The protective role of carnosine against type 2 diabetes-induced cognitive impairment.

The morbidity and mortality associated with type 2 diabetes mellitus (T2DM) have grown exponentially over the last 30 years. Together with its associated complications, the mortality rates have increased. One important complication in those living with T2DM is the acceleration of age-related cognitive decline. T2DM-induced cognitive impairment seriously affects memory, executive function, and quality of life. However, there is a lack of effective treatment for both diabetes and cognitive decline. Thus, finding novel treatments which are cheap, effective in both diabetes and cognitive impairment, are easily accessible, are needed to reduce impact on patients with diabetes and health-care systems. Carnosine, a histidine containing dipeptide, plays a protective role in cognitive diseases due to its antioxidant, anti-inflammation, and anti-glycation properties, all of which may slow the development of neurodegenerative diseases and ischemic injury. Furthermore, carnosine is also involved in regulating glucose and insulin in diabetes. Herein, we discuss the neuroprotective role of carnosine and its mechanisms in T2DM-induced cognitive impairment, which may provide a theoretical basis and evidence base to evaluate whether carnosine has therapeutic effects in alleviating cognitive dysfunction in T2DM patients.

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-ß in Alzheimer's disease.

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-ß (Aß) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aß in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aß co-aggregates account for ~50% of the mass of diffusible Aß aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aß tune disease-related functions of Aß aggregates throughout the course of aggregation. 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 Aß. Selectively removing non-lipidated apoE4-Aß co-aggregates enhances clearance of toxic Aß by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Gene Expression Studies in Down Syndrome: What Do They Tell Us about Disease Phenotypes?

Down syndrome is a well-studied aneuploidy condition in humans, which is associated with various disease phenotypes including cardiovascular, neurological, haematological and immunological disease processes. This review paper aims to discuss the research conducted on gene expression studies during fetal development. A descriptive review was conducted, encompassing all papers published on the PubMed database between September 1960 and September 2022. We found that in amniotic fluid, certain genes such as COL6A1 and DSCR1 were found to be affected, resulting in phenotypical craniofacial changes. Additionally, other genes such as GSTT1, CLIC6, ITGB2, C21orf67, C21orf86 and RUNX1 were also identified to be affected in the amniotic fluid. In the placenta, dysregulation of genes like MEST, SNF1LK and LOX was observed, which in turn affected nervous system development. In the brain, dysregulation of genes DYRK1A, DNMT3L, DNMT3B, TBX1, olig2 and AQP4 has been shown to contribute to intellectual disability. In the cardiac tissues, dysregulated expression of genes GART, ETS2 and ERG was found to cause abnormalities. Furthermore, dysregulation of XIST, RUNX1, SON, ERG and STAT1 was observed, contributing to myeloproliferative disorders. Understanding the differential expression of genes provides insights into the genetic consequences of DS. A better understanding of these processes could potentially pave the way for the development of genetic and pharmacological therapies.

Histidine-containing dipeptide supplementation improves delayed recall: a systematic review and meta-analysis.

CONTEXT: Histidine-containing dipeptides (carnosine, anserine, beta-alanine and others) are found in human muscle tissue and other organs like the brain. Data in rodents and humans indicate that administration of exogenous carnosine improved cognitive performance. However, RCTs results vary. OBJECTIVES: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) of histidine-containing dipeptide (HCD) supplementation on cognitive performance in humans to assess its utility as a cognitive stabiliser. DATA SOURCES: OVID Medline, Medline, EBM Reviews, Embase, and Cumulative Index to Nursing and Allied Health Literature databases from 1/1/1965 to 1/6/2022 for all RCT of HCDs were searched. DATA EXTRACTION: 2653 abstracts were screened, identifying 94 full-text articles which were assessed for eligibility. Ten articles reporting the use of HCD supplementation were meta-analysed. DATA ANALYSIS: The random effects model has been applied using the DerSimonian-Laird method. HCD treatment significantly increased performance on Wechsler Memory Scale (WMS) -2 Delayed recall (Weighted mean difference (WMD) (95% CI (CI)) = 1.5 (0.6, 2.5), P < .01). Treatment with HCDs had no effect on Alzheimer's Disease Assessment Scale-Cognitive (WMD (95% CI) = -0.2 (-1.1, 0.7), P = .65, I2 = 0%), Mini-Mental State Examination (WMD (95% CI) = 0.7 (-0.2, 1.5), P = .14, I2 = 42%), The Wechsler Adult Intelligence Scale (WAIS) Digit span Backward (WMD (95% CI) = 0.1 (-0.3, 0.5), P = .51, I2 = 0%), WAIS digit span Forward (WMD (95% CI) = 0.0 (-0.3, 0.4), P = .85, I2 = 33%) and the WMS-1 Immediate recall (WMD (95% CI) = .7 (-.2, 1.5), P = .11, I2 = 0%). The effect on delayed recall remained in subgroup meta-analysis performed on studies of patients without mild cognitive impairment (MCI), and in those without MCI where average age in the study was above 65. CONCLUSION: HCD, supplementation improved scores on the Delayed recall examination, a neuropsychological test affected early in Alzheimer's disease. Further studies are needed in people with early cognitive impairment with longer follow-up duration and standardization of carnosine doses to delineate the true effect. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42017075354.

tVNS in Stroke: A Narrative Review on the Current State and the Future.

Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke.

Thrombolysis Outcomes in Acute Ischaemic Stroke Patients with Pre-Existing Cognitive Impairment.

BACKGROUND: Thrombolysis treatment for ischaemic stroke in patients with pre-existing disabilities, including cognitive impairment, remains controversial. Previous studies have suggested functional outcomes post-thrombolysis are worse in patients with cognitive impairment. This study aimed to compare and explore factors contributing to thrombolysis outcomes, including haemorrhagic complications, in cognitively and non-cognitively impaired patients with ischaemic stroke. MATERIALS AND METHODS: A retrospective analysis of 428 ischaemic stroke patients who were thrombolysed between January 2016 and February 2021 was performed. Cognitive impairment was defined as a diagnosis of dementia, mild cognitive impairment, or clinical evidence of the condition. The outcome measures included morbidity (using NIHSS and mRS), haemorrhagic complications, and mortality, and were analysed using multivariable logistic regression models. RESULTS: The analysis of the cohort revealed that 62 patients were cognitively impaired. When compared to those without cognitive impairment, this group showed worse functional status at discharge (mRS 4 vs. 3, p < 0.001) and a higher probability of dying within 90 days (OR 3.34, 95% CI 1.85-6.01, p < 0.001). A higher risk of a fatal ICH post-thrombolysis was observed in the cognitively impaired patients, and, after controlling for covariates, cognitive impairment remained a significant predictor of a fatal haemorrhage (OR 4.79, 95% CI 1.24-18.45, p = 0.023). CONCLUSIONS: Cognitively impaired ischaemic stroke patients experience increased morbidity, mortality, and haemorrhagic complications following thrombolytic therapy. However cognitive status is not independently predictive of most outcome measures. Further work is required to elucidate contributing factors to the poor outcomes observed in these patients and help guide thrombolysis decision-making in clinical practice.

The neurology of space flight; How does space flight effect the human nervous system?

RATIONALE AND HYPOTHESIS: Advancements in technology, human adaptability, and funding have increased space exploration and in turn commercial spaceflight. Corporations such as Space X and Blue Origin are exploring methods to make space tourism possible. This could lead to an increase in the number of patients presenting with neurological diseases associated with spaceflight. Therefore, a comprehensive understanding of spaceflight stressors is required to manage neurological disease in high-risk individuals. OBJECTIVES: This review aims to describe the neurological effects of spaceflight and to assess countermeasures such as pre-flight prophylaxis, training, and possible therapeutics to reduce long-term effects. METHODOLOGY: A literature search was performed for experimental studies conducted in astronauts and in animal models that simulated the space environment. Many studies, however, only discussed these with scientific reasoning and did not include any experimental methods. Relevant studies were identified through searching research databases such as PubMed and Google Scholar. No inclusion or exclusion criteria were used. FINDINGS: Analysis of these studies provided a holistic understanding of the acute and chronic neurological changes that occur during space flight. Astronauts are exposed to hazards that include microgravity, cosmic radiation, hypercapnia, isolation, confinement and disrupted circadian rhythms. Microgravity, the absence of a gravitational force, is linked to disturbances in the vestibular system, intracranial and intraocular pressures. Furthermore, microgravity affects near field vision as part of the spaceflight-associated neuro-ocular syndrome. Exposure to cosmic radiation can increase the risk of neurodegenerative conditions and malignancies. It is estimated that cosmic radiation has significantly higher ionising capabilities than the ionising radiation used in medicine. Space travel also has potential benefits to the nervous system, including psychological development and effects on learning and memory. Future work needs to focus on how we can compare a current astronaut to a future space tourist. Potentially the physiological and psychological stresses of space flight might lead to neurological complications in future space travellers that do not have the physiological reserve of current astronauts.

Antithrombotic treatment after intracerebral hemorrhage: Surveys among stroke physicians in Scandinavia and the United Kingdom.

Background and Aims: It is unclear whether patients with previous intracerebral hemorrhage (ICH) should receive antithrombotic treatment to prevent ischemic events. We assessed stroke physicians' opinions about this, and their views on randomizing patients in trials assessing this question. Methods: We conducted three web-based surveys among stroke physicians in Scandinavia and the United Kingdom. Results: Eighty-nine of 205 stroke physicians (43%) responded to the Scandinavian survey, 161 of 180 (89%) to the UK antiplatelet survey, and 153 of 289 (53%) to the UK anticoagulant survey. In Scandinavia, 19 (21%) stroke physicians were uncertain about antiplatelet treatment after ICH for ischemic stroke or transient ischemic attack (TIA) and 21 (24%) for prior myocardial infarction. In the United Kingdom, 116 (77%) were uncertain for ischemic stroke or TIA and 115 (717%) for ischemic heart disease. In Scandinavia, 32 (36%) were uncertain about anticoagulant treatment after ICH for atrial fibrillation, and 26 (29%) for recurrent deep vein thrombosis or pulmonary embolism. In the United Kingdom, 145 (95%) were uncertain about anticoagulants after ICH in at least some cases. In both regions combined, 191 of 250 (76%) would consider randomizing ICH survivors in a trial of starting versus avoiding antiplatelets, and 176 of 242 (73%) in a trial of starting versus avoiding anticoagulants. Conclusion: Considerable proportions of stroke physicians in Scandinavia and the United Kingdom were uncertain about antithrombotic treatment after ICH. A clear majority would consider randomizing patients in trials assessing this question. These findings support the need for such trials.

Antiplatelet Use in Ischemic Stroke.

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.

Mitochondrial Dysfunction in Alzheimer's Disease: A Biomarker of the Future?

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.

Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.

Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mechanisms and potential therapies aiming to preserve neuronal health. Here, we show that induced astrocytes from fibroblasts donors in their childhood or adulthood display age-related transcriptional differences and functionally diverge in a spectrum of age-associated features, such as altered nuclear compartmentalisation, nucleocytoplasmic shuttling properties, oxidative stress response and DNA damage response. Remarkably, we also show an age-related differential response of induced neural progenitor cells derived astrocytes (iNPC-As) in their ability to support neurons in co-culture upon pro-inflammatory stimuli. These results show that iNPC-As are a renewable, readily available resource of human glia that retain the age-related features of the donor fibroblasts, making them a unique and valuable model to interrogate human astrocyte function over time in human CNS health and disease.

Peripheral Glycolysis in Neurodegenerative Diseases.

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.

Deficits in Mitochondrial Spare Respiratory Capacity Contribute to the Neuropsychological Changes of Alzheimer's Disease.

Alzheimer'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.

Cerebral Venous Thrombosis at High Altitude: Analysis of 28 Cases.

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.

Altered frontal and insular functional connectivity as pivotal mechanisms for apathy in Alzheimer's disease.

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 < .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.

Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease.

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.

A Pilot Study Investigating a Novel Non-Linear Measure of Eyes Open versus Eyes Closed EEG Synchronization in People with Alzheimer's Disease and Healthy Controls

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 < 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 < 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075; IQR 0.03, p < 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.

Treatment of the unknown patient: insights from acute stroke.

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.