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Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA)., Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19)., Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator., Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA., Funding: Bristol Myers Squibb and Janssen Research & Development., Competing Interests: Declaration of interests MS has received consulting fees from Janssen, HLS Therapeutics, and Bayer; and has served in a leadership or fiduciary role for the Canadian Stroke Consortium. CAM has received honoraria from Bristol Myers Squibb and Boehringer Ingelheim. KT has received honoraria from Bayer, Daiichi Sankyo, Bristol Myers Squibb, Otsuka, Novartis, and Abbott Medical. DB has received consulting fees from Bristol Myers Squibb, Bayer, Ipsen, and Boehringer Ingelheim; and has received honoraria from Novo Nordisk, HUMAN BioPlazma, and Parexel. SEK has received grants or contracts from Bristol Myers Squibb; and has received consulting fees from Bristol Myers Squibb. HL has received consulting fees from Bristol Myers Squibb; has participated on steering committees or advisory boards for Bristol Myers Squibb, the US National Institute of Neurological Disorders and Stroke, and Coherex Medical; and is on the Editorial Board for Medscape Neurology. GT has received consulting fees from Bristol Myers Squibb. GN has received financial support from Bristol Myers Squibb. AC has participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Bristol Myers Squibb; and has previously served as the President of the Cerebrovascular Section of Polish Neurological Society, honorary president of the Polish Neurological Society, and in a leadership role for the Angels Initiative— Poland. PA has participated on a steering committee for Bristol Myers Squibb and Janssen; has received grants or contracts from Sanofi, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, AltheraPharm, and the French Government; has received consulting fees from Bayer, Novartis, and Novo Nordisk; has received honoraria from Viatris and Sanofi; and has participated in an advisory board for Novartis. ME has received grants or contracts from Bayer; has received consulting fees from Bayer; has received honoraria from Abbott, Boehringer Ingelheim, Pfizer, Amgen, GSK, Sanofi, and Novartis; has participated on data safety monitoring boards or advisory boards for Bristol Myers Squibb, Bayer, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, and Covidien; has served in a leadership or fiduciary role for the European Academy of Neurology, German Neurological Society (DGN), International Society for Cerebral Blood Flow and Metabolism, American Heart Association/American Stroke Association, European Stroke Organisation, World Stroke Organization, German Center for Cardiovascular Research (DZHK), and German Center for Neurodegenerative Diseases (DZNE); and has been a recipient of materials from Amgen. DTa has received consulting fees from QuantaIX Neuroscience, Babylink, and Pi-cardia, and for being a national leader in a randomised controlled trial. DTo has received honoraria from Abbott, Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, and Pfizer. LY has participated in steering committees for Bristol Myers Squibb and Janssen Research & Development; has received honoraria from Bayer, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; and has received support for attendance at the World Stroke Congress from the World Stroke Organization Future Stroke Leaders Program. PvWM has received contracts and support for attending an investigator meeting from Bristol Myers Squibb; and has served as a national leader and member of a steering committee for Bristol Myers Squibb. GSS has received support from and participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Boehringer Ingelheim; has received consulting fees from Bristol Myers Squibb and Boehringer Ingelheim; and has participated in an advisory board for Bristol Myers Squibb. AAv has received grants and honoraria from Bayer. JD has received support from Bristol Myers Squibb; has received grants from Pfizer; and has received honoraria from Pfizer, Daiichi Sankyo, and AstraZeneca. DS has received contracts, support for attending a steering committee meeting, and materials and drugs for performing the trial from Bristol Myers Squibb. TT has received grants from the University of Gothenburg, Sahlgrenska University Hospital, and Wennerstrom's Foundation; and has received consulting fees from Bayer, Inventiva Pharma, Bristol Myers Squibb, and Portola Pharmaceuticals. JE has received travel support from Bristol Myers Squibb for attending steering committee meetings. SFA has received grants from Bayer and Boehringer Ingelheim; and has received honoraria from Novo Nordisk and Abbott. JRW has served as President Elect of the Austrian Society of Neurology. ECS has received honoraria from Bristol Myers Squibb, Daiichi Sankyo, and Boston Scientific. NGP has served as the President of the Russian National Society of Preventive Cardiology. PML has received grants from Bristol Myers Squibb and Janssen; has received honoraria from Boehringer Ingelheim and Pfizer; has received support for attending the Global Stroke Alliance; has participated on a data safety monitoring board or advisory board for RapidAI; and has served as the President of the Chilean Stroke Association. DG has received grants or contracts, or both, from the US National Heart, Lung and Blood Institute and the US National Institutes of Health; has received consulting fees from Bristol Myers Squibb, Ionis, Janssen, and Anthos Therapeutics; and has participated on a steering committee for Bristol Myers Squibb. HCD has received support from Bristol Myers Squibb; has received grants from Boehringer Ingelheim and AstraZeneca; has received honoraria from Boehringer Ingelheim, Pfizer, Sanofi, and Bristol Myers Squibb; has received support for attending meetings or travel, or both, from Boehringer Ingelheim; and has participated on data safety monitoring boards or advisory boards for Actelion, the German Research Council, and the ELAN Study. RAB has received consulting fees from and has participated on a steering committee for Bristol Myers Squibb. CC has received honoraria from Bristol Myers Squibb and Amgen; and has participated on data safety monitoring boards or advisory boards for AstraZeneca and Biogen. GA, MD, and CP are employees and shareholders of Bristol Myers Squibb. AK and DL are employees and shareholders of Bristol Myers Squibb; and have a pending patent application related to this study. GJH has received consulting fees from Bristol Myers Squibb, Janssen Research & Development, and Bayer; has received honoraria from Janssen Medical Affairs; has received honoraria for participating on a data safety monitoring board for AC Immune; and has received honoraria from the American Heart Association for serving as an Associate Editor for Circulation. SIB, AS, BWY, and AAr declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate., Methods: This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study was conducted across 14 countries and 79 clinical sites. We recruited people aged 18 years or older with a documented diagnosis of rheumatoid arthritis at least 16 weeks before screening with an inadequate response to methotrexate with or without inadequate response to up to two tumour necrosis factor inhibitors. Participants were randomly assigned (1:1:1:1) to oral BMS-986142 (100 mg, 200 mg, or 350 mg) or placebo once daily for 12 weeks. Randomisation was done using an interactive voice response system and stratified by prior treatment status and geographical region. All participants, care providers, investigators, and outcome assessors were masked to treatment allocation. Co-primary endpoints were 20% and 70% improvement in American College of Rheumatology criteria (ACR20 and ACR70) at week 12. Primary endpoints were assessed in the efficacy analysis population (all randomised patients who received at least one dose of the study drug and did not discontinue the study). Safety endpoints were analysed in the as-treated analysis population, which included all patients who received at least one dose of the study drug (patients were grouped according to the treatment they actually received vs the treatment to which they were randomised). This trial was registered with ClinicalTrials.gov, number NCT02638948., Findings: Between Feb 24, 2016 and May 3, 2018, 248 patients were randomised (73 in the BMS-986142 100 mg group, 73 in the 200 mg group, 26 in the 350 mg group, and 75 in the placebo group; one post-randomisation exclusion); mean age was 56·7 years (SD 12·7); 214 (87%) of 247 were women, 33 (13%) were men, and 188 (76%) were White. Pre-specified interim analysis resulted in discontinuation of the 350 mg BMS-986142 dose due to elevated liver enzymes and absence of benefit versus placebo. Co-primary endpoints were not met. Response rates for ACR20 (placebo: 23 [31%] of 75; 100 mg: 26 [36%] of 73; 200 mg: 31 [42%] of 73) and ACR70 (placebo: three [4%] of 75; 100 mg: three [4%] of 73; 200 mg: seven [10%] of 73) were not significantly different to placebo; estimate of difference versus placebo for ACR20 was 4·9 (95% CI -10·2 to 20·1; p=0·52) for 100 mg and 11·8 (-3·6 to 27·2; p=0·14) for 200 mg, and for ACR70 the estimate of difference was 0·1 (-16·0 to 16·5; nominal p=1·00) for 100 mg and 5·6 (-10·5 to 21·9; nominal p=0·21) for 200 mg. Six patients experienced serious adverse events (four in the placebo group [mouth ulceration, open globe injury, rheumatoid arthritis flare, and endometrial adenocarcinoma] and two in the BMS-986142 100 mg group [angina pectoris and intestinal obstruction]); there were no deaths., Interpretation: Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests PGC reports speaker or consultancy fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, GlaxoSmithKline, Merck, Novartis, Pfizer, Regeneron, and UCB. MN, SD, YL, JL, CP, AF, and IMC are full-time employees of and shareholders in Bristol Myers Squibb. DMG is a full-time employee of, shareholder in, and has received travel support from Bristol Myers Squibb. MØ reports research grants from Amgen, Bristol Myers Squibb, Celgene, Merck, and Novartis; and speaker or consultancy fees from AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, Merck, Novartis, Pfizer, and UCB., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA., Methods: We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested., Results: MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences -0.966 (P = 0.039) and -1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [-1.019, -0.940, -2.275 (P &lt; 0.05), respectively, day 365 vs day 169]. Structural outcomes changed minimally across groups., Conclusion: Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials., Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background and Purpose: Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease., Methods: Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models., Results: Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death., Conclusions: Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other's onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers., (© 2015 American Heart Association, Inc.)

Importance: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms., Objectives: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia., Design, Setting, and Participants: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity., Interventions: Oral avagacestat or placebo daily., Main Outcomes and Measure: Safety and tolerability of avagacestat., Results: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures., Conclusions and Relevance: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD., Trial Registration: clinicaltrials.gov Identifier: NCT00890890.

Background and Purpose: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease., Methods: We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background., Results: Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance., Conclusions: We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD)., Design: Randomized, double-blind, placebo-controlled,24-week phase 2 study., Setting: Global, multicenter trial., Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups., Intervention: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily., Main Outcome Measures: Safety and tolerability of avagacestat., Results: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients., Conclusions: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD., Trial Registration: clinicaltrials.gov Identifier: NCT00810147

Cerebral small vessel disease is the most common cause of vascular cognitive impairment. It typically manifests with lacunar infarcts and ischaemic white matter lesions. However, little is known about how these lesions relate to the cognitive symptoms. Previous studies have found a poor correlation between the burden of ischaemic lesions and cognitive symptoms, thus leaving much of the variance in cognitive performance unexplained. The objective of the current study was to investigate the relationship between the location of subcortical ischaemic lesions and cognitive symptoms in small vessel disease. We applied a voxel-based lesion-symptom mapping approach to data from 215 patients with CADASIL, a genetically defined small vessel disease with mutations in the NOTCH3 gene. All patients were examined by magnetic resonance imaging and comprehensive neuropsychological testing. Lacunar lesions and white matter lesions were segmented on three-dimensional T(1) and fluid-attenuated inversion recovery sequences, respectively. One hundred and forty-five subjects had a total of 854 lacunar lesions (range 1-13 per individual). The normalized volume of white matter hyperintensities ranged from 0.0425% to 21.5% of the intracranial cavity. Significant clusters for cognitive performance were detected for both lacunar lesions and white matter hyperintensities. The most prominent results were obtained on a compound score for processing speed, the predominantly affected cognitive domain in this group of patients. Strategic locations included the anterior parts of the thalamus, the genu and anterior limb of the internal capsule, the anterior corona radiata and the genu of the corpus callosum. By combining the lesion-symptom mapping data with information from a probabilistic white matter atlas we found that the majority of the processing speed clusters projected on the anterior thalamic radiation and the forceps minor. In multivariate models that included demographic parameters, brain atrophy and the volume of ischaemic lesions, regional volumes of lacunar lesions and white matter hyperintensities in the anterior thalamic radiation predicted performance in processing speed tasks, whereas there was no independent contribution of the global volume of ischaemic lesions. These observations emphasize the importance of lesion location for both lacunar and ischaemic white matter lesions. Our findings further highlight the anterior thalamic radiation as a major anatomical structure impacting on processing speed. Together these findings provide strong support for a central role of frontal-subcortical circuits in cerebral small vessel disease and vascular cognitive impairment.

Purpose: To evaluate the agreement and diagnostic accuracy of Contrast enhanced magnetic resonance angiography (CE-MRA), Doppler ultrasound (DUS) and Digital subtraction angiography (DSA) in the assessment of carotid stenosis., Methods: DUS, CE-MRA and DSA were performed in 56 patients included in the Carotide-angiographie par résonance magnétique-échographie-doppler-angioscanner (CARMEDAS) multicenter study with a carotid stenosis ≥ 50%. Three readers evaluated stenoses on CE-MRA and DSA (NASCET criteria). Velocities criteria were used for stenosis estimation on DUS., Results: CE-MRA had a sensitivity and specificity of 96-98% and 66-83% respectively for carotid stenoses ≥ 50% and a sensitivity and specificity of 94% and 76-84% respectively for carotid stenoses ≥ 70%. The interobserver agreement of CE-MRA was excellent, except for moderate stenoses (50-69%). DUS had a sensitivity and specificity of 88 and 75% respectively for carotid stenoses ≥ 50% and a sensitivity and specificity of 83 and 86% respectively for carotid stenoses ≥ 70%. Combined concordant CE-MRA and DUS had a sensitivity and specificity of 100 and 85-90% respectively for carotid stenoses ≥ 50% and a sensitivity and specificity of 96-100% and 80-87% respectively for carotid stenoses ≥ 70%. The positive predictive value of the association CE-MRA and DUS for carotid stenoses ≥ 70% is calculated between 77 and 82% while the negative predictive value is calculated between 97 and 100%. CE-MRA and DUS have concordant findings in 63-72%, and the overestimations cases were recorded only for carotid stenosis ≤ 69%., Conclusion: Combined DUS-CE-MRA is excellent for evaluation of severe stenosis but remains debatable in moderate stenosis (50-69%) due to the risk of overestimations., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia., (Copyright 2008 Elsevier Inc. All rights reserved.)

Recent evidence suggests that hippocampal changes are present in vascular cognitive impairment but their importance and relationship with ischaemic mechanisms remain controversial. To investigate these issues we performed MRI and cognitive assessment in a large cohort (n=144) of patients with CADASIL, a hereditary small vessel disease and model of pure vascular cognitive impairment. Dementia status was ascribed according to DSM-IV and global cognitive function assessed with the Minimental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS). Hippocampal volume (HV) correlated with age (r=-0.33, p<0.001), brain volume (r=0.39, p<0.001) and lacunar lesion volume (r=-0.23, p=0.008), but not white matter lesions or microhaemorrhages. HV was reduced in dementia (2272+/-333 mm(3) versus 2642+/-349 mm(3), p<0.001) in the whole cohort and the subgroup progressing to dementia before age 60. HV correlated with MMSE (r=0.30, p<0.001), MDRS (r=0.40, p<0.001) and in a multivariate model predicted cognition independent of typical vascular lesions and whole brain atrophy. These findings strengthen the view that hippocampal atrophy is an important pathway of cognitive impairment in vascular as well as degenerative disease.

Purpose: To evaluate the reproducibility of fluid attenuated inversion recovery (FLAIR) and four other magnetic resonance imaging (MRI) sequences in the quantitative assessment of final cerebral infarct volume., Materials and Methods: FLAIR, T1-3D, magnetization transfer ratio (MTR)-map, diffusion-weighted trace (DWI)-trace, and apparent diffusion coefficient (ADC)-map, were acquired and measured in 33 patients 30-45 days after onset of a first-ever ischemic stroke. The infarct area was visually detected and manually delineated two times by two readers separately after images and sequences randomization. The reliability was assessed by using an intraclass correlation coefficient (ICC) and its two-sided 95% confidence interval (95% CI)., Results: DWI-trace had the best reliability, with an ICC of 0.96 (95% CI = 0.93-0.98). FLAIR had an ICC of 0.86 (95% CI = 0.73-0.93), and a much higher volume. T1-3D, MTR-map and ADC-map had lower reliability or excessive volume values equal to 0 in comparison to DWI-trace., Conclusion: DWI-trace performed within 30th and 45th day following onset of acute ischemic stroke was the most reliable sequence for final infarct volume quantification. This sequence should be added to FLAIR evaluation to strengthen the statistical results of the pharmacological trials and reduce their variability.

Measurement of brain atrophy has been proposed as a surrogate marker in MS and degenerative dementias. Although cerebral small vessel disease predominantly affects white and subcortical grey matter, recent data suggest that whole brain atrophy is also a good indicator of clinical and cognitive status in this disease. Automated methods to measure atrophy are available that are accurate and reproducible in disease-free brains. However, optimal methods in small vessel disease have not been established and the impact of ischaemic lesions on different techniques has not been explored systematically. In this study, three contrasting techniques -- Statistical Parametric Mapping 5 (SPM5), SIENAX and BrainVisa -- were applied to measure cross-sectional atrophy (brain parenchymal fraction or BPF) in a large (n=143) two-centre cohort of patients with CADASIL, a genetic model of small vessel disease. All three techniques showed similar sensitivity to trends in BPF associated with age and lesion load. No single technique was particularly vulnerable to error as a result of lesions. Provided major errors in registration were excluded by visual inspection, manual correction of segmentations had a negligible impact with mean errors of 0.41% for SIENAX and 0.46% for BrainVisa. BPF correlated strongly with global cognitive function and physical disability, independent of the technique used. Correlation coefficients with the Minimental State Examination score were: BrainVisa 0.58, SIENAX 0.58, SPM5 0.60 (for all, p<0.001). These results suggest that all three methods can be applied reliably in patients with ischaemic lesions. Choice of analysis approach for this kind of clinical question will be determined by factors other than their robustness and precision, such as a desire to explore subtle localised changes using extensions of these processing tools.

Background and Purpose: In the concept of ischemic penumbra, the volume of salvaged penumbra is considered as the volume of FLAIR normalization on follow-up MRI compared with early diffusion and perfusion abnormalities. Using magnetization transfer imaging, very sensitive to macromolecular disruption, we investigated whether FLAIR normalization was a good marker for tissue full recovery., Methods: We prospectively included 30 patients with acute middle cerebral artery stroke. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging were performed within 12 hours after onset (MRI.1), and the final infarct was documented by MRI with FLAIR and magnetization transfer at 1-month follow-up (MRI.2). We compared magnetic transfer ratio of a normal region with values measured at 1 month (MRI.2) in 4 regions of interest: (1) the initial DWI hypersignal (CORE=DWI MRI.1); (2) the infarct growth area (infarct growth=FLAIR MRI.2-DWI MRI.1); (3) the hypoperfused area that normalized (reversible perfusion abnormalities=perfusion-weighted imaging MRI.1-FLAIR&#95; MRI.2); and (4) the early DWI abnormalities that normalized (reversible diffusion abnormalities=DWI MRI.1- FLAIR&#95;MRI.2)., Results: In comparison with values obtained in normal tissue (magnetic transfer ratio=49.8%, SD=1.9), magnetic transfer ratio at 1 month was significantly decreased in reversible perfusion abnormalities (45.2%, SD=2.5; P<0.0001) and reversible diffusion abnormalities (43.2%, SD=2.8; P=0.0156). It was also markedly reduced, as expected, in the CORE (40.9%, SD=5.2) and infarct growth regions (43.1%, SD=2.0)., Conclusions: Magnetic transfer ratio assessed presence of microstructural damages in the MRI-defined salvaged penumbra. This may imply cellular loss and partial infarction. Evaluation of the efficacy of therapies that promote reperfusion or neuroprotection may benefit from this additional information.

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy caused by mutations of the Notch3 gene. The disease is characterized by T2-hyperintense lesions (subcortical white matter lesions), T1-hypointense lesions (lacunar lesions), and T2*-weighted gradient-echo (GE) lesions (cerebral microhemorrhages [CMs]) visualized on clinical MRI sequences and is considered as a model of "pure" subcortical ischemic vascular dementia. Although numerous studies have investigated the impact of white matter lesions in patients with CADASIL, the clinical importance of lacunar lesions remains unknown. Our purpose was to examine the influence of the visible MRI markers in the disease, including the load of lacunar lesions on cognitive impairment and disability in CADASIL., Methods: We collected clinical data from 147 consecutive patients enrolled in an ongoing two-center prospective cohort study. Degree of disability was assessed by modified Rankin scale and Barthel index. Degree of cognitive impairment was assessed by Mattis Dementia Rating Scale and Mini-Mental Status Examination. T1-weighted, fluid-attenuated inversion recovery, and GE images were obtained on a 1.5-T MRI. Volume and location of lacunar lesions, white matter hyperintensities (WMHs), and CMs were assessed., Results: There was a significant independent association between age, volume of lacunar lesions, and global cognitive function scales when analyzed in a multivariable model. In contrast, WMHs and CMs had no independent influence on cognitive function. Disability in this cohort was associated with volume of lacunar lesions, CMs, systolic blood pressure, and age but not with WMHs., Conclusions: Among the lesions observed on conventional MRI in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the overall lacunar lesion burden seems to have the most important impact on cognitive function and disability. These findings suggest that preventive strategies to decrease the risk of lacunar lesions as observed on MRI may reduce disease-related impairment in CADASIL. These results suggest that lacunar lesions may also play a key role in disability and cognitive impairment in more common forms of small-vessel disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary arteriopathy caused by mutations of the Notch3 gene. The risk factors for cerebral microhaemorrhages (CM), their relationship to other MRI lesions in the disease and their potential clinical impact have not been previously defined. Our purpose was to examine the frequency, number and location of microhaemorrhages in a multicentre cohort study, defining predisposing factors and associated radiographic markers in CADASIL patients. We collected clinical data from 147 consecutive patients enrolled in an ongoing prospective cohort study. Degree of neurological disability and cognitive impairment were assessed by standardized scales. T(1)-weighted, FLAIR and T2*-weighted gradient-echo (GE) MRI sequences were performed. Volume and location of lacunar infarcts and white matter hyperintensity (WMH) were assessed. Number and location of CM were recorded. CM were present in 35% patients, most commonly occurring in the thalamus, brainstem and basal ganglia. The location of CM qualitatively differed from areas of lacunar infarction and WMH. There was a significant association between the presence of CM and a history of hypertension (P = 0.005), systolic blood pressure (SBP) (P = 0.014), haemoglobin A1c (HbA1c) (P = 0.004) and the volume of lacunar infarcts (P = 0.010) and WMHs (P = 0.046). The number of CM was independently associated with SBP (P = 0.005), the diagnosis of hypertension (P = 0.0004), volume of WMH (P = 0.0005) and lacunar infarcts (P = 0.004). In contrast, no association was found between blood pressure or HbA1c and the load of WMH or lacunar infarcts. The presence of CM was independently associated with increased modified Rankin scores. CM are independently associated with blood pressure and HbA1c as well as with lacunar infarct and WMH volume in CADASIL. Both the vascular risk factors and regional distribution of CM appear distinct from those associated with other MRI markers, suggesting a distinct pathological process. These lesions have a potential clinical impact in CADASIL. These findings further suggest that modulation of blood pressure and glucose levels might influence the course of the disease.

The authors sought to determine in a retrospective analysis whether carotid plaque soft TD on CT is associated with recent ischemic neurologic events. Among 141 patients (99 asymptomatic), 106 plaques with more than 50% stenosis were selected for density measurements. They found an odds ratio for neurologic events associated with a 10-point decrease in density of 1.54 (p = 0.002), showing an association between plaque density and neurologic events.

The clinical diagnosis of Marchiafava-Bignami disease (MBD) can be difficult. Acute demyelination of the corpus callosum is characteristic of the disease. The authors report the use of MR diffusion-weighted imaging (DWI) in six cases of acute MBD. They show that apparent diffusion coefficient restriction of the corpus callosum and cortical lesions were associated with a higher mortality rate and more severe cognitive sequelae.

Objectives: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging., Methods: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted., Results: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases., Conclusions: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.

The main goal of the study was to determine on MRI the cranial sutures, the craniometric points and craniometric measurements, and to correlate these results with classical anthropometric measurements. For this purpose, we reviewed 150 cerebral MRI examinations considered as normal (Caucasian population aged 20-49 years). For each examination we individualized 11 craniometric landmarks (Glabella, Bregma, Lambda, Opisthocranion, Opisthion, Basion, Inion, Porion, Infra-orbital, Eurion) and three measurements. Measurements were also calculated independently on 498 dry crania (Microscribe 3-DX digitizer). To validate the MRI procedure, we measured four dry crania by MRI and with compass or digital caliper gauges. Cranial sutures always appeared without signal (black), whatever the MRI sequence used, and they are better visualized with a 5 mm slice thickness (compact bone overlapping). Slice dynamic analysis and multiplanar reformatting allowed the detection of all craniometric points, some of these being more difficult to detect than others (Porion, Infra-orbital). The measurements determined by these points were as follows: Vertex-Basion height=135.66+/-6.56 mm; Eurion-Eurion width=141.17+/-5.19 mm; Glabella-Opisthocranion length=181.94+/-6.40 mm. On the midline T1-weighted sagittal image, all median craniometric landmarks can be individualized and the Glabella-Opisthocranion length, Vertex-Basion height and parenchyma indices can be calculated. Craniometric points and measurements between these points can be estimated with a standard cerebral MRI examination, with results that are similar to anthropometric data.

Objectives: To correlate changes of cranial vault measurements of an adult population during the aging process with brain size using the maximum width of the third ventricle in the axial AC-PC plane., Materials and Methods: Prospective study of 126 adult subjects (range: 20 to 80 years) with normal brain MRI and without history of neuropsychiatric disorder. MEASUREMENTS INCLUDED: Cranial vault (Maximum length: Glabella-Opisthocranion, Maximum width: euryon-euryon, and maximum height: Basion-Vertex) measurements and maximum width of the third ventricle in the A C-PC plane., Results: Vault measurements (length, width, high) were similar for every age group, irrespective of gender. The variability of cranial vault measurements between individuals was low (<1 cm). Cranial vault measurements were larger for men, but this was not significant when adjusted for body height Comparatively, a gradual widening of the third ventricle, with an exponential behavior, was observed with advancing age., Conclusion: Our results indicate that cranial vault measurements are stable over time (between 20-80 years) comparatively to brain atrophy with advancing age. The low variability of cranial vault measurements and their stability over time should be taken into account during segmentation and normalization of brain parenchymal structures.

Background and Purpose: To replace digital subtraction angiography (DSA) in carotid stenosis evaluation, noninvasive imaging techniques have to reach a high concordance rate. Our purpose is to compare the concordance rates of contrast-enhanced MR angiography (CEMRA) and CT angiography (CTA) with Doppler ultrasound (DUS) in clinical routine practice., Methods: We evaluated prospectively with DUS, CEMRA, and CTA 150 patients suspected of carotid stenosis. The overall concordance rates of the 3 techniques were calculated for symptomatic stenosis > or =50% and > or =70%, for asymptomatic stenosis > or =60%, and for occlusion. For the carotid arteries treated by surgery (n=97), the results of each method and combined techniques were recorded, and misclassification rates were evaluated from surgical reports., Results: The overall concordance rates of DUS-CEMRA, DUS-CTA, and CEMRA-CTA were not statistically different. However, the concordance rate of DUS-CEMRA (92.53%) was significantly higher than that for DUS-CTA (79.10%) in the surgical asymptomatic stenosis group (P=0.0258). CTA considered alone would misclassify the stenosis in a significant number of cases (11 of 64) in the surgical asymptomatic group compared with CEMRA (3 of 67) and DUS (1 of 66) (P=0.0186 versus MRA, P=0.0020 versus DUS)., Conclusions: With the techniques as utilized in our study, the overall concordance rates of combined noninvasive methods are similar for measuring carotid stenosis in clinical routine practice, but in asymptomatic carotid stenosis, the decision making for surgery is significantly altered if DUS and CTA are considered in place of DUS and CEMRA.

A method is presented for fully automated detection of Multiple Sclerosis (MS) lesions in multispectral magnetic resonance (MR) imaging. Based on the Fuzzy C-Means (FCM) algorithm, the method starts with a segmentation of an MR image to extract an external CSF/lesions mask, preceded by a local image contrast enhancement procedure. This binary mask is then superimposed on the corresponding data set yielding an image containing only CSF structures and lesions. The FCM is then reapplied to this masked image to obtain a mask of lesions and some undesired substructures which are removed using anatomical knowledge. Any lesion size found to be less than an input bound is eliminated from consideration. Results are presented for test runs of the method on 10 patients. Finally, the potential of the method as well as its limitations are discussed.

Quantitative assessment of Magnetic Resonance Imaging (MRI) lesion load of patients with multiple sclerosis (MS) is the most objective approach for a better understanding of the history of the pathology, either natural or modified by therapies. To achieve an accurate and reproducible quantification of MS lesions in conventional brain MRI, an automatic segmentation algorithm based on a multiresolution approach using pyramidal data structures is proposed. The systematic pyramidal decomposition in the frequency domain provides a robust and flexible low level tool for MR image analysis. Context-dependent rules regarding MRI findings in MS are used as high level considerations for automatic lesion detection.

Magnetic resonance imaging (MRI) has provided considerable insight into the pathological process and disease activity and progression in multiple sclerosis. MRI has become an important tool for the diagnosis of multiple sclerosis, and increasingly for monitoring treatment trial. The growing use of MRI calls for careful consideration in applications so that the technology is not misused. Here we propose a summary of the literature on MRI in application in clinical neurology.