By Dr. Inna Lutsenko, ESO Social Media and PR Committee

@inna_lutsenko

Chairs: Jean-Claude Baron (Paris, France) and Natan Bornstein (Tel Aviv, Israel)

Changes to the Blood-Brain-Barrier in Alzheimer’s disease

Presented by Axel Montagne (United Kingdom)

There is a very dense network of small vessels in the brain, called “capillaries”, which represent 85% of the total vasculature of the brain. If you put all the capillaries which represent the brain in a row, they will be 600 km in length. One capillary usually provides the circulation for one neuron. Small capillaries, which are branching from the arteries, are surrounded with pericytes, which play a significant role: they maintain the integrity of the brain-blood barrier. The artery, branching capillaries and pericytes is a very complex neurovascular unit. Pericytes are also consisting of the different subtypes: prearterial, thin and postcapillary venule pericytes, which are having different functions.

There are a lot of papers showing that vascular dysfunction can lead to neurodegeneration and cognitive decline. Postmortem brain tissue analyses showed blood-derived molecules leaking out into extravascular space (e.g., fibrinogen), the extravascular deposits were found, pericyte coverage). New biofluid biomarkers – 1 Qaib, 1 sPDGFRB (a marker of the pericyte damage) are discovered. Neuroimaging methods are used to measure brain-blood barrier BBB, CBF, microbleeds, WML. One of the neuroimaging methods, dynamic contrast enhanced MRI to investigate subtle BBB dysfunction. After the gadolinium contrast injection, the patient’s brain is analyzed in a special color-coding MRI to measure the blood leaking fluids into the brain tissue. Increased BBB leakage was found in the hippocampus, a region critical for learning and memory, during normal aging. It worsens with mild cognitive impairment and correlates with injury to BBB-associated pericytes (Montagne et al. Neuron 2015).

In another paper Axel Montagne and his team looked at the correlation of the BBB Integrity and the presence of the APOE4 which is the major genetic risk factor for AD. Presence of APOE4 allele leads to brain-blood barrier dysfunction. Brain capillary breakdown initiates WM dysfunction, which can be reversed by limiting fibrinogen extravascular deposits. It has implications for the pathogenesis and treatment of human WM disease associated with AD and small vessels disease dementia (Montagne et al. Nat Med 2018). Leaking fibrinogen to the extravascular space is toxic to the brain.

Imaging vascular function in neurodegeneration in the human – what does it tell us?

Presented by Simon Duchesne (Canada)

The vascular wall can undergo a large number of damage, which in ex vivo imaging could be detected as stiffening, thickening, infiltrations, perivascular tissue infiltrations, demyelination, luminal narrowing and occlusion, impaired autoregulation, discrete ischaemia and discrete infarction. In vivo imaging we can confirm the following pathologies: infarcts, lacunes, perivascular spaces lesions, microbleeds, white matter hyperintensities and atrophy.

In his talk Simon Duchesne aimed to answer the following questions: 1) imaging: can we image small vessel disease disease (SVD) reliably in vivo, 2) vascular dysfunction: can we measure all presentations and 3) neurodegeneration: is it informative with respect to cognition?

In the paper “Neuroimaging standards for research into small vessel disease and its contribution to aging and neurodegeneration” by Joanna M Wardlaw et.al (1) a team of international researchers highlighted the imaging changes during different forms of a SVD, such as ischaemic leukoaraiosis, subcortical leukoaraiosis, white matter lesions, white matter hyperintensity, subcortical hypertintensivity, age related white matter disease and ischemic white matter disease. In this prominent paper using MRI sequences ( DWI, FLAIR, T2, T1, T2 weighted GRE) the differential diagnosis between different types of SVD is proposed.

The precision of the brain atrophy measurement could depend on the make and model of the measuring devices used, reaching 10% differences in total brain volume across sites. To solve this issue Simon Duchesne gave the example of the developed “The Canadian Dementia Imaging Protocol:

Harmonizing National Cohorts” under his coordination (2). The advantage of this protocol is that it developed in such a way that images could look the same within different imaging manufacturers and across different vendors.

In the Canadian Consortium on Neurodegeneration in aging ongoing study there are 976 participants already enrolled from normal cognition till all the variants of the cognitive impairment based on the brain atrophy and the study will display the correlation of the images with phenotypes of the diseases leading to dementia.

In the paper “White matter hyperintensities may be an early marker for age-related cognitive decline” by Cassandra Morrison with a team examined the association between small vessel disease (CSVD), amyloid, and pTau with a collaborative influence on cognitive decline in cognitively normal older adults without subjective cognitive decline (3). In results they highlighted that “only baseline WMH load is associated with follow-up executive functioning, indicating that it may be one of the earliest pathologies that contributes to future cognitive decline”.

In his conclusion Simon Duchesne underlined that it is recommended to use the united imaging protocol when diagnosing SVD, make it harmonized, and use as many biomarkers as you can. SVD should be strongly monitored and neuroimaging should be done in vivo as it has a large impact on the future cognitive decline.

Does reversing vascular dysfunction help prevent neurodegeneration? Insights from preclinical models

Presented by Denis Vivien (France)

Tissue type plasminogen activator (tPA), a fibrinolytic, produced by our brains during stroke is activated by endothelial cells and is released in the blood flow to participate in the thrombus dilution, activating the plasminogen into the plasmine which leads to recanalisation and to the reperfusion of the tissue. The less known fact is that tPA is produced by neurons, which can store tPA in synaptic vesicles and during the repolarization neurons can release tPA into the synaptic cleft and when tPA reaches the cleft, it can interact with the glutamate and NMDA-receptors and improve neuroplasticity. But overactivation of the NMDA- receptors in stroke can provoke the neurotoxic effects of tPA. In his lab, Denis Vivien with his team developed the several molecules, the fist one is “a tPA, which can not bind to NMDA-receptors” and the second one is the monoclonal antibody Glunomab which can block the tPA binding to the NMDA-receptors. So future directions for the stroke treatment is not only using the alteplase which is already proven medication in combination with thrombectomy, but also using so called “cocktails” with N-acetylcysteine to prevent the secondary formation of the thrombi and the Glunomab to reduce the neurotoxic effects of tPA.

Do interventions to improve cardiovascular risk factors or function delay cognitive decline and vascular or Alzheimer’s dementias?

Presented by William Whiteley (United Kingdom)

Whether dementia is really preventable? With this question William Whiteley opened his talk. What is optimistic, is that dementia incidence has been falling by 13% each decade since 1998. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission suggests that ca. 40% of dementia cases are preventable, but estimated population attributable risk from vascular factors is small:

• 5% smoking
• 2% hypertension
• 1% obesity
• 1% diabetes

Causality of many risk factors is still unclear. Limitations to observational dementia epidemiology consist of confounding (education and socioeconomic status; APOE E4: elevated LDL cholesterol, reduced obesity, reduced diabetes), loss to follow up (If biased to high level of risk factors and no dementia), the measurement error (diet; blood pressure) and reverse causality. If we look at the observational prospective studies linking increased BMI with the development of dementia, then we see that studies which lasted not more than 5-7 years did not demonstrate enough casualty and the studies which followed patients over 15 years demonstrated the increasing the dementia rates over time in subjects whose BMI was > 25 and this casualty seems to be true.

According to some studies (4), there is a steep correlation between elevated blood pressure and the risk of dementia, but significant in the young age, while in older age there is no such an association and the similar findings were displayed with a stroke as an outcome, though Hughes with a team demonstrated in the metaanalysis that for blood pressure lowering RR is 0.87 (95%C| 0.78, 0.97) for dementia prevention.

There are no significant changes while using statins on the long-term dementia prevention and REWIND study of diabetes control showed HR: 0.86; 95%Cl: 0.79, 0.95 for the GLP-1 (dulaglutide) with the outcome as significant cognitive impairment.

There is no strong association between genetic vascular risk-factors and the development of dementia ( meta-analysis from Edinburg researchers).

In conclusion William Whiteley underlined that “if new evidence is needed for population-wide dementia prevention, then new large trials are necessary. They need to have:

• sufficiently long follow up
• a very large number of participants
• use adjudicated dementia or MCI as an outcome (in the absence of areliable intermediate biomarker)”.

Different roles of vascular mural cell in brain capillary blood flow control

Presented by Martin Lauritzen (Denmark)

At the beginning of his talk, Martin Lauritzen mentioned that vascular signals are the basis for functional neuroimaging and vascular pathology is cause & effect of secondary damage in strokes. On the example of mother and child bonding and examined with MRI, Prof. Lauritzen brought the information that for the bonding process active nerve cells release neurotransmitters, astrocytes release vasodilators from endfeet and mural cells on arterioles and capillaries dilate. One of the significant roles in the neurotransmission plays the sphincter from penetrating arteriole to the cortex. The so called “microvascular inflow tract” plays a significant role and consists of the penetrating arteriole, the sphincter and the pericytes on the capillaries wall, and this microvascular inflow tract controls the vascular blood flow and the can reflect on the images supply.

In MCAO, mice models of the middle cerebral artery occlusion, the weaker signal from capillaries, thicker anastomosis but other large vessels which appear thinner were found, which is speculated to be “a postischemic microvascular vasoconstriction”.

Precapillary sphincters maintain perfusion in the cerebral cortex with a mechanism when sphincter resistance preserves perfusion pressure in the penetrating arteriole and safeguards equal perfusion at all cortical depths (Gruhh st al 2020 Nature Communications).

Cardiac arrest triggers pericyte constriction & astrocyte swelling.

In summary Martin Lauritzen underlined that:

• Precapillary sphincters do exist in the mouse brain
• They have higher occurrence in superficial than in deeper cortical layers
• Sphincters safeguard equal perfusion along the penetrating arteriole
• They control the flux of red blood cells to the capillaries
• Cortical spreading depolarizations constrict sphincters and cause vascular entrapment of blood cells
• In strokes and reperfusion, vascular response are time-variant and heterogenous.

 

 

References

1. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge Rv, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013 Aug;12(8):822-38. doi: 10.1016/S1474-4422(13)70124-8. PMID: 23867200; PMCID: PMC3714437.
2. Duchesne S, Chouinard I, Potvin O, Fonov VS, Khademi A, Bartha R, Bellec P, Collins DL, Descoteaux M, Hoge R, McCreary CR, Ramirez J, Scott CJM, Smith EE, Strother SC, Black SE; CIMA-Q group and the CCNA group. The Canadian Dementia Imaging Protocol: Harmonizing National Cohorts. J Magn Reson Imaging. 2019 Feb;49(2):456-465. doi: 10.1002/jmri.26197. Epub 2018 Sep 17. PMID: 30635988.
3. Morrison C, Dadar M, Villeneuve S, Collins L, for Alzheimer’s Disease Neuroimaging Initiative. White matter hyperintensities may be an early marker for age-related cognitive decline. bioRxiv 2021.09.23.461560; doi: https://doi.org/10.1101/2021.09.23.461560
4. Connor A. Emdin , Peter M. Rothwell , Gholamreza Salimi-Khorshidi , Amit Kiran , Nathalie Conrad , Thomas Callender , Ziyah Mehta , Sarah T. Pendlebury , Simon G. Anderson , Hamid Mohseni , Mark Woodward and Kazem Rahimi. Blood Pressure and Risk of Vascular Dementia Evidence From a Primary Care Registry and a Cohort Study of Transient Ischemic Attack and Stroke. 2016 https://doi.org/10.1161/STROKEAHA.116.012658Stroke. 2016;47:1429–1435

By Stela Rutovic

Chairs: Paola Santalucia (Italy), Diana Aguiar de Sousa (Portugal)

The first lecture was presented by Cheryl Bushnell (United States) on the topic, Stroke Care Access: Why are older women still undertreated? Overview of current studies showed that women present with more non-traditional stroke symptoms, and are more likely to have diagnosis of stroke mimics. At the time of stroke onset women are older than men, which is associated with more comorbidities and lower pre-stroke function, as well as more severe strokes. Women are less likely to receive defect- free care, and social determinants of health are major factors in access to care before, during and after stroke.

The second speech on the topic, Women and AF- A dangerous relationship? by Julia Ferrari (Austria) reported that although atrial fibrillation is more common in men, women have higher risk of stroke than men, more debilitating strokes and higher stroke mortality. Women are more likely to experience atypical Afib symptoms, tend to have more frequent and longer- lasting AFib episodes than men, and are less likely to receive oral anticoagulation therapy. Several factors contribute to higher stroke severity in women such as higher rates of total anterior circulation strokes (TACS), smaller vessel diameter and influence of sex hormones on coagulation system.

The third lecture, Carotid stenosis management in women: important considerations for endarterectomy, by Seemant Chaturvedi (United States) discussed approach to carotid revascularization. Results of CREST study showed that women have higher complication rate with CAS compared to men. Indications for carotid revascularization do not differ between genders. The choice of optimal treatment should consider evaluation of patient’s risk profile, anatomic criteria, plaque morphology and medical comorbidities. Atherosclerotic plaques in women are different in morphology and composition compared to men. As a result, women may require different treatment than men. Women tend to be older than men at the time of revascularization. Previous studies have suggested uncertain benefit for asymptomatic women, and reduced benefit for symptomatic women. However, representation of women in carotid trials has been suboptimal and ongoing studies such as CREST 2 and SCORE are needed to provide data on risk/benefit ratio of revascularization vs. intensive medical therapy.

The fourth talk was on Adverse pregnancy events and outcomes- opportunity for primary prevention of stroke by Svetlana Lorenzano (Italy). Pregnancy is associated with many physiological changes which may contribute to occurrence of adverse pregnancy outcomes (APO) including hypertensive disorders of pregnancy, preterm delivery, small for gestational age, large for gestational age, placenta abruption, and pregnancy loss. Presence of APOs is associated with increased risk for development of cerebrovascular diseases (CVD), as well as traditional risk factors later in life post-pregnancy. So far, most CVD stratification studies have been conducted in middle aged and older women, who are more likely to have also developed conventional CVD risk factors. Studies in primary prevention of stroke have shown that low-dose aspirin started in early pregnancy reduces risk for some APOs among higher-risk females. It is important to implement healthcare system changes to improve the transition of care after pregnancy, with longer postpartum follow-up care to screen for CVD risk factors and provide CVD prevention counseling.

The last lecture in the session was on the topic of Rare causes of stroke in women, by Diana Aguiar de Sousa (Portugal) who emphasized the need of careful clinical evaluation of every patient with postpartum headache. Although it is a common complaint, clinicians should consider less common causes of secondary headache which are more common in women, such as cerebral venous sinus thrombosis (CVST), postpartum preeclampsia and eclampsia, PRES and RCVS. Hypertensive disorders of pregnancy are major risk factors for maternal stroke. CVST accounts for approximately 1/3 of pregnancy related strokes. In an ongoing Covid-19 pandemic, we should consider that CVST can also be a manifestation of vaccine induced immune thrombotic thrombocytopenia, which is rare side-effect of vaccination against Covid-19. The risk of pregnancy related stroke is also increased in several rare diseases such as fibromuscular dysplasia, moyamoya disease, peripartum cardiomyopathy, choriocarcinoma. Improving outcomes is dependent on proper identification of rare causes of stroke in women and early treatment.

By Pietro Caliandro

Chairs: Prof Iris Grunwald, United Kingdom and Prof William Whiteley, United Kingdom

Artificial intelligence applications in acute stroke recognition 

Presented by prof Helle Collatz Christensen, Denmark

Prof Christensen emphasizes how difficult it is to correctly identify stroke patients during phone calls at the emercengy number and how it is important that operators properly recognize patients and activate the stroke management chain. Only 35% of strokes are recognized at the time of the phone call and this aspect needs to be improved to facilitate access to treatment. Artificial intelligence algorithms can be instructed to recognize a patient as a stroke patient by interpreting the phone calls that are recorded during the distress call. This procedure requires the creation of linguistic models that the algorithm should be able to recognize during phone calls. An important issue is linked to the management of sensitive patient data.

Strengths and weaknesses of current AI tools for stroke imaging diagnosis 

Presented by prof Philip White, United Kingdom

Prof Philip White presented the different AI tools currently able to diagnose stroke by interpreting neuroimaging. He underlined how the introduction of some AI models such as RAPID or VIiz in LVO has made it possible to significantly improve stroke treatment by making revascularization times faster and therefore more effective. Prof White underlines that AI tools are a great promise as decision support tools but caution is required in its use because we need regulatory rules and more robust evidence.

Artificial intelligence and big data in stroke prevention due to AF 

Presented by prof Signild Åsberg, Sweden

Prof Åsberg began his interesting presentation by explaining the concepts of AI and big data. When we talk about big data we refer to a considerable amount of information that must be managed appropriately, while AI represents the set of calculation tools that allow information to be processed. She then demonstrated how these concepts can be applied to improve the identification and treatment of stroke patients in whom atrial fibrillation is suspected. AI algorithms can create predictive models of the presence of atrial fibrillation, identify atrial fibrillation in patients with stroke, and monitor NOAC therapy. She underlined that AI has the potential to improve stroke prevention in AF but its role, circumstances of its application, and the optimal methods need to be defined.

Computational modelling of acute stroke therapy 

Professor Alfons Hoekstra, Netherlands

Professor Hoekstra illustrated the concept of in silico trial and highlighted how AI algorithms can be used to create virtual patient cohorts in which to define the localization and the extent of the ischemic lesion, the type of revascularization treatment to which they are subjected and evaluate the outcome based on the results of real clinical trials such as MR-CLEAN. A similar approach makes it possible to simulate the clinical conditions of the individual patient and predict the evolution in advance based on the information obtained from the trials. Furthermore, Prof Hoekstra highlighted how modeling tools can be useful for designing new real clinical trials.

Looking to the future – AI tools in rehabilitation and re-integration 

Professor Christian Gerloff, Germany

Professor Christian Gerloff begins his stimulating report by recalling the results of NETS trial which highlighted the lack of efficacy of tDCS in improving the motor function of the upper limb in stroke patients. He invites us to reflect on the possible causes that led to this result and underlined how the location of the lesion, skull and skin thicknesses, different strutural anatomy, different co-morbiditie and so on may have prevented the effectiveness of tDCS since the stimulus parameters rwere not personalised according to subjective characteristics of the patient. AI can be a powerful mean of calculation which, based on typical elements of the individual subject, can allow us to customize the stimulation parameters. He then illustrated how this personalization can be applied to rehabilitation approaches such as upper limb support tools that can be customized by integrating multiple data recorded by motion sensors positioned on the patient’s upper limb. The last example presented is the application of AI as a tool for predicting the outcome after the recanalization procedure in a “real world” population and not selected as that typical of clinical trials.

Artificial intelligence increasingly enters our daily life and its use in the treatment of stroke is a frontier to be explored. It is not a question of delegating the physician’s function to an algorithm, but implementing the tools available to the physician in order to make increasingly personalized and effective therapeutic choices. Artificial intelligence applied to stroke must be a patient-centric and privacy-preserving tool whose development requires the involvement of physicians, patients and caregivers in order to meet the needs of the end user.