Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Friday, August 31, 2018

Vicious Circle Leads to Loss of Brain Cells in Old Age

You'll have to ask your doctor to come up with prevention protocols for this.  But that won't occur, your doctor has had decades to come up with protocols for stroke and completely failed, so failure will occur here also. It won't make a difference, you'll be dead before anything is done with this.
https://www.rdmag.com/news/2018/08/vicious-circle-leads-loss-brain-cells-old-age?
The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of "sensor" with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result - probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.
The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain's immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.
This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. "We know that so-called endocannabinoids play an important role in this", explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. "These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells."
Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. "However, microglial cells have virtually no CB1 and very low level of CB2 receptors," emphasizes Bilkei-Gorzo. "They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals - why this is the case, has been puzzling so far."
Neurons as "middlemen"
The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen - a certain group of neurons, because this group has a large number of CB1 receptors. "We have studied laboratory mice in which the receptor in these neurons was switched off," explains Bilkei-Gorzo. "The inflammatory activity of the microglial cells was permanently increased in these animals."
In contrast, in control mice with functional CB1 receptors, the brain's own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. "Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells," said Bilkei-Gorzo. "However, we cannot yet say whether this is also the case in humans."
This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulatory the other major glial cell type, the astroglial cells.
During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: "Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running."
It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator - even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.


Suffering a stroke may double the risk of dementia finds large-scale study

Well this just joins all this other research about dementia risk after stroke. I bet this is still not enough for your stroke hospital to create a protocol to prevent such dementia. Double the risk tells you absolutely nothing.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013.

https://www.yahoo.com/news/suffering-stroke-may-double-risk-dementia-finds-large-100237857.html
In the largest study of its kind ever conducted, new UK research has found that people who suffer a stroke could be around twice as likely to develop dementia.
Led by researchers at the University of Exeter Medical School, the new meta-analysis looked at data on stroke and dementia risk gathered from 48 studies with a total of 3.2 million people around the world.
After taking into account other risk factors for dementia, such as blood pressure, diabetes and cardiovascular disease, the researchers found that having a stroke still significantly increased the risk of the condition, providing the strongest evidence yet that stroke plays a role in dementia risk.
The findings also support previous research which has also found an association between the two conditions, however previous studies did not establish to what extent a stroke may increase the risk of dementia.
"We found that a history of stroke increases dementia risk by around 70%, and recent strokes more than doubled the risk. Given how common both stroke and dementia are, this strong link is an important finding. Improvements in stroke prevention and post-stroke care may therefore play a key role in dementia prevention," said study author Dr. Ilianna Lourida, of the University of Exeter Medical School.
"Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke. Our findings indicate that this figure could be even higher, and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia," added Dr. David Llewellyn.
The team noted that as most people who have a stroke do not go on to develop dementia, further research is now needed to assess whether other factors could modify the increased risk of dementia, and whether differences in care and lifestyle following a stroke can reduce the risk of dementia further.
According to the World Health Organization, 15 million people have a stroke each year and around 50 million people have dementia.
The findings can be found published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

Sedentary behavior after stroke: A new target for therapeutic intervention

Great victim blaming here.  Obviously your doctor has NO responsibility in getting you recovered enough to exercise properly.  Be prepared to be blamed for your lack of recovery.
http://journals.sagepub.com/doi/abs/10.1177/1747493018784505
First Published July 4, 2018 Editorial


Over the last 10 years, evidence has emerged that too much sedentary time (e.g. time spent sitting down) has adverse effects on health, including an increased risk of cardiovascular disease incidence and mortality. A considerable amount of media attention has been given to the topic. The current UK activity guidelines recommend that all adults should minimize the amount of time spent being sedentary for extended periods. How best to minimize sedentary behavior is a focus of ongoing research. Understanding the impact of sedentary behaviors on the health of people with stroke is vital as they are some of the most sedentary individuals in society. Implementing strategies to encourage regular, short breaks in sedentary behaviors has potential to improve health outcomes after stroke. Intervention work already conducted with adults and older adults suggests that sedentary behaviors can be changed. A research priority is to explore the determinants of sedentary behavior in people with stroke and to develop tailored interventions.


Sedentary behaviour after stroke: a new target for therapeutic intervention: Sarah Morton

Well Ms. Lahiff-Jenkins what the hell are you doing to get the stroke medical world to get all survivors 100% recovered to accomplish this exercise? This is just another victim blaming exercise. 
https://www.podbean.com/media/share/pb-gy5qp-989950#.W4kmqKDZjt8.facebook
Over the last 10 years evidence has emerged that too much sedentary time (e.g. time spent sitting down) has adverse effects on health, including an increased risk of cardiovascular disease incidence and mortality. A considerable amount of media attention has been given to the topic. The current UK activity guidelines recommend that all adults should minimise the amount of time spent being sedentary for extended periods. How best to minimise sedentary behaviour is a focus of ongoing research.
I’m Carmen Lahiff-Jenkins, Managing Editor of the International Journal of Stroke and I spoke to Dr Sarah Morton lead author of the opinion piece Sedentary behaviour after stroke: a new target for therapeutic intervention.
The International Journal of Stroke is the flagship publication of the World Stroke Organization - please consider becoming a member.
https://www.world-stroke.org/membership/join-wso

Achy breaky stroke hand

On one of my long driving trips I managed to get my affected hand open and spread on top of my left leg. Normally the thumb loses its position soon and the whole arm falls into the abyss between the seat and the door. Then I have to hope like hell I never get T-boned on that side because I can't lift the arm out without using my right hand. This particular time it stayed there for about an hour. By which time the thumb muscles were very painful. It is completely disgusting that 12 years after my stroke spasticity still prevents my recovery.  Don't suggest botox or muscle relaxants, they don't do anything for recovery.

Is There Full or Proportional Somatosensory Recovery in the Upper Limb After Stroke? Investigating Behavioral Outcome and Neural Correlates

The objective of this research is completely wrong. It should be to create stroke protocols that recover Somatosensory functions. Hell, that was figured out in a Margaret Yekutiel  book about this from 2001, 'Sensory Re-Education of the Hand After Stroke'? And I bet 17 years later your stroke hospital is still incompetent, not having the book in the library or making sure every doctor and therapist has read it and applied the protocols to all stroke survivors.

Is There Full or Proportional Somatosensory Recovery in the Upper Limb After Stroke? Investigating Behavioral Outcome and Neural Correlates 

First Published July 10, 2018 Research Article




Background: Proportional motor recovery in the upper limb has been investigated, indicating about 70% of the potential for recovery of motor impairment within the first months poststroke.  
Objective: To investigate whether the proportional recovery rule is applicable for upper-limb somatosensory impairment and to study underlying neural correlates of impairment and outcome at 6 months.  What a fucking lazy piece of shit objective.
Methods: A total of 32 patients were evaluated at 4 to 7 days and 6 months using the Erasmus MC modification of the revised Nottingham Sensory Assessment (NSA) for impairment of (1) somatosensory perception (exteroception) and (2) passive somatosensory processing (sharp/blunt discrimination and proprioception); (3) active somatosensory processing was evaluated using the stereognosis component of the NSA. Magnetic resonance imaging scans were obtained within 1 week poststroke, from which lesion load (LL) was calculated for key somatosensory tracts.
Results: Somatosensory perception fully recovered within 6 months. Passive and active somatosensory processing showed proportional recovery of 86% (95% CI = 79%-93%) and 69% (95% CI = 49%-89%), respectively. Patients with somatosensory impairment at 4 to 7 days showed significantly greater thalamocortical and insulo-opercular tracts (TCT and IOT) LL (P < .05) in comparison to patients without impairment. Sensorimotor tract disruption at 4 to 7 days did not provide significant contribution above somatosensory processing score at 4 to 7 days when predicting somatosensory processing outcome at 6 months.  
Conclusions: Our sample of stroke patients assessed early showed full somatosensory perception but proportional passive and active somatosensory processing recovery. Disruption of both the TCT and IOT early after stroke appears to be a factor associated with somatosensory impairment but not outcome.
Keywords

Bilateral Motor Cortex Plasticity in Individuals With Chronic Stroke, Induced by Paired Associative Stimulation

Another description of a problem but NO solution. Survivors want solutions, not this lazy crapola.
http://journals.sagepub.com/doi/abs/10.1177/1545968318785043
First Published July 4, 2018 Research Article


Background: In the chronic phase after stroke, cortical excitability differs between the cerebral hemispheres; the magnitude of this asymmetry depends on degree of motor impairment. It is unclear whether these asymmetries also affect capacity for plasticity in corticospinal tract excitability or whether hemispheric differences in plasticity are related to chronic sensorimotor impairment. Methods: Response to paired associative stimulation (PAS) was assessed bilaterally in 22 individuals with chronic hemiparesis. Corticospinal excitability was measured as the area under the motor-evoked potential (MEP) recruitment curve (AUC) at baseline, 5 minutes, and 30 minutes post-PAS. Percentage change in contralesional AUC was calculated and correlated with paretic motor and somatosensory impairment scores.  
Results: PAS induced a significant increase in AUC in the contralesional hemisphere (P = .041); in the ipsilesional hemisphere, there was no significant effect of PAS (P = .073). Contralesional AUC showed significantly greater change in individuals without an ipsilesional MEP (P = .029). Percentage change in contralesional AUC between baseline and 5 m post-PAS correlated significantly with FM score (r = −0.443; P = .039) and monofilament thresholds (r = 0.444, P = .044).  
Discussion: There are differential responses to PAS within each cerebral hemisphere. Contralesional plasticity was increased in individuals with more severe hemiparesis, indicated by both the absence of an ipsilesional MEP and a greater degree of motor and somatosensory impairment. These data support a body of research showing compensatory changes in the contralesional hemisphere after stroke; new therapies for individuals with chronic stroke could exploit contralesional plasticity to help restore function.

Bilateral reaching deficits after unilateral perinatal ischemic stroke: a population-based case-control study

Worthless, survivors want to know what protocol will fix those reaching deficits but you instead did nothing useful. Your senior researchers and mentors need to be fired.

Bilateral reaching deficits after unilateral perinatal ischemic stroke: a population-based case-control study

Journal of NeuroEngineering and Rehabilitation201815:77
  • Received: 8 January 2018
  • Accepted: 31 July 2018
  • Published:

Abstract

Background

Detailed kinematics of motor impairment of the contralesional (“affected”) and ipsilesional (“unaffected”) limbs in children with hemiparetic cerebral palsy are not well understood. We aimed to 1) quantify the kinematics of reaching in both arms of hemiparetic children with perinatal stroke using a robotic exoskeleton, and 2) assess the correlation of kinematic reaching parameters with clinical motor assessments.

Methods

This prospective, case-control study involved the Alberta Perinatal Stroke Project, a population-based research cohort, and the Foothills Medical Center Stroke Robotics Laboratory in Calgary, Alberta over a four year period. Prospective cases were collected through the Calgary Stroke Program and included term-born children with magnetic resonance imaging confirmed perinatal ischemic stroke and upper extremity deficits. Control participants were recruited from the community. Participants completed a visually guided reaching task in the KINARM robot with each arm separately, with 10 parameters quantifying motor function. Kinematic measures were compared to clinical assessments and stroke type.

Results

Fifty children with perinatal ischemic stroke (28 arterial, mean age: 12.5 ± 3.9 years; 22 venous, mean age: 11.5 ± 3.8 years) and upper extremity deficits were compared to healthy controls (n = 147, mean age: 12.7 ± 3.9 years). Perinatal stroke groups demonstrated contralesional motor impairments compared to controls when reaching out (arterial = 10/10, venous = 8/10), and back (arterial = 10/10, venous = 6/10) with largest errors in reaction time, initial direction error, movement length and time. Ipsilesional impairments were also found when reaching out (arterial = 7/10, venous = 1/10) and back (arterial = 6/10). The arterial group performed worse than venous on both contralesional and ipsilesional parameters. Contralesional reaching parameters showed modest correlations with clinical measures in the arterial group.

Conclusions

Robotic assessment of reaching behavior can quantify complex, upper limb dysfunction in children with perinatal ischemic stroke. The ipsilesional, “unaffected” limb is often abnormal and may be a target for therapeutic interventions in stroke-induced hemiparetic cerebral palsy.

Thursday, August 30, 2018

Optimization of Prehospital Triage of Patients With Suspected Ischemic Stroke

Once again the stroke medical world is cherry picking the easier stroke cases to treat. All survivors should be treated and get to 100% recovery. Does NO ONE actually want to solve stroke? Or is that too fucking hard?
https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.022041?platform=hootsuite

Results of a Mathematical Model
Originally publishedStroke. 2018;0:STROKEAHA.118.022041

Background and Purpose—

Prehospital routing algorithms for patients with suspected stroke because of large vessel occlusions should account for likelihood of benefit from endovascular therapy (EVT), risk of alteplase delays, and transport times. We built a mathematical model to give a real-time, location-based optimal emergency medical service routing location based on local resources, transport times, and patient characteristics.

Methods—

Using location, onset time, age, sex, and prehospital stroke severity, we calculated odds of a favorable outcome for a patient with suspected large vessel occlusions under 2 scenarios: direct to EVT-capable hospital versus transport to the nearest alteplase-capable hospital with transfer to EVT-capable hospital if appropriate. We project lifetime outcomes incorporating disability, quality of life utility, and cost. Multiple parameter sets of center-specific times (eg, door to alteplase) were randomly selected within a clinically plausible range to account for the model sensitivity to these estimates; for each iteration, the optimal strategy was defined as the most cost-effective outcome (threshold, $100 000 per quality-adjusted life-years gained). After 1000 simulations, the most frequently occurring optimal strategy was the final recommendation, with its strength measured as the proportion of runs for which it was optimal.

Results—

Routing recommendations were highly sensitive to small changes in model input parameters. Under many scenarios, the recommendations for direct transfer to the EVT site increased with increasing stroke severity and geographic proximity but did not vary substantially with respect to sex, age, or onset time.

Conclusions—

We present a mathematical decision model that determines ideal prehospital routing recommendations for patients with suspected stroke because of large vessel occlusions, with consideration of patient characteristics and location at onset. This model may be further refined by incorporating real-time data on traffic patterns and actual EVT and alteplase timeliness performance. Further studies are needed to verify model predictions.

Long-Term Study Shows Endothelial Progenitor Cells Are Safe for Treating Stroke Patients

Nothing here talks about results, just safety, so followup will be needed
https://www.benzinga.com/pressreleases/18/08/r12276499/long-term-study-shows-endothelial-progenitor-cells-are-safe-for-treati
DURHAM, N.C., Aug. 29, 2018 A new study recently published in STEM CELLS Translational Medicine demonstrates the long-term safety of laboratory-expanded endothelial progenitor cells for treating ischemic stroke. This could be good news for the 15 million people who, according to to the World Stroke Organization, suffer from this dangerous condition each year.
Ischemic stroke is the most common type of stroke, affecting nearly 90 percent of all cases. It is caused by a blocked blood vessel in the brain. In the normal central nervous system, endothelial progenitor cells (EPCs) play an active role in building blood vessels. This has led researchers to wonder whether EPCs circulating in the blood could be recruited after a stroke to assist in repairing damaged vessels in the brain. However, there is one major problem with this idea: The number of circulating EPCs is too low to provide much regenerative capacity – a number that further decreases in the aging or in those with heart problems.
This makes ex vivo (lab) expanded EPCs an attractive alternative.
"Transplantation of EPCs was already determined in animal experiments to be a safe and effective method for treating ischemic stroke. However, their safety and efficacy had yet to be determined in humans," said Zhenzhou Chen, M.D., Ph.D., Southern Medical University, Guangzhou, China, and a corresponding author on the study. "In our trial, we tested the safety and feasibility of transplanting an acute ischemic stroke patient with his or her own (autologous) ex vivo expanded EPCs."
Eighteen patients were recruited for the randomized, single-blinded study. Each received conventional treatment after their stroke then, seven days after symptom onset, underwent a bone marrow aspiration to collect EPCs and bone marrow stromal cells (BMSCs) for expansion in the lab. The patients were divided into three groups and, beginning at week four after the aspiration, one group was intravenously infused with their own EPCs, while the other two groups received either their own BMSCs or a saline placebo as the controls.
Each patient was then monitored for 48 months. Study co-author Xiaodan Jiang, M.D., Ph.D., also from Southern Medical University, explained, "We watched for mortality of any cause, adverse events and any new-onset diseases or conditions. Changes in neurological deficits were also assessed at different time points."
In the end the researchers found no toxicity events nor did they see any infusional or allergic reactions in any of the patients. "The EPC group had less serious adverse events compared to the placebo-controlled group, although there were no statistical differences in mortality among the three groups," Dr. Chen reported. "Ex vivo expansion always raises concerns that it may cause instability in the chromosomes or maybe lead to tumors. However, in our long-term study we observed no increased tumorigenicity. This safety indicator was also confirmed by many animal studies and other trials using expanded bone marrow-derived stem cells for treatment of ischemic stroke."
The researchers did note limitations in their study, including lack of patient-centered quality of life outcomes. "Moreover, because of the small size of the cohorts involved, we could neither identify the neurological or functional benefits of EPCs on ischemic stroke, nor determine the pros and cons between EPCs and BMSCs for stroke treatment," Dr. Jiang said. "Thus, we believe a larger phase 2 trial is warranted."
"This is a promising line of cell therapy research using a novel treatment method that is simple and non-invasive," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "We look forward to larger phase 2 trial results."
The full article, "Autologous endothelial progenitor cells transplantation for acute ischemic stroke: A four-year follow-up study," can be accessed at http://www.stemcellstm.com.
About STEM CELLS Translational Medicine: STEM CELLS Translational Medicine (SCTM), published by AlphaMed Press, is a monthly peer-reviewed publication dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices. SCTM is the official journal partner of Regenerative Medicine Foundation.

Pericytes Make Spinal Cord Breathless after Injury

With any brains at all in stroke leadership this research would be matched up with this post-stroke problem and research started to see if this SCI intervention would help in stroke.

How to stop pericytes from strangling capillaries post-stroke has yet to be answered. 

 The possible solution here:

Pericytes Make Spinal Cord Breathless after Injury

First Published September 21, 2017 Research Article



Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury.

Enough NCDs! Enough Stroke!

I see absolutely nothing here that even remotely suggests that there is any strategy and leadership that will solve all the problems in stroke.

This is just puffery, no one is taking responsibility.  The WSO has no leadership role that I have ever seen in stroke.

What fucking laziness and trying to run away from responsibility. WSO, stroke is in your name, that usually means YOU are responsible. I guess you are NO leader and would rather just sit on the sidelines, crying that governments and private entities need to solve stroke. Fuck, get the hell out of the way and let some leaders run your organization.

Enough NCDs! Enough Stroke!

In a few weeks world leaders will gather at the UN HLM in New York to review progress toward their commitment to reduce premature deaths from NCDs by 30% by 2030.
The World Stroke Organization, along with our partners in the NCD Alliance, has been active in advocating for increased awareness, access and action on NCD and stroke prevention. Our leadership recently made a statement as part of the UN preparations for the UN HLM which you can read elsewhere on this blog. Wow, ALL HAT AND NO CATTLE, get the hell out of the way and let some real leaders run things. No action verbs anywhere in here.

From September 3rd, the WSO is getting behind the Enough NCDs Week of Action and advocating for urgent action on stroke prevention and treatment as a mechanism to achieve global health and development goals. 

We have had enough of slow progress and failed promises on stroke prevention and treatment and we know that our impatience is shared by stroke survivors, caregivers, support and professional organisations around the world.  
To add your voice to ours and to increase the pressure on our leaders to take stroke seriously we are calling on the stroke community to get involved in the campaign. Our Enough Stroke! Enough NCDs Campaign Brief provides background information and resources including suggested tweets and Facebook posts to help you put stroke at the centre of the NCD debate. 
Other things you can do
  • Check out the campaign resources that can complement your stroke messaging available from NCD Alliance campaign website.
  • Find out if your local NCD Alliance has any on the ground activities planned and mobilise stroke supporters to get involved.
  • Join the conversation on social media using hashtags #EnoughNCDs #EnoughStroke
Follow us on Facebook and Twitter.

Role of Immune Cells Migrating to the Ischemic Brain

I got nothing out of this that could help any survivor recover better. But since I'm not medically trained I obviously know nothing. 

Role of Immune Cells Migrating to the Ischemic Brain

Originally publishedStroke. 2018;49:2261-2267
The central nervous system and the immune system are tightly interconnected through complex communicating networks.1 Immune cells are distributed in specific central nervous system compartments. Microglia are the innate immune cells resident in the brain parenchyma. Macrophages surround the blood vessels and also line the leptomeninges and the choroid plexus together with dendritic cells and lymphocytes, among other immune cells, where they play immunosurveillance functions. Therefore, the immune system keeps a close watch on brain function and reacts when brain homeostasis is lost because of injuries or diseases. Sterile organ damage may turn immune cells into harmful agents and for this reason they are regarded as targets for therapeutic intervention in acute stroke.2 Stroke induces strong inflammatory reactions involving the local production of cytokines, such as TNF-α (tumor necrosis factor-α) by various brain cells, including human neurons,3 activation of glial and endothelial cells, blood-brain barrier damage, and infiltration of different types of leukocytes after an orchestrated time course.4 Given the variety of leukocyte subsets trafficking to the ischemic brain tissue, this review will focus on neutrophils, monocyte/macrophages, and T and NK (natural killer) lymphocytes. For further information, the readers are addressed to previous reviews on dendritic cells5 and B lymphocytes.6 The different immune cells are considered separately in the next sections, but leukocyte infiltration surely comprises intercellular crosstalks by mechanisms that are not entirely known.

Neutrophils

Neutrophils are among the first cells attracted to the brain after ischemic stroke where they are detected in the microvessels within the first hour7 and peak at 1 to 3 days.4,7,8 Neutrophils are short-lived innate immune cells containing different types of granules with antimicrobial pro-oxidant and proteolytic enzymes that can damage the tissues. Accordingly, neutrophils are regarded as detrimental following compelling evidence associating these cells with blood-brain barrier breakdown and brain injury.7,9 Also, higher blood neutrophil counts are associated with larger infarct volumes in acute ischemic stroke patients.10 Nevertheless, the pathogenic role of neutrophils in ischemic stroke is still not conclusive. For instance, there are conflicting results in the literature on the potential benefit of neutrophil depletion in experimental ischemia models.9,11 Furthermore, we lack entire demonstration that neutrophils reach the ischemic tissue before substantial neuronal death has occurred.11 Nonetheless, neutrophils can exert detrimental effects already from the vessel wall. Adhesion of neutrophils to the inflamed endothelium after ischemia/reperfusion is involved in the no-reflow phenomenon, obstructing blood flow in precapillary arterioles, postcapillary venules, and the capillary bed.7,12 In addition, neutrophils in the vessel lumen and at perivascular locations can damage the blood-brain barrier by releasing proteolytic enzymes and pro-oxidant molecules (Figure).9 Moreover, neutrophils can produce NETs (neutrophil extracellular traps) promoting clot formation.13 NETs can precipitate thrombotic events and impair tPA (tissue-type plasminogen activator)-induced thrombolysis.14 In turn, thrombolysis may exacerbate detrimental effects of neutrophils because tPA promotes neutrophil transmigration to the reperfused tissue by proteolytic activation of plasmin and matrix metalloproteinases.15 These effects might contribute to explain why neutrophilia and high neutrophil-to-lymphocyte ratio are associated with the risk of hemorrhagic transformation in ischemic stroke patients treated with tPA.16 After permanent middle cerebral artery occlusion (MCAo) in mice, we observed the formation of intravascular NETs and found NETs in perivascular locations and in the brain parenchyma.17
Figure.
Figure. Schematic representation of leukocyte infiltration to the ischemic brain tissue. Neutrophils are attracted to the activated endothelium and reach perivascular spaces after extravasation from intracerebral venules and leptomeningeal vessels. Activated neutrophils are prothrombotic and can damage the blood-brain barrier (BBB). The presence of neutrophils in the brain parenchyma is observed only under certain circumstances, but the conditions determining that neutrophils remain in perivascular spaces or reach the parenchyma are still poorly defined. Attracted by certain chemokines, immature proinflammatory monocytes infiltrate the ischemic tissue where they mature to macrophages, acquire signs of alternative polarization, and seem to be involved in tissue repair. Current experimental evidence suggests that lymphocytes, in particular T cells and γδ T cells, play detrimental roles in the acute phase of stroke by promoting thromboinflammation and tissue damage. Natural killer (NK) cells are attracted to the ischemic tissue, but their function is not fully clear. RBC indicates red blood cells.
There is also some controversy on whether neutrophils actually reach the ischemic brain parenchyma at all. An elegant study by Enzmann et al18 noticed the massive accumulation of neutrophils in perivascular spaces surrounding venules within the ischemic tissue after ischemia/reperfusion in mice. Most neutrophils remained perivascular, and only a few were detected in the brain parenchyma.18 This is an important observation because it highlights that perivascular spaces are a niche for neutrophils where they accumulate after transient MCAo. We also detected neutrophils in perivascular locations and leptomeningeal spaces in the mouse after permanent MCAo.17 These results suggest that, besides extravasating from intracerebral venules, neutrophils extravasate from leptomeningeal vessels and migrate from the subpial space along the vessels penetrating the cortex.17 However, our study17 and previous studies7 found neutrophils in the ischemic brain parenchyma using models of permanent MCAo. Ischemic conditions involving severe endothelial damage, vessel rupture, and microbleeds or hemorrhagic transformation, are expected to facilitate the presence of neutrophils in the brain parenchyma. Other conditions, such as high blood glucose, also promote neutrophil infiltration.19 A recent study20 analyzed the postmortem brain of 16 ischemic stroke patients and confirmed the presence of neutrophils in the leptomeninges and perivascular spaces, but neutrophils were rare in the infarcted parenchyma with the exception of 1 patient deceased 3 days after stroke with no signs of infection. Interestingly, the time to death of this series of patients was 1 day in 2 cases, 3 days in the case above mentioned, and then times ranged from 8 days to 240 days poststroke.20 Neutrophils display a specific time-window of attraction to the damaged tissues after acute injuries, and they have a short life in tissues. Therefore, the time to death of ischemic stroke patients is critical to look for the presence of neutrophils in the brain parenchyma. More studies of human tissue within the first days poststroke are necessary to understand under which conditions neutrophils might gain access to the infarcted brain parenchyma.
Despite many advances, there are aspects of neutrophil behavior in stroke that are still difficult to interpret. For instance, neutrophils with anti-inflammatory and repair phenotypes were found in the ischemic brain tissue of experimental animals,21 neutrophils of ischemic stroke patients show a reduced oxidative burst and NET formation,22 and microglia surrounding blood vessels phagocyte neutrophils.23 The possibility that neutrophils were passive bystanders under some circumstances but active players in others depending on specific features of the ischemic lesion needs further consideration.

Monocyte/Macrophages

After brain ischemia, microglia acquire a reactive morphology resembling macrophages. Classically, immunohistochemical studies have described the presence of reactive microglia/macrophages peaking at ≈4 days postischemia in rats or mice, but it was not possible to distinguish whether these cells derived from resident microglia or they infiltrated from the periphery. Nowadays, flow cytometry, cell type-specific fluorescent reporter mice, adoptive transfer of fluorescent cells, generation of chimeras, and recently identified specific microglia markers, allow differentiating resident reactive microglia from infiltrating macrophages. Monocyte infiltration is detected within the first 24 hours postischemia, peak at 4 days, and some of these cells persist for weeks and acquire features of tissue macrophages. Immature CCR2+Ly6Chi proinflammatory monocytes are the subset of monocytes first attracted to the ischemic brain tissue.24–26 These cells might be released by the bone marrow, but a study reported that monocytes reaching the ischemic brain originate in the spleen.25
Infiltrating macrophages were classically associated with inflammation and brain damage after ischemic stroke. In mice, monocyte infiltration is largely dependent on CCR2 (C-C motif chemokine receptor type 2), the receptor of the chemokine CCL2 (C-C motif chemokine ligand 2), also known as MCP1 (monocyte chemoattractant protein 1). To investigate the role of monocytes, several studies used CCR2-deficient mice or CCR2 inhibitors, with the limitation that besides the subset of Ly6Chi monocytes other cells, like some T cells, also express CCR2. CCR2-deficiency reduced the ischemic brain lesions in mice.27 Challenging this view, CCR2 drug inhibitors exacerbated the brain lesion.28 Furthermore, anti-CCR2 blocking antibodies impaired spontaneous long-term functional recovery,29 depletion of monocytes/macrophages worsened the ischemic lesion,30 and infiltrating macrophages prevented hemorrhagic transformation of the ischemic lesion.24 By systemic injection of fluorescent monocytes after brain ischemia, we observed fluorescent cells in the subpial space, and along the vessels penetrating the cortex,26 supporting the view that a subset of infiltrating macrophages establish persistent interactions with the blood vessels (Figure).
The phenotype of activated macrophages depends on the environmental stimuli. The M1 and M2 phenotypes are prototypical states of macrophage polarization achieved in culture after exposure to certain cytokines. The M1 phenotype is proinflammatory whereas the M2 phenotype promotes resolution of inflammation and repair. Macrophages infiltrating the ischemic tissue, including the Ly6Clo population and some of the Ly6Chi monocytes, acquire features of alternatively polarized M2 macrophages during the first week postischemia.26,28–30 Studies of human ischemic infarcts reported that macrophages initially showed proinflammatory features that with lesion maturation transformed into anti-inflammatory phenotypes.20 Interestingly, a study noticed that after ischemia in mice, the expression of M2 markers increased within the first week but then decreased, whereas proinflammatory markers persisted and predominated at week 2, suggesting a long-lasting inflammatory status.31
The factors that contribute to the time-dependent changes in macrophage phenotypes in the ischemic brain tissue are not entirely identified. Increased anaerobic glycolysis and activation of the hypoxia-inducible factor-1 are associated with proinflammatory M1 phenotypes, whereas energy production in M2 phenotypes rather relies on fatty acid oxidation.32 In M1 activated macrophages, arginine metabolism occurs through inducible nitric oxide synthase leading to generation of reactive oxygen and nitrogen species that damage proteins, lipids, and DNA. In contrast, M2 macrophages metabolize arginine through arginase-1 generating polyamines involved in cell division and collagen synthesis, among other functions.32 However, under pathological conditions 1 single phenotypic feature may not be sufficient to attribute any specific phenotype to the cells. Likely, cellular metabolic adaptations to ischemia and reperfusion together with the cytokine environment and phagocytic activity have an impact on the phenotype and function of macrophages and microglia.

Lymphocytes

T Cells

Severe stroke reduces the numbers of lymphocytes in the circulation and lymphoid organs.33 In contrast, T-cell numbers increase in the ischemic brain within the first 24 hours and can persist for long times.4 During the first hours after ischemia/reperfusion, T cells facilitate adhesion of platelets and leukocytes to the vascular endothelium34 causing a phenomenon called thromboinflammation35 by which molecular and cellular players in thrombosis and coagulation promote proinflammatory pathways exacerbating the brain lesion.36 However, the interaction of T cells with platelets may also have hemostatic effects preventing hemorrhagic transformation after severe ischemic stroke.37 T cells are found in subpial and cortical vessels and infiltrating the ischemic lesion.38,39 In addition, the choroid plexus is a gateway for T cells migrating to the periphery of cortical infarction.40 Importantly, CD8+ cytotoxic T cells were detected in human ischemic infarcts.20 Also, ischemic stroke patients show increased frequency of CD4+CD28null cells in blood associated with stroke severity and serum levels of proinflammatory cytokines.41 CD4+CD28null T cells are an interesting subset of T cells because they have enhanced effector functions, are associated with senescent T cells, and expand under inflammatory conditions.42 At later phases, CD4+ cells accumulate in the brain of mice peaking at day 14 and persisting at day 30 after ischemia/reperfusion.43 Furthermore, emerging evidence suggests that antigen-mediated T-cell responses take place in subacute or chronic stages after stroke and may worsen stroke outcome.43–47 However, in central nervous system trauma, protective autoimmunity mediated by T-cell responses is involved in promoting recovery.48 Overall, T cells seem to play innate functions and interact with players in thrombosis and hemostasis in the acute phase of stroke, whereas at later stages they exert adaptive functions that could affect stroke outcome in the long term.

γδ T Cells

Subsets of unconventional innate T cells with invariant T-cell receptor could play a role in acute ischemic brain damage. Growing evidence supports that γδ T cells are pathogenic in experimental brain ischemia/reperfusion by secreting IL (interleukin)-17 and exacerbating the inflammatory response.49–51 Moreover, IL-17A+ lymphocytes were detected in the postmortem brain of stroke patients.50 Interestingly, γδ T cells are abundant in the gut from where they seem to traffic to the leptomeninges after brain ischemia.52 T helper 17 cells (Th17) and γδ T cells increase in the blood of stroke patients in association with increased levels of IL-17A, IL-23, IL-6, and IL-1β.53 In spite of the fact that IL-17 producing cells are a small subset of cells, they seem to play a prominent role in orchestrating the inflammatory response in acute stroke and exacerbating the lesion (Figure).

Regulatory Lymphocytes

Regulatory lymphocytes exert immunomodulatory and immunosuppressor functions. Several lines of evidence support beneficial effects of regulatory T cells (Treg)54 and regulatory B cells55 in experimental brain ischemia. However, other studies found acute detrimental effects of Treg in brain ischemia/reperfusion56 as previously reviewed.57 Although the number of Treg found in the ischemic brain parenchyma during the first days poststroke is low, Treg strongly accumulate in the ischemic lesion 15 days poststroke where potentially they could inhibit autoimmune responses.43 Increased apoptosis of Tregs, loss of Tregs in peripheral blood, and impaired suppressive function of the remaining Treg population has been reported in ischemic stroke patients.53,58,59 However, other studies reported upregulation of Tregs in stroke patients in spite that decreased Treg function was observed, particularly in female patients.60 Notably, an increased proportion of Treg cells was reported in the spleen of mice 4 days after transient MCAo.61

NK Cells

NK innate lymphocytes show a rapid and transient increase in the ischemic brain tissue.4,8 A study reported no benefits of depleting NK cells in permanent or transient MCAo.44 In contrast, another study suggested pathogenic actions of NK cells by promoting inflammation and neuronal cytotoxicity.62 This study reported infiltration of NK cells in the ischemic brain tissue of humans and mice where NK cell numbers peaked as soon as 3 hours postischemia and then declined.62 Interestingly, the β2-nACh-R (nicotinic acetylcholine) receptor seems to be involved in the NK cell decline observed in the ischemic tissue from 3 hours postischemia.63 Induced-persistence of NK cells in the ischemic tissue achieved by interfering with this cholinergic receptor did not modify lesion size but increased systemic IFNγ (interferon γ), protected from bacterial infection, and enhanced poststroke survival.63 More studies are needed to validate the putative capacity of brain infiltrating NK cells to prevent poststroke infection, the role of central acetylcholine in this process, as well as the suggested rapid pathogenic effect of NK cells worsening the acute ischemic brain lesion.

Therapeutic Intervention

Strategies designed to prevent negative actions of leukocytes have been taken to the clinic in acute ischemic stroke patients but with no success to date.64 Several studies with drugs blocking the action of neutrophils were investigated.11,64 As an example, the ASTIN trial (Acute Stroke Therapy by Inhibition of Neutrophils) investigated a compound known as UK-279 276, a recombinant neutrophil inhibitory factor that selectively binds the CD11b integrin of macrophage-1 antigen (CD11b/CD18).65 The treatment did not improve recovery above placebo. This trial followed encouraging results of a few preclinical studies with UK-279 276 in experimental models of brain ischemia/reperfusion.66 However, only a fifth of patients in the ASTIN trial received tPA.65
Monocyte/macrophages may acutely exacerbate the inflammatory responses, but experimental studies have identified their involvement in resolution of inflammation, vascular protection, and recovery of function,24,27–29 possibly linked to the phagocytic and vasculoprotective roles of these cells. These protective actions of monocytes are in line with the beneficial effects of administration of autologous bone marrow–derived mononuclear cells (MNC) after experimental ischemic stroke.67 MNC contain myeloid and lymphoid cells, as well as hematopoietic and mesenchymal stem cells. MNC administration 24 hours after MCAo improved functional recovery, reduced lesion size and proinflammatory cytokines, and enhanced vessel density and neurogenesis,68 and these benefits were long lasting.69 Furthermore, MNC reduced blood-brain barrier permeability and decreased the severity of hemorrhagic transformation after tPA in an embolic stroke model.70 However, MNC therapy did not improve outcome in hypertensive rats.71 MNC reach the periphery of brain infarction soon after administration,68 and then the cells seem to differentiate into smooth muscle cells and endothelial cells, incorporate into vessel walls, and enhance the growth of leptomeningeal anastomoses, the circle of Willis, and basilar arteries.69 Phase I trials administering MNC to ischemic stroke patients have shown safety, but the clinical efficacy of this cell therapy awaits demonstration.72
Anti-inflammatory treatments, such as minocycline, have not been successful in the clinic.64 Experimental evidences, including a cross-laboratory preclinical study in mouse models of brain ischemia,73 support the therapeutic potential of the IL-1Ra (IL-1β receptor antagonist). A recent clinical trial with subcutaneous administration of IL-1Ra showed safety and reduction of plasma IL-6.74 However, the analysis excluded a major clinical benefit of the treatment, and negative effects potentially attributable to interactions of IL-1Ra with tPA became apparent.74
Experimental studies support damaging effects of T lymphocytes in the acute phase of stroke. Accordingly, fingolimod, a drug approved for remitting-relapsing multiple sclerosis that sequesters lymphocytes in the lymph nodes preventing lymphocyte access to the inflamed tissues, showed beneficial effects in preclinical studies and small clinical trials in acute ischemic stroke patients, including patients receiving thrombolysis.64 By acting on S1P1 (sphingosine-1-phosphate receptor 1), fingolimod induces sustained lymphopenia, but current data do not show higher incidence of poststroke infection in patients receiving fingolimod. Fingolimod also acts on endothelial S1P1 receptor increasing vascular barrier function that might contribute to the observed benefits of this drug in ischemic stroke. Given that the benefits of fingolimod seem to be mediated by S1P1, whereas certain side effects are dependent on other S1P receptors, selective S1P1 agonists were studied in experimental stroke showing reduced lesion size after ischemia/reperfusion in mice.75 In contrast to the benefits of blocking T-cell trafficking, systemic administration of regulatory T lymphocytes in rodent models of ischemic stroke reduced infarct size, ameliorated the neurological functions,76 and reduced hemorrhagic transformation after tPA.77
Leukocyte recruitment to inflammatory sites is attenuated by blocking α4β1 integrin (VLA-4 [very late antigen-4]) with natalizumab, an antibody in clinical use for multiple sclerosis treatment. Blockade of VLA-4 with CD49d antibody was investigated in a multicentric preclinical study in mice using 2 different models of cerebral ischemia.78 CD49d antibody attenuated leukocyte infiltration and reduced infarct volume in small cortical lesions but not in large infarctions. Natalizumab was investigated in ischemic stroke patients in the ACTION trial (Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke).79 Natalizumab did not meet the primary end point of the study, but secondary and exploratory end points suggested improvement of clinical outcomes,64,79 encouraging the second ACTION2 trial. This phase-IIb trial was recently completed and the notes released by the sponsor (Biogen) state that natalizumab did not improve clinical outcomes compared with placebo.

Final Remarks

Experimental studies support detrimental effects of certain types of leukocytes in acute ischemic stroke. However, to date, this knowledge has not been translated into clinical treatments. No doubt immunomodulatory interventions in the acute phase of stroke need fine-tuning and long-term experimental studies to ensure that repair processes in subacute and chronic phases are not disturbed and the neurological deficits are attenuated. Cell therapies based on administration of autologous MNC have shown promising results in preclinical studies by promoting functional recovery, but clinical efficacy remains to be demonstrated. Results of various experimental models of brain ischemia suggest the possibility that the putative pathogenic contribution of certain leukocytes to the acute ischemic lesion might differ depending on lesion severity, regions affected, and degree of reperfusion. Importantly, most of the studies described above were obtained in young healthy male mice in spite of the fact that aging, sex, and comorbidities influence the phenotype and function of immune cells. Identification of the ischemic conditions where leukocytes might have a meaningful contribution to the brain lesion, the relevant subsets of leukocytes, and the time-window for intervention, requires more investigation. Combining immunomodulatory strategies with reperfusion therapies offer the opportunity to attenuate negative responses of the immune system that might impair reperfusion at the microvascular bed or trigger detrimental effects on the brain tissue.

Acknowledgments

I acknowledge relevant studies used to prepare this article that could not be cited because of word count restriction.

Footnotes

Correspondence to Anna M. Planas, PhD, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Rosselló 161, Planta 6, 08036-Barcelona, Spain. Email