MERRY CHRISTMAS

Melanopsin retinal ganglion cell loss in Alzheimer diseas

Objective

Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.

Methods

We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest–activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.

Results

We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.

Interpretation

We show variable degrees of rest–activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. 

Ann Neurol 2015

ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

Objective

Distal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent onset distal myopathy.

Methods

Four patients from 2 unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis.

Results

Patients had an adolescent onset distal myopathy phenotype that included distal dominant weakness, facial muscle weakness, rimmed vacuoles, and mild elevation of serum creatine kinase. Exome sequencing identified completely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1, which encodes a muscle-specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the mutation sites were located in well-conserved regions. Both the D304N and I350fs mutations inADSSL1 led to decreased enzymatic activity. The knockdown of the Adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knockdown zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect.

Interpretation

We suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adolescent onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics.

Annals of Neurology 2015

Clinical assessment of social cognitive function in neurological disorders

Social cognition broadly refers to the processing of social information in the brain that underlies abilities such as the detection of others' emotions and responding appropriately to these emotions. Social cognitive skills are critical for successful communication and, consequently, mental health and wellbeing. Disturbances of social cognition are early and salient features of many neuropsychiatric, neurodevelopmental and neurodegenerative disorders, and often occur after acute brain injury. Its assessment in the clinic is, therefore, of paramount importance. Indeed, the most recent edition of the American Psychiatric Association's Diagnostic and Statistical Manual for Mental Disorders (DSM-5) introduced social cognition as one of six core components of neurocognitive function, alongside memory and executive control. Failures of social cognition most often present as poor theory of mind, reduced affective empathy, impaired social perception or abnormal social behaviour. Standard neuropsychological assessments lack the precision and sensitivity needed to adequately inform treatment of these failures. In this Review, we present appropriate methods of assessment for each of the four domains, using an example disorder to illustrate the value of these approaches. We discuss the clinical applications of testing for social cognitive function, and finally suggest a five-step algorithm for the evaluation and treatment of impairments, providing quantitative evidence to guide the selection of social cognitive measures in clinical practice.

Nature Reviews Neurology 2015

Genetic risk factors for spontaneous intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is associated with the greatest morbidity and mortality of all stroke subtypes. Established risk factors for ICH include hypertension, alcohol use, current cigarette smoking, and use of oral anticoagulants and/or antiplatelet agents. Familial aggregation of ICH has been observed, and the heritability of ICH risk has been estimated at 44%. Few genes have been found to be associated with ICH at the population level, and much of the evidence for genetic risk factors for ICH comes from single studies conducted in relatively small and homogenous populations. In this Review, we summarize the current knowledge of genetic variants associated with primary spontaneous ICH. Two variants of the gene encoding apolipoprotein E (APOE) — which also contributes to the pathogenesis of cerebral amyloid angiopathy — are the most likely candidates for variants that increase the risk of ICH. Other promising candidates for risk alleles in ICH include variants of the genes ACE, PMF1/SLC25A44, COL4A2, and MTHFR. Other genetic variants, related to haemostasis, lipid metabolism, inflammation, and the CNS microenvironment, have been linked to ICH in single candidate gene studies. Although evidence for genetic contributions to the risk of ICH exists, we do not yet fully understand how and to what extent this information can be utilized to prevent and treat ICH

Nature Reviews Neurology 2015

Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P <0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood–brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1–28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood–brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.

Brain 2015

Axial myopathy: an overlooked feature of muscle diseases

Classically, myopathies are categorized according to limb or cranial nerve muscle affection, but with the growing use of magnetic resonance imaging it has become evident that many well-known myopathies have significant involvement of the axial musculature. New disease entities with selective axial muscle involvement have also been described recently, but overall the axial myopathy is unexplored. We performed a PubMed search using the search terms ‘myopathy’, ‘paraspinal’, ‘axial’ and ‘erector’. Axial myopathy was defined as involvement of paraspinal musculature. We found evidence of axial musculature involvement in the majority of myopathies in which paraspinal musculature was examined. Even in diseases named after a certain pattern of non-axial muscle affection, such as facioscapulohumeral and limb girdle muscular dystrophies, affection of the axial musculature was often severe and early, compared to other muscle groups. Very sparse literature evaluating the validity of clinical assessment methods, electromyography, muscle biopsy and magnetic resonance imaging was identified and reference material is generally missing. This article provides an overview of the present knowledge on axial myopathy with the aim to increase awareness and spur interest among clinicians and researchers in the field.

Brain 2015

Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants

Importance  Intracerebral hemorrhage (ICH) is the most devastating adverse event in patients receiving oral anticoagulation. There is only sparse evidence regarding ICH related to the use of non–vitamin K antagonist oral anticoagulant (NOAC) agents.

Objective  To evaluate the early clinical and radiological course, acute management, and outcome of ICH related to NOAC use.

Design, Setting, and Participants  Prospective investigator-initiated, multicenter observational study. All diagnostic and treatment decisions, including administration of hemostatic factors (eg, prothrombin complex concentrate), were left to the discretion of the treating physicians. The setting was 38 stroke units across Germany (February 1, 2012, to December 31, 2014). The study included 61 consecutive patients with nontraumatic NOAC-associated ICH, of whom 45 (74%) qualified for the hematoma expansion analysis.

Main Outcomes and Measures  Hematoma expansion, intraventricular hemorrhage, and reversal of anticoagulation during the acute phase. Recorded were the 3-month functional outcome, factors associated with an unfavorable outcome (modified Rankin Scale score, 3-6), any new intraventricular extension or an increase in the modified Graeb score by at least 2 points, and the frequency of substantial hematoma expansion (defined as relative [≥33%] or absolute [≥6-mL] volume increase).

Results  In total, 41% (25 of 61) of patients with NOAC-associated ICH were female, and the mean (SD) patient age was 76.1 (11.6) years. At admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range, 4-18). The mean (SD) baseline hematoma volume was 23.7 (31.3) mL. In patients with sequential imaging for the hematoma expansion analysis, substantial hematoma expansion occurred in 38% (17 of 45). New or increased intraventricular hemorrhage was observed in 18% (8 of 45). Overall mortality was 28% (17 of 60 [follow-up data were missing in 1 patient]) at 3 months, and 65% (28 of 43) of survivors had an unfavorable outcome (modified Rankin Scale score, 3-6). Overall, 57% (35 of 61) of the patients received prothrombin complex concentrate, with no statistically significant effect on the frequency of substantial hematoma expansion (43% [12 of 28] for prothrombin complex concentrate vs 29% [5 of 17] for no prothrombin complex concentrate, P = .53, or on the occurrence of an unfavorable outcome (modified Rankin Scale score, 3-6) (odds ratio, 1.20; 95% CI, 0.37-3.87; P = .76).

Conclusions and Relevance  Non–vitamin K antagonist oral anticoagulant–associated ICH has a high mortality and an unfavorable outcome, and hematoma expansion is frequent. Larger-scale prospective studies are needed to determine whether the early administration of specific antidotes can improve the poor prognosis of NOAC-associated ICH.

JAMA Neurology 2015

Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease

Importance  A reliable method of detecting Alzheimer disease (AD) in its prodromal state is needed for patient stratification in clinical trials or for personalizing existing or potential upcoming therapies. Current cerebrospinal fluid (CSF)– or imaging-based single biomarkers for AD offer reliable identification of patients with underlying AD but insufficient prediction of the rate of AD progression.

Objective  To optimize prediction of progression from mild cognitive impairment (MCI) to AD dementia by combining information from diverse patient variables.

Design, Setting, and Participants  This cohort study from the Alzheimer Disease Neuroimaging Initiative (ADNI) enrolled 928 patients with MCI at baseline and 249 selected variables available in the ADNI data set. Variables included clinical and demographic data, cognitive scores, magnetic resonance imaging–based brain volumetric data, the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes, and analyte levels measured in the CSF and plasma. Data were collected in July 2012 and analyzed from July 1, 2012, to June 1, 2015.

Main Outcomes and Measures  Progression from MCI to AD within 1 to 6 years. To determine whether combinations of markers could predict progression from MCI to AD within 1 to 6 years, the elastic net algorithm was used in an iterative resampling of a training- and test-based variable selection and modeling approach.

Results  Among the 928 patients with MCI in the ADNI database, 94 had 224 of the required variables available for the modeling. The results showed the contributions of age, Clinical Dementia Rating Sum of Boxes composite test score, hippocampal volume, and multiple plasma and CSF factors in modeling progression to AD. A combination of apolipoprotein A-II and cortisol levels in plasma and fibroblast growth factor 4, heart-type fatty acid binding protein, calcitonin, and tumor necrosis factor–related apoptosis-inducing ligand receptor 3 (TRAIL-R3) in CSF allowed for reliable prediction of disease status 3 years from the time of sample collection (80% classification accuracy, 88% sensitivity, and 70% specificity).

Conclusions and Relevance  These study findings suggest that a combination of markers measured in plasma and CSF, distinct from β-amyloid and tau, could prove useful in predicting midterm progression from MCI to AD dementia. Such a large-scale, multivariable-based analytical approach could be applied to other similar large data sets involving AD and beyond.

JAMA Neurology 2015

Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study NINDS Stroke Genetics Network (SiGN), International Stroke Genetics Consortium (ISGC)† †Members listed at end of the paper

Background

The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.

Methods

To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.

Findings

We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13–1·30, p=4·50 × 10−8; joint OR 1·19, 1·12–1·26, p=1·30 × 10−9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29–1·49, p=3·26 × 10−19; joint OR 1·37, 1·30–1·45, p=2·79 × 10−32) and ZFHX3 (first stage OR 1·19, 1·11–1·27, p=2·93 × 10−7; joint OR 1·17, 1·11–1·23, p=2·29 × 10−10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18–1·42, p=3·50 × 10−8; joint OR 1·24, 1·15–1·33, p=4·52 × 10−9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12–1·28, p=6·82 × 10−8; joint OR 1·17, 1·11–1·23, p=2·92 × 10−9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.

Interpretation

Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke

Lancet Neurology 2015

Clinical features of neuromyelitis optica in children US Network of Pediatric MS Centers report

Objective: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases.

Methods: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified.

Results: Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS.

Conclusion: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.

Neurology 2015

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Predictors for atrial fibrillation detection after cryptogenic stroke Results from CRYSTAL AF

Objective: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM).

Methods: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS₂ score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models.

Results: Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4–2.8], p = 0.002), CHADS₂ score (HR 1.9 per one point [1.3–2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2–1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3–12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0–5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3–2.8], p = 0.0009) and PR interval (HR 1.3 [1.2–1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70–0.85). The same predictors were found at 36 months.

Conclusion: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Neurology 2015

Neuroleptic-induced Parkinsonism: Clinicopathological study

Background

Drug-induced parkinsonism is a well-known complication of several different drugs—the most common being neuroleptic-induced parkinsonism. However, very few autopsies have been reported in such cases.

Methods

Patients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept.

Results

Brains were obtained from 7 drug-induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine-blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies.

Conclusion

This study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, l-dopa does not appear to be toxic to SN. 

Movement Disorders 2015

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

BACKGROUND

Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.

METHODS

Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti–factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.

RESULTS

Among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti–factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels ofd-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.

CONCLUSIONS

Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects

NEJM 2015

Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME

Objective

Within the context of a prospective randomized trial (SWIFT PRIME), we assessed whether early imaging of stroke patients, primarily with computed tomography (CT) perfusion, can estimate the size of the irreversibly injured ischemic core and the volume of critically hypoperfused tissue. We also evaluated the accuracy of ischemic core and hypoperfusion volumes for predicting infarct volume in patients with the target mismatch profile.

Methods

Baseline ischemic core and hypoperfusion volumes were assessed prior to randomized treatment with intravenous (IV) tissue plasminogen activator (tPA) alone versus IV tPA + endovascular therapy (Solitaire stent-retriever) using RAPID automated postprocessing software. Reperfusion was assessed with angiographic Thrombolysis in Cerebral Infarction scores at the end of the procedure (endovascular group) and Tmax > 6-second volumes at 27 hours (both groups). Infarct volume was assessed at 27 hours on noncontrast CT or magnetic resonance imaging (MRI).

Results

A total of 151 patients with baseline imaging with CT perfusion (79%) or multimodal MRI (21%) were included. The median baseline ischemic core volume was 6ml (interquartile range = 0–16). Ischemic core volumes correlated with 27-hour infarct volumes in patients who achieved reperfusion (r = 0.58, p < 0.0001). In patients who did not reperfuse (<10% reperfusion), baseline Tmax > 6-second lesion volumes correlated with 27-hour infarct volume (r = 0.78, p = 0.005). In target mismatch patients, the union of baseline core and early follow-up Tmax > 6-second volume (ie, predicted infarct volume) correlated with the 27-hour infarct volume (r = 0.73, p < 0.0001); the median absolute difference between the observed and predicted volume was 13ml.

Interpretation

Ischemic core and hypoperfusion volumes, obtained primarily from CT perfusion scans, predict 27-hour infarct volume in acute stroke patients who were treated with reperfusion therapies. 

Ann Neurol 2015