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BackgroundAstrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitter synaptic homeostasis. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The neuronal support provided by astrocytes has a high metabolic demand. Deficits in astrocytic mitochondrial metabolic functioning and glycolysis could impair neuronal function. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti-amyloid treatments in AD.MethodsIn this project, we characterised mitochondrial and glycolytic function in astrocytes derived from patients with sporadic (n=6) and familial (PSEN1, n=3) forms of AD. Astrocytes were derived using direct reprogramming methods. Astrocyte metabolic outputs: ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene.ResultsThere was a reduction of total cellular ATP of 20% (p=0.05 in sAD astrocytes) and of 48% (pConclusionAD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These functional deficits can be improved by correcting hexokinase expression deficits with adenoviral vectors. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.

Objective: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. Data sources: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. Study selection and data extraction: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. Data synthesis: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. Relevance to patient care and clinical practice: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. Conclusions: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.

Background: Apathy is a common and early symptom in Alzheimer’s disease (AD) and is linked to poorer prognosis. Theoretical interpretations of apathy implicate alterations of connections amongst fronto-striatal and limbic regions. Objective: To test the association between presence of apathy and patterns of brain functional connectivity in patients with clinically-established AD. Methods: Seventy AD patients were included. Thirty-five patients experienced apathy as defined by the screening question of the Neuropsychiatric Inventory, and thirty-five did not. All patients agreed to undergo an MRI protocol inclusive of resting-state acquisitions. The hemodynamic-dependent signal was extracted bilaterally from five regions of interest: ventromedial prefrontal cortices, anterior cingulate cortices, dorsolateral prefrontal cortices, insulae and amygdalae. t tests were run to compare connectivity maps of apathetic and non-apathetic patients. Age, education, Mini Mental State Examination score, gray matter volumes and gray matter fractions served as covariates. Results: At a pFWE < 0.05 threshold, apathetic patients had reduced connectivity between the left insula and right superior parietal cortex. Apathetic patients had also increased connectivity between the right dorsolateral prefrontal seed and the right superior parietal cortex. Patients with apathy were significantly more likely to experience other psychiatric symptoms. Conclusion: Our findings support a role of frontal and insular connections in coordinating value-based decisions in AD. Both down-regulation and maladaptive up-regulation mechanisms appear to be at play in these regions.

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ∼50% of the mass of soluble Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics.

Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. Copyright: © 2021 by the authors. Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use. Wellcome 4ward North Academy and ARUK Yorkshire Network Centre Small Grant Scheme; Parkinson’s UK (F1301); NIHR Sheffield Biomedical Research Centre; European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 601055, VPH-DARE@IT; NIHR Senior Investigator award; NIHR Clinical Research Facility—Sheffield Teaching Hospital

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients’ needs to be accomplished first to meet this aim.

Alzheimer&rsquo, s disease (AD) is diagnosed using neuropsychological testing, supported by amyloid and tau biomarkers and neuroimaging abnormalities. The cause of neuropsychological changes is not clear since they do not correlate with biomarkers. This study investigated if changes in cellular metabolism in AD correlate with neuropsychological changes. Fibroblasts were taken from 10 AD patients and 10 controls. Metabolic assessment included measuring total cellular ATP, extracellular lactate, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolytic function. All participants were assessed with neuropsychological testing and brain structural MRI. AD patients had significantly lower scores in delayed and immediate recall, semantic memory, phonemic fluency and Mini Mental State Examination (MMSE). AD patients also had significantly smaller left hippocampal, left parietal, right parietal and anterior medial prefrontal cortical grey matter volumes. Fibroblast MMP, mitochondrial spare respiratory capacity (MSRC), glycolytic reserve, and extracellular lactate were found to be lower in AD patients. MSRC/MMP correlated significantly with semantic memory, immediate and delayed episodic recall. Correlations between MSRC and delayed episodic recall remained significant after controlling for age, education and brain reserve. Grey matter volumes did not correlate with MRSC/MMP. AD fibroblast metabolic assessment may represent an emergent disease biomarker of AD.

Natalizumab is one of the most effective therapies for relapsing-remitting multiple sclerosis. One complication is progressive multifocal leucoencephalopathy, a viral brain infection caused by John Cunningham virus (JCV). Monitoring of neurological symptoms, JCV serology and regular brain imaging are required to ensure safe use of this therapy. Local audit data from 2015 indicated poor compliance with safety monitoring: under 25% of investigations were within recommended timeframes. Subsequently, a protocol was implemented to improve monitoring, with specialist nurses coordinating requests for MRI scans and arranging JCV serology, with frequency determined according to JCV index. A re-audit assessed the impact of this protocol (n=155). Some 97.4% of patients were appropriately tested for JCV and 88.4% were imaged within the recommended interval. Additional work with the informatics and virology team ensured serology results became more easily accessible. The use of a standardised, nurse-led operating procedure has resulted in marked improvement in the safety monitoring of natalizumab.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease patients as well as several animal models of AD and Parkinson's disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition, we show reductions in dynamin-related protein 1 (Drp1) level, particularly the amount localized to mitochondria in both sAD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease., Graphical Abstract Unlabelled Image, Highlights • Sporadic and PSEN1 fibroblasts share a changed mitochondrial phenotype. • This phenotype consists of reduced membrane potential and altered morphology. • Ursodeoxycholic acid corrects mitochondrial morphology and membrane potential. • Ursodeoxycholic acid effects act via action on Drp1 quantity and localization. • This paper highlights the potential use of UDCA to treat Alzheimer's disease.

Objective: An association between cerebral venous sinus thrombosis (CVST) and high altitude has been previously proposed, but limited published data exist to support this association. We investigated 28 cases of CVST occurring at high altitude and sought to describe patient demographics, altitude and acclimatization, hematological laboratory findings, neuroimaging, treatment, and prognosis in these cases. Methods: Twenty-eight cases of symptomatic CVST occurring at high altitude were identified between the months of August 2017 and December 2018, in collaboration with Military Hospital, Rawalpindi and Combined Military Hospital, Skardu (Pakistan). Follow-up visits were performed at 1 and 6 months. Results: Twenty-seven (96%) of the patients were males, and the mean age was 33 years. In total, 32.1% were smokers. The mean NIHSS score on presentation was 5.5. 85.7% of the cases occurred at altitude higher than 8,000 feet. On average 107.8 days were spent at a high altitude prior to CVST. Totally, 71.4% had acclimatized for >2 weeks. The mean hemoglobin (Hb) value was 16.7 g/dL and 50% had d-dimer levels higher than 1,000 ng/mL. On MRI, 25% showed signs of hemorrhage and 14.3% showed infarcts. Treatments provided include low-molecular-weight heparin and Rivaroxaban and were associated with good outcomes. Conclusion: CVST is not uncommon at high altitude (>8,000 feet). It is predominantly a male disease. Most patients have high Hb and high D-dimer levels. The overall outcome was good.

When an unidentified patient who cannot communicate presents with symptoms and signs suggesting an acute stroke, the decision to thrombolyse is a particular challenge. In a time-pressured environment, clinicians need clear thought processes for diagnosis and treatment. Ethical considerations, diagnosis, identity and previous history, contraindications, time of symptom onset (EDICT) can help decision-making in this situation.

Background: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. Methods: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. Results: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization, but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44, interquartile range (IQR) 0.41 vs. HC = 0.15, IQR 0.17, p &lt, 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p &lt, 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075, IQR 0.03, p &lt, 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). Conclusion: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD.

INTRODUCTION: Autologous haematopoietic cell transplantation (AHCT) is an evolving treatment avenue in multiple sclerosis (MS), which may be highly effective in controlling disease activity and improving disability. However, AHCT is associated with intrinsic toxicities and risks compared with conventional therapies. With growing experience in patient selection and treatment delivery, AHCT is increasingly considered an option in patients with aggressive disease that's responding poorly to disease modifying therapy. AREAS COVERED: This article provides an introduction to AHCT and looks at its development as a treatment for MS over the last 20 years. It also highlights potential mechanisms of action, patient selection, and future trends for this treatment approach. EXPERT OPINION: Currently published data suggest that AHCT's use is associated with significant reduction in MS disease activity and marked improvement in disability when used in patients with highly active relapsing remitting disease. Its long term safety and efficacy have not been fully evaluated but as increasing clinical trial data are published, its use is likely to grow. Further randomised controlled studies are needed to compare AHCT with standard disease modifying therapies and to optimise transplant regimens. Mechanistic studies may provide potential markers for response and a better understanding of disease pathogenesis.

Natalizumab is one of the most effective therapies for relapsing-remitting Multiple Sclerosis. One complication is Progressive Multifocal Leucoencephalopathy (PML), a viral brain infection in patients already infected with JC virus. Monitoring of neurological symptoms, JC virus serology and regular brain imaging are required to ensure safe use of this therapy. Local audit data from 2015 indicated poor compliance with safety monitoring, with less than 25% of patients undergoing required investigations within the recommended time intervals. Subsequently a protocol was implemented to improve monitoring, with specialist nurses coordinating the requests for MRI scans and arranging JC virus serology, the frequency of which was determined according to the JC virus index. The records of all patients receiving Natalizumab at the centre were audited to assess the impact of this protocol (n=155). 99.2% of patients were appropriately tested for JC virus and 95.3% were imaged within the recommended interval. Additional work with the informatics and virology team ensured serology results became more easily accessible. The use of a standardised nurse-led operating procedure has resulted in marked improvement in the safety monitoring of Natalizumab.

Intracerebral haemorrhage (ICH) has an overall incidence of 24.6 per 100,000 person-years and is associated with a high case fatality. Understanding the risk factors for ICH occurrence informs primary prevention strategies. This article provides an update on the current global patterns of ICH incidence and the common and emerging risk factors associated with ICH.We searched Ovid Medline (from 1980 to Oct 2014) for systematic reviews that addressed the epidemiology of ICH and for recent original studies that revealed new insights into the frequency of and the risk factors associated with ICH.The incidence of ICH has not changed over the last 30 years, and this consistency is thought to be due to changes in the risk factor profiles of ICH patients. It appears that ICH is more common in men and during the winter months. ICH affects Asian populations more frequently than other populations. In addition to the known risk factors of hypertension and increasing age, alcohol consumption, the presence of the apolipoprotein ε2 or ε4 allele, extremes of body mass index, diabetes, and ophthalmic conditions have been suggested to be associated with ICH. Factors associated with a reduced risk of ICH include hypercholesterolaemia and a diet high in fruits and vegetables.The overall incidence of ICH has remained unchanged, but its regional incidence varies by race, sex, season and geographical location. In high income countries, the beneficial effect of improving blood pressure control may be counterbalanced by the increased use of antithrombotic drugs. Emerging modifiable risk factors include alcohol consumption, body mass index, diabetes, and fruit and vegetable intake, all of which may be amenable to interventions for the primary prevention of ICH (as well as many other diseases).

Introduction: Intracerebral haemorrhage (ICH) has an overall incidence of 24.6 per 100,000 person-years and is associated with a high case fatality. Understanding the risk factors for ICH occurrence informs primary prevention strategies. This article provides an update on the current global patterns of ICH incidence and the common and emerging risk factors associated with ICH. Methods: We searched Ovid Medline (from 1980 to Oct 2014) for systematic reviews that addressed the epidemiology of ICH and for recent original studies that revealed new insights into the frequency of and the risk factors associated with ICH. Results: The incidence of ICH has not changed over the last 30 years, and this consistency is thought to be due to changes in the risk factor profiles of ICH patients. It appears that ICH is more common in men and during the winter months. ICH affects Asian populations more frequently than other populations. In addition to the known risk factors of hypertension and increasing age, alcohol consumption, the presence of the apolipoprotein e2 or e4 allele, extremes of body mass index, diabetes, and ophthalmic conditions have been suggested to be associated with ICH. Factors associated with a reduced risk of ICH include hypercholesterolaemia and a diet high in fruits and vegetables. Conclusions: The overall incidence of ICH has remained unchanged, but its regional incidence varies by race, sex, season and geographical location. In high income countries, the beneficial effect of improving blood pressure control may be counterbalanced by the increased use of antithrombotic drugs. Emerging modifiable risk factors include alcohol consumption, body mass index, diabetes, and fruit and vegetable intake, all of which may be amenable to interventions for the primary prevention of ICH (as well as many other diseases).

A 66-year-old man presented to the emergency department with paraesthesia starting in the first two fingers of his right hand, spreading up his right arm into the right side of his face and mouth over 10 min. During this, his mouth felt numb “like after a dental injection”. He had three further similar episodes in the emergency department. He had a past history of hypothyroidism and irritable bowel syndrome. After a CT scan of head (figure 1), he started treatment with an antiplatelet medication for a presumed transient ischaemic attack (TIA). An MR scan of brain the next day showed a small amount of subarachnoid blood in the left central (rolandic) sulcus (figure 2). We therefore stopped the antiplatelet treatment. Over the next month, he continued having almost daily episodes of tingling and numbness affecting his hand and face, each lasting 20 min. One episode affected his throat, leaving him unable to speak for several minutes (figure 3 and supplementary video on the website). Figure 1 Non-enhanced CT brain shows high attenuation acute subarachnoid blood within the left central sulcus. …

Stroke medicine is a multifaceted specialty that offers opportunities to work in acute settings and help patients in their long term rehabilitation

Introduction Quantitative Electroencephalography (qEEG) has been shown to distinguish AD patients from healthy controls (HC) at a group but not at an individual level. A novel qEEG data analysis method created at the University of Sheffield can measure linear and non-linear levels of brain synchronisation in the time domain. Methods Patients with AD and HV had resting state EEGs. The standard 10–20 international system of EEG electrode placement was used. All patients had MRI and detailed neuropsychology as part of the European VPH-DARE@IT project. Custom made software (Error Reduction Ratio-causality (ERR-causality) analysed average strength of linear and non-linear synchronization in bicentroparietal region. Results 10 HC and 10 AD EEGs were included. Mean ages were 58.1 (AD) versus 62.2 y (HV). Mean mini-mental state examinations were 17.5 (AD) and 28.50 (HV). The ratio of bi-centroparietal synchronisation between eyes open & eyes close (EO/EC) showed a striking difference between the two groups (AD ratio 0.814 versus HC ratio 0.282, p=0.0006). Conclusions These results suggest that patients with AD have higher levels of EO bi-centroparietal synchronisation & in particular the ratio between EO/EC synchronisation has potential to be used as a non-invasive and inexpensive biomarker or diagnostic tool for AD.

BackgroundAutologous haemopoietic stem cell transplantation (AHSCT) is an evolving therapy for multiple sclerosis (MS). Here we present the Sheffield experience since 2006.MethodsRetrospective review of MS cases referred for and treated with AHSCT. Toxicity, clinical and radiological outcome were assessed.Results14 patients (8 Rapidly evolving severe [REMS], 3 Relapsing Remitting [RRMS], 3 Secondary Progressive [SPMS]) were selected for AHSCT. One patient underwent AHSCT on a clinical trial (data excluded from analysis). Mean age 34.6 years (SD 8.69), median pretreatment EDSS 6.5 (IQR0.5). All had clinically and radiologically aggressive disease, non-responsive to standard treatment. Follow up range was 3 to 96 months.All patients were successfully mobilized, 2 patients progressed only to harvest (1 compliance issues, 1 leg ulcer). All patients were treated according to international guidelines. No excess toxicity or treatment related mortality was observed.Post-transplant MRI's showed no active disease. No patients with RRMS suffered relapse post-transplant, median reduction in EDSS scores was 2 at both 100 days (IQR 2) and at last follow up (IQR 2.5). EDSS scores stabilised in patients with SPMS.ConclusionAHSCT is an effective treatment with acceptable toxicity in patients with aggressive, inflammatory MS.

The 2009 Dementia strategy promoted a ‘memory clinic in every town’. We investigated the patient mix seen in a neurology-led memory clinic. Retrospective review (2004, 2006, 2012) attendees to memory clinic. Prospective review memory clinic from October 2012–Dec 2013. Survey to neurologists in Specialist Interest Group in Cognition (ABN). Survey of local GPs. Results Percentage of attendees with benign memory complaints increased from 30% & 32% in 2004 and 2006 to 55% in 2012. Oct 2012–Dec 2013 >50% attendees do not have dementia or MCI. 9 responders: A mean of 27% of attendees of neurology-led memory clinics in the UK have ‘benign memory complaints’. The following terms were used: ▸ Attentional amnestic disorder, ▸ Attentional cognitive complaints, ▸ Worried well, ▸ Subjective memory complaints, ▸ Subjective memory impairment, ▸ Normal cognitive ageing, ▸ Hypocondrial, ▸ ‘Stress related.’ 4. GPs used; ‘worried well’, ‘benign senescent forgetfulness’, ‘Possible dementia’, ‘mild neurocognitive disorder’ and ‘late life forgetfulness’ & treated with antidepressants but also referred to psychology or memory clinic. People attending memory clinic frequently do not have dementia and currently there is no consensus for diagnostic label or treatment.