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Abstract 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 diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ 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 Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Abstract 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.

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.

Stroke remains a leading cause of long-term disability worldwide. There is an unmet need for neuromodulatory therapies that can mitigate against neurovascular injury and potentially promote neurological recovery. Transcutaneous vagus nerve stimulation has been demonstrated to show potential therapeutic effects in both acute and chronic stroke. However, previously published research has only investigated a narrow range of stimulation settings and indications. In this review, we detail the ongoing studies of transcutaneous vagus nerve stimulation in stroke through systematic searches of registered clinical trials. We summarize the upcoming clinical trials of transcutaneous vagus nerve stimulation in stroke, highlighting their indications, parameter settings, scope, and limitations. We further explore the challenges and barriers associated with the implementation of transcutaneous vagus nerve stimulation in acute stroke and stroke rehabilitation, focusing on critical aspects such as stimulation settings, target groups, biomarkers, and integration with rehabilitation interventions.

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.

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.

We describe an unusual case of stroke manifesting as alien hand syndrome (AHS) causing sudden onset of abnormal hand movements. The patient reported his left arm would move outside his control and grab things in his surroundings without his conscious will. He felt his arm did not belong to him. Examination showed left arm brisk reflexes, astereognosis, and agraphesthesia in the left hand. Imaging revealed an established right parietal lobe ischaemic stroke. Lesions of the parietal cortex can cause AHS by disrupting the interpretation of somatosensory feedback when a movement is made and decreasing the ability to consciously monitor motor intentions. A low threshold should be adopted for arranging brain imaging and a thorough neurological examination is needed in any sudden onset movement disorder.