Abstract Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms, which will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

BackgroundIncreasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms.Methods/designThis paper outlines the clinical, cognitive and imaging protocol of “Insight 46”, a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer’s disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60–64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73).DiscussionThrough the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

No abstract

Aim To describe the neuroradiological changes in patients with coronavirus disease 2019 (COVID-19). Materials and methods A retrospective review was undertaken of 3,403 patients who were confirmed positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and admitted to our institution between 1 March 2020 and 31 May 2020, and who underwent neuroimaging. Abnormal brain imaging was evaluated in detail and various imaging patterns on magnetic resonance imaging MRI were identified. Results Of the 3,403 patients with COVID-19, 167 (4.9%) had neurological signs or symptoms warranting neuroimaging. The most common indications were delirium (44/167, 26%), focal neurology (37/167, 22%), and altered consciousness (34/167, 20%). Neuroimaging showed abnormalities in 23% of patients, with MRI being abnormal in 20 patients and computed tomography (CT) in 18 patients. The most consistent neuroradiological finding was microhaemorrhage with a predilection for the splenium of the corpus callosum (12/20, 60%) followed by acute or subacute infarct (5/20, 25%), watershed white matter hyperintensities (4/20, 20%), and susceptibility changes on susceptibility-weighted imaging (SWI) in the superficial veins (3/20, 15%), acute haemorrhagic necrotising encephalopathy (2/20, 10%), large parenchymal haemorrhage (2/20, 10%), subarachnoid haemorrhage (1/20, 5%), hypoxic–ischaemic changes (1/20, 5%), and acute disseminated encephalomyelitis (ADEM)-like changes (1/20, 5%). Conclusion Various imaging patterns on MRI were observed including acute haemorrhagic necrotising encephalopathy, white matter hyperintensities, hypoxic-ischaemic changes, ADEM-like changes, and stroke. Microhaemorrhages were the most common findings. Prolonged hypoxaemia, consumption coagulopathy, and endothelial disruption are the likely pathological drivers and reflect disease severity in this patient cohort.

We present a validation study comparing results from a patient-specific lattice-Boltzmann simulation to transcranial Doppler (TCD) velocity measurements in four different planes of the middle cerebral artery (MCA). As part of the study, we compared simulations using a Newtonian and a Carreau-Yasuda rheology model. We also investigated the viability of using downscaled velocities to reduce the required resolution. Simulations with unscaled velocities predict the maximum flow velocity with an error of less than 9%, independent of the rheology model chosen. The accuracy of the simulation predictions worsens considerably when simulations are run at reduced velocity, as is for example the case when inflow velocities from healthy individuals are used on a vascular model of a stroke patient. Our results demonstrate the importance of using directly measured and patient-specific inflow velocities when simulating blood flow in MCAs. We conclude that localized TCD measurements together with predictive simulations can be used to obtain flow estimates with high fidelity over a larger region, and reduce the need for more invasive flow measurement procedures.

ObjectiveTo summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study.DesignProspective observational sub-study of a birth cohort.SettingSingle-day assessment at a research centre in London, UK.Participants502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female.Outcome measuresData regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated.Results93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11).ConclusionsIn older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings.

Objective: This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). Methods: Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data. Results: Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. Interpretation: We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. ANN NEUROL 2016;80:882-895 T he cause of focal epilepsy syndromes, including frontal lobe epilepsies (FLEs), is being regularly advanced through clinical, genetic, and pathological studies. 1 Novel gene mutations have been recently identified; for example, DEPDC5 mutations are associated with familial FLE syndromes (familial focal epilepsy with variable foci 1,2 as well as cases of sporadic FLE and with pathologically proven focal cortical dysplasia (FCD). [3][4][5] Historically, studies of histologically defined malformations of cortical development in symptomatic epilepsies have significantly advanced identification of specific genetic defects and causative cellular pathways. 6,7 FCD is a cortical malformation first recognized in an epilepsy surgical pathology series in 1971 8 and is now the commonest histologically confirmed malformation, with a predilection for the frontal lobe. 9 Although FCD mainly occurs sporadically, somatic or germline mutations in mammalian target of rapamycin (mTOR) pathway genes have now been reported by several groups. [10][11][12] There are currently nine subtypes of FCD, defined by their pathological characteristics of cytoarchitectural and associated abnormalities. 13 FCD ty...

Objective: To find the covert patterns of abnormality in patients with unilateral temporal lobe epilepsy (TLE) and visually normal brain magnetic resonance images (MRI-negative), comparing them to those with visible abnormalities (MRI-positive). Methods: We used multimodal brain MRI from patients with unilateral TLE and employed contemporary machine learning methods to predict the known laterality of seizure onset in 104 subjects (82 MRI-positive, 22 MRI-negative). A visualization approach entitled "Importance Maps" was developed to highlight image features predictive of seizure laterality in both the MRI-positive and MRI-negative cases. Results: Seizure laterality could be predicted with an area under the receiver operating characteristic curve of 0.981 (95% confidence interval [CI] =0.974-0.989) in MRI-positive and 0.842 (95% CI = 0.736-0.949) in MRI-negative cases. The known image features arising from the hippocampus were the leading predictors of seizure laterality in the MRI-positive cases, whereas widespread temporal lobe abnormalitieswere revealed in the MRI-negative cases. Significance: Covert abnormalities not discerned on visual reading were detected in MRI-negative TLE, with a spatial pattern involving the whole temporal lobe, rather than just the hippocampus. This suggests that MRI-negative TLE may be associated with subtle but widespread temporal lobe abnormalities. These abnormalities merit close inspection and postacquisition processing if there is no overt lesion. K E Y W O R D Sabnormality, data-driven, epilepsy, machine learning, MRI-negative