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Objective: Multi-assessment batteries are necessary for diagnosing and quantifying the multifaceted deficits observed post-stroke. Extensive batteries are thorough but impractically long for clinical settings or large-scale research studies. Clinically-targeted “shallow” batteries superficially cover a wide range of language skills relatively quickly but can struggle to identify mild deficits or quantify the impairment level. Our aim was to compare these batteries across a large group of chronic stroke aphasia and to test a novel data-driven reduced version of an extensive battery that maintained sensitivity to mild impairment, ability to grade deficits and the underlying component structure. Methods: We tested 75 chronic left-sided stroke participants, spanning global to mild aphasia. The underlying structure of these three batteries was analysed using cross-validation and principal component analysis, in addition to univariate and multivariate lesion-symptom mapping. Results: This revealed a four-factor solution for the extensive and data-reduced batteries, identifying phonology, semantic skills, fluency and executive function in contrast to a two-factor solution using the shallow battery (language severity and cognitive severity). Lesion symptom mapping using participants’ factor scores identified convergent neural structures for phonology (superior temporal gyrus), semantics (inferior temporal gyrus), speech fluency (precentral gyrus) and executive function (lateral occipitotemporal cortex). The two shallow battery components converged with the phonology and executive function clusters. In addition, we show that multivariate models could predict the component scores using neural data, however not for every component. Conclusions: Overall, the data-driven battery appears to be an effective way to save time yet retain maintained sensitivity to mild impairment, ability to grade deficits and the underlying component structure observed in post-stroke aphasia.

BACKGROUND: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. METHODS: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. RESULTS: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p, Research grants from the UK Alzheimer's Society, the US Alzheimer’s Association and philanthropic donations. This work was funded by a grant for the PREVENT-Dementia programme from the UK Alzheimer’s Society (grant numbers 178 and 264), and the PREVENT-Dementia study is also supported by the US Alzheimer’s Association (grant number TriBEKa-17–519007) and philanthropic donations. AL is supported by the Lee Kuan Yew Fitzwilliam PhD Scholarship and the Tan Kah Kee Postgraduate Scholarship. JDS is a Wellcome clinical PhD fellow funded on grant 203914/Z/16/Z to the Universities of Manchester, Leeds, Newcastle and Sheffield. EM is supported by Alzheimer’s Society Junior Research Fellowship (RG 9611). LS is supported by the Cambridge NIHR Biomedical Research Centre (BRC) and Alzheimer’s Research UK (ARUK-SRF2017B-1). HSM is supported by an NIHR Senior Investigator award. JOB and HSM receive infrastructural support from the Cambridge NIHR Biomedical Research Centre (BRC). This research was supported by the NIHR Cambridge BRC (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Aphasia recovery post-stroke is classically and most commonly hypothesised to rely on regions that were not involved in language premorbidly, through 'neurocomputational invasion' or engagement of 'quiescent homologues'. Contemporary accounts have suggested, instead, that recovery might be supported by under-utilised areas of the premorbid language network, which are downregulated in health to save neural resources ('variable neurodisplacement'). Despite the importance of understanding the neural bases of language recovery clinically and theoretically, there is no consensus as to which specific regions are more likely to be activated in post-stroke aphasia (PSA) than healthy individuals. Accordingly, we performed an Activation Likelihood Estimation (ALE) meta-analysis of language functional neuroimaging studies in PSA. We obtained coordinate-based functional neuroimaging data for 481 individuals with aphasia following left-hemisphere stroke and 530 linked controls from 33 studies that met predefined inclusion criteria. ALE identified regions of consistent, above-chance spatial convergence of activation, as well as regions of significantly different activation likelihood, between participant groups and language tasks. Overall, these findings dispute the prevailing theory that aphasia recovery involves recruitment of novel right hemisphere territory into the language network post-stroke. Instead, multiple regions throughout both hemispheres were consistently activated during language tasks in both PSA and controls. Regions of the right anterior insula, frontal operculum and inferior frontal gyrus (IFG) pars opercularis were more likely to be activated across all language tasks in PSA than controls. Similar regions were more likely to be activated during higher than lower demand comprehension or production tasks, consistent with them representing enhanced utilisation of spare capacity within right hemisphere executive-control related regions. This provides novel evidence that 'variable neurodisplacement' underlies language network changes that occur post-stroke. Conversely, multiple undamaged regions were less likely to be activated across all language tasks in PSA than controls, including domain-general regions of medial superior frontal and paracingulate cortex, right IFG pars triangularis and temporal pole. These changes might represent functional diaschisis, and demonstrate that there is not global, undifferentiated upregulation of all domain-general neural resources during language in PSA. Such knowledge is essential if we are to design neurobiologically-informed therapeutic interventions to facilitate language recovery.

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression., Highlights • Heritable risk factors related to SVD progression, despite lower levels of inflammation. • SVD progression had more pronounced adverse effects on reaction time in at-risk individuals. • Association between SVD and inflammation was stronger in those at-risk.

IntroductionAssociations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging.MethodsForty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer’s disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195.ResultsGlobal [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=FDR=0.001–0.004).ConclusionMicroglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Aphasia recovery post-stroke is classically and most commonly hypothesised to rely on regions that were not involved in language premorbidly, through ‘neurocomputational invasion’ or engagement of ‘quiescent homologues’. Contemporary accounts have suggested, instead, that recovery might be supported by under-utilised areas of the premorbid language network, which are downregulated in health to save neural resources (‘variable neurodisplacement’). Despite the importance of understanding the neural bases of language recovery clinically and theoretically, there is no consensus as to which specific regions are activated more consistently in post-stroke aphasia (PSA) than healthy individuals. Accordingly, we performed an Activation Likelihood Estimation analysis of language functional neuroimaging studies in PSA and linked control data. We obtained coordinate-based functional neuroimaging data for 481 individuals with aphasia following left hemisphere stroke (one third of which was previously unpublished) and for 530 healthy controls. Instead of the language network expanding by activating novel right hemisphere regions ‘de novo’ post-stroke, as would be predicted by neurocomputational invasion/quiescent homologue engagement mechanisms of recovery, we found that multiple regions throughout both hemispheres were consistently activated during language tasks in PSA and controls. Multiple undamaged regions were less consistently activated in PSA than controls, including domain-general regions of medial superior frontal cortex and right fronto-temporal cortex. In the reverse direction, the right anterior insula and inferior frontal gyrus were more consistently activated in PSA than controls, particularly for executively-demanding comprehension tasks. These regions overlap with control networks known to be recruited during difficult tasks in healthy individuals and were more consistently activated by patients during higher than lower demand tasks in this meta-analysis. Overall, these findings run counter to neurocomputational invasion of the language network into new territory or engagement of quiescent homologues. Instead, many parts of the pre-existing language network are less consistently activated in PSA, except for more consistent use of spare capacity within right hemisphere executive-control related regions (cf. variable neurodisplacement). This study provides novel insights into the language network changes that occur post-stroke. Such knowledge is essential if we are to design neurobiologically-informed therapeutic interventions to facilitate language recovery.

Objective To explore the association between enzyme replacement therapy (ERT), clinical characteristics, and the rate of progression of white matter hyperintensities (WMH) in patients with Fabry disease (FD). Methods Patients with a confirmed diagnosis of FD, aged 18 years or older, participating in an existing FD observational study (NCT00196742), with at least 2 serial MRI brain scans at least 2 years apart for the period between December 2006 and August 2016 were included in this cohort study. Total WMH volume was estimated for each image using a semiautomated procedure. We performed linear regression to calculate the primary outcome measure of WMH change rate for each participant. Associations between ERT, clinical characteristics, and the primary outcome were explored using multiple linear regression. Results Eight hundred sixty-three MRI time points were analyzed for the 149 included participants. Age (p < 0.0005; increasing age associated with faster WMH progression), total cholesterol (p = 0.03; increasing total cholesterol associated with slower WMH progression), and a history of peripheral pain (p = 0.02; peripheral pain associated with faster WMH progression) were independently associated with WMH change rate in the primary analysis. We did not find an association between “ERT at any point between baseline and final MRI” and WMH change rate (p = 0.22). Conclusion In a large cohort of patients with FD, we did not find an association between ERT and WMH progression, while higher total cholesterol was associated with slower WMH progression. Further research is needed into the pathogenesis and treatment of cerebrovascular disease in this rare condition.

BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases.METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication.RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63).CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice.

INTRODUCTION:Cerebral small vessel disease (CSVD) is associated with late-onset Alzheimer's disease (LOAD) and might contribute to the relationship between apolipoprotein E ε4 (APOE ε4) and LOAD, in older people. However, it is unclear whether CSVD begins in middle age in individuals genetically predisposed to LOAD.METHODS:We assessed the relationship between radiological markers of CSVD, white matter hyperintensities and microbleeds, and genetic predisposition to LOAD in a cross-sectional analysis of cognitively normal subjects aged 40-59 years recruited from the PREVENT Dementia study.RESULTS:Microbleed prevalence was 14.5%, and mean ± standard deviation white matter hyperintensity percentage of total brain volume was 0.41 ± 0.28%. There was no significant association between APOE ε4 carrier status or history of parental dementia and white matter hyperintensity volume (P = .713, .912 respectively) or microbleeds (P = .082, .562 respectively) on multiple regression.DISCUSSION:Genetic predisposition to LOAD, through APOE genotype or AD family history, is not associated with CSVD in middle age.

Background Appropriate dissemination of clinical data is crucial for minimising bias. Despite this, high rates of study discontinuation and non-publication have been reported among clinical trials. Cardiovascular medicine receives a substantial proportion of academic funding; however, predictors of non-publication among cardiovascular trials are not well-established. Methods The National Clinical Trials database was searched for cardiovascular trials completed between January 2010 and January 2014. Associated publications were identified in Medline or Embase. Relevant variables were extracted and subject to chi-squared and logistic regression to identify predictors of discontinuation and non-publication. Results After reviewing 2035 trials, 431 trials were included, of which 82.1% ( n =354; 119,233 participants) were completed. Among completed trials, 70.3% ( n =249; 99,095 participants) were published. Industry funding was associated with increased likelihood of non-publication (odds ratio [OR] 2.84; 95% confidence interval [CI] 1.47–5.51; P =0.002), while non-randomised studies were more likely to remain unpublished than randomised counterparts. Industry-funded studies were over three times more likely to be discontinued than those sponsored by academic institutions (OR 3.89; CI 1.54–9.83; P =0.004). Trials studying heart failure and atrial fibrillation were more likely to be discontinued compared to trials studying coronary artery disease (OR 2.83; CI 1.23–6.51; and OR 3.10; CI 1.21–7.96, respectively). Of the total 135,714 participants, 25,565 were recruited into unpublished studies. Conclusions Discontinuation and non-publication of cardiovascular trials are common, resulting in data from thousands of participants remaining unpublished. Funding source and randomisation are strong predictors of non-publication, while sponsor type, phase and blinding status are key predictors of discontinuation.

IntroductionStroke is highly prevalent, with an estimated 25.7 million occurring worldwide in 20131. In an effort to reduce mortality and length of hospital stay2, hyperacute stroke services have been fully centralised in Greater Manchester since 2015 such that all possible strokes within 48 hours of onset are transferred for assessment at one of three stroke centres. However, there have been concerns regarding the transfer of stroke mimic diagnoses along such pathways.MethodsA retrospective analysis was performed of patients assessed by the hyperacute stroke team in the Emergency Department of the Comprehensive Stroke Centre (Salford Hospital) in December 2015.ResultsIn December 2015, 309 patients with queried stroke were assessed by the Comprehensive Stroke Centre hyperacute stroke team. Of these, 82% had been redirected or transferred from another hospital. 47% had a non-stroke diagnosis at discharge or repatriation, resulting in a combined 331 days of stay at Salford hospital by patients without a stroke. The five most common non-stroke diagnoses were TIA, migraine, infection, seizure and functional neurological disorder.ConclusionsThe optimal clinical care of non-stroke patients should be considered when planning centralisation of hyperacute stroke services.References1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. (2017). Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 135:0. doi:10.1161/CIR.00000000000004852. Morris S, Hunter RM, Ramsay AIG, et al. Impact of centralising acute stroke services in English metropolitan areas on mortality and length of study: Difference-in-differences analysis. BMJ 2014;349:4757.

Objective To investigate the characteristics associated with trial discontinuation and non-publication in four major neurodegenerative diseases. Methods We searched ClinicalTrials.gov for all randomised, interventional, phase II-IV trials that were registered between 1 st January 2000 and 31 st December 2009 and included adults with Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, or motor neurone disease. We identified publications from these trials by extensive online searching and contact with authors. Results We identified 362 eligible trials, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after five years. Trial discontinuation was independently associated with number of patients (p=0.015; more likely in trials with ≤100 patients) and phase of trial (p=0.009; more likely in phase IV trials). Trial non-publication was independently associated with blinding status (p=0.005; more likely in single-blind trials), number of centres (p=0.010; more likely in single-centre trials), phase of trial (p=0.041; more likely in phase II trials), and sponsor category (p=0.001; more likely in industry-sponsored trials). Conclusions We found evidence of dissemination bias in randomised trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases.

“So what do you want to specialise in?” It was a question I’d been dreading from my neurosurgery consultant. I wanted to do neurology, and told him so. His face lit up at the chance to preach his favourite message—I was told, with great pleasure, that neurologists “don’t do anything for patients” and …

AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts. METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints. RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups. CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.

Background Immunosuppression in Human Immunodeficiency Virus can predispose to opportunistic infections of the central nervous system and can be life threatening without early recognition and management. This can be delayed in undiagnosed Human Immunodeficiency Virus. The present article is the only case report in the literature to describe a first presentation of Acquired Immune Deficiency Syndrome as cerebral Nocardia abscesses that were initially treated as a stroke. Case presentation A previously well 59 year old Caucasian man presented with sudden onset of left sided hemiparesis and sensory change, right sided headache, diplopia and confusion. The patient was initially treated as a stroke but was eventually found to have pulmonary and cerebral Nocardia abscesses secondary to a new diagnosis of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome. Conclusion Human Immunodeficiency Virus infection can produce a variety of neurological presentations with the added possibility of multiple pathological processes being present simultaneously. This is only further complicated in instances, such as the present case, when Human Immunodeficiency Virus infection has not yet been diagnosed. It is therefore imperative that appropriate neuroimaging is done at an early stage to ensure timely initiation of appropriate therapy. Cerebral Nocardia abscesses are a serious and potentially life threatening complication of Human Immunodeficiency Virus.

Background: Circus type re-entry is classically associated with reduced action potential (AP) conduction velocity through partially refractory tissue resulting in unidirectional conduction block. We assessed the extent to which premature extrasystolic APs under such conditions resulted in ventricular arrhythmogenesis in isolated Langendorff-perfused murine hearts.Methods and Results: A novel programmed electrical stimulation (PES) protocol applied trains of 8 S1 stimuli at 100 ms intervals followed by extrasystolic S2 stimuli at successively decreasing S1S2 intervals. S2 stimulus strengths required to overcome refractoriness, reduce ventricular effective refractory period (VERP) and thereby elicit extrasystolic APs, increased with shortened S1S2 intervals, despite constant durations at 90% recovery (APD90) of the preceding APs. Critical interval, CI, the difference APD90-VERP, consequently increased with stimulus strength. The corresponding latencies and peak amplitudes of the extrasystolic APs consequently sharply increased and decreased respectively with CI thereby potentially replicating necessary conditions for re-entrant, circus-type, arrhythmia. The dependence of CI upon stimulus strength tended to consistent limiting values expected from approaches to absolute refractory periods. These values were greater in arrhythmogenic (mean CI 18.9±0.55 ms, n=4) than in non-arrhythmogenic hearts (mean CI 15.1±0.37, n=4; P=0.001, ANOVA), despite their statistically indistinguishable APD90 (arrhythmogenic hearts: 40.9±2.23 ms, n=4 vs non-arrhythmogenic hearts: 36.5±2.61ms, n=4; p>0.05, ANOVA) or VERP values (arrhythmogenic hearts: 22.5±2.66 ms, n=4 vs non-arrhythmogenic hearts: 21.8±2.53 ms, n=4; p>0.05, ANOVA).Conclusions: These findings suggest existence of a specific CI (CI∗) in turn corresponding to specific conditions of latency and action potential amplitude that would be sufficient to result in arrhythmogenesis.