with mild-to-moderate Alzheimer's disease andwas associated with treatment-related adverse events. (Funded by Merck;ClinicalTrials.gov number, NCT01739348 .).

参考文献：RandomizedTrial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med.2018 May 3;378(18):1691-1703.

 

九.     老年斑和脑萎缩的不同：Aβ和海马萎缩对记忆的影响不同。

摘要：

IMPORTANCE:

The prevalence of pathologic conditions ofthe brain associated with Alzheimer disease increases strongly with age. Littleis known about the distribution and clinical significance of preclinicalbiomarker staging in the oldest old, when most individuals without dementia arelikely to have positive biomarkers.

OBJECTIVE:

To compare the patterns of long-termcognitive decline in multiple domains by preclinical biomarker status in theoldest old without dementia.

DESIGN, SETTING, AND PARTICIPANTS:

A longitudinal observational study with amean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conductedin an academic medical center from August 24, 2000, to January 14, 2016,including and extending observations from the Ginkgo Evaluation of Memorystudy. A total of 197 adults who had completed the Ginkgo Evaluation of Memorystudy, were free of dementia, and were able to undergo magnetic resonance imagingwere eligible for a neuroimaging study in 2009. Of these patients, 175 wereincluded in the present analyses; 140 (80%) were cognitively normal and 35(20%) had mild cognitive impairment.

MAIN OUTCOMES AND MEASURES:

Biomarker groups included amyloid βnegative (Aβ-)/neurodegeneration negative (ND-), amyloid β positive (Aβ+)/ND-,Aβ-/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh CompoundB retention and hippocampal volume in 2009. Participants completed baselineneuropsychological testing from 2000 to 2002 and annual testing from 2004 to2016. Domains included memory, executive function, language, visual-spatialreasoning, and attention and psychomotor speed. Slopes of decline wereevaluated with linear mixed models adjusted for age, sex, and years ofeducation.

RESULTS:

Of the 175 participants (71 women and 104men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). Atotal of 42 participants (24.0%) were Aβ-/ND-, 32 (18.3%) were Aβ+/ND-, 35(20.0%) were Aβ-/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures,the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ-/ND- group,the amyloid deposition alone (Aβ+/ND-) group showed faster decline on tests ofverbal and visual memory (-0.3513; 95% CI, -0.5269 to -0.1756), executivefunction (0.0158; 95% CI, 0.0013-0.0303), and language (-0.1934; 95% CI,-0.3520 to -0.0348). The Aβ-/ND+ group showed faster visual memory decline thanthe Aβ-/ND- reference group (-0.3007; 95% CI, -0.4736 to -0.1279).

CONCLUSIONS AND RELEVANCE:

In the oldest old without dementia,presence of either or both Aβ and hippocampal atrophy is typical (>75%).Isolated hippocampal volume atrophy is associated only with greater decline inmemory. However, isolated Aβ is associated with decline in memory plus languageand executive functions. These findings suggest different underlyingpathophysiologic processes in the Aβ+/ND- and Aβ-/ND+ groups.

参考文献：Amyloidβ Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive DeclinePatterns for 12 Years in Oldest Old Participants Without Dementia. JAMA Neurol.2018 Jan 1;75(1):88-96.

 

 

十.     AD免疫疗法新进展：增加Aβ清除率不能改善AD患者的认知功能。

摘要：

BACKGROUND:

Alzheimer's disease is characterized byamyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonalantibody solanezumab was designed to increase the clearance from the brain ofsoluble Aβ, peptides that may lead to toxic effects in the synapses and precedethe deposition of fibrillary amyloid.

METHODS:

We conducted a double-blind,placebo-controlled, phase 3 trial involving patients with mild dementia due toAlzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of20 to 26 (on a scale from 0 to 30, with higher scores indicating bettercognition) and with amyloid deposition shown by means of florbetapirpositron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid.Patients were randomly assigned to receive solanezumab at a dose of 400 mg orplacebo intravenously every 4 weeks for 76 weeks. The primary outcome was thechange from baseline to week 80 in the score on the 14-item cognitive subscaleof the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to90, with higher scores indicating greater cognitive impairment).

RESULTS:

A total of 2129 patients were enrolled, ofwhom 1057 were assigned to receive solanezumab and 1072 to receive placebo. Themean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumabgroup and 7.44 in the placebo group, with no significant between-groupdifference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to0.14; P=0.10). As a result of the failure to reach significance with regard tothe primary outcome in the prespecified hierarchical analysis, the secondaryoutcomes were considered to be descriptive and are reported withoutsignificance testing. The change from baseline in the MMSE score was -3.17 inthe solanezumab group and -3.66 in the placebo group. Adverse cerebral edema oreffusion lesions that were observed on magnetic resonance imaging afterrandomization occurred in 1 patient in the solanezumab group and in 2 in theplacebo group.

CONCLUSIONS:

Solanezumab at a dose of 400 mgadministered every 4 weeks in patients with mild Alzheimer's disease did notsignificantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3ClinicalTrials.gov number, NCT01900665 .).

参考文献：Trialof Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018Jan 25;378(4):321-330.

欢迎加入“临床科研那些事”交流群，原文将在群里进行分享。