Phagocytic microglia and macrophages in brain injury and repair

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question.

Phagocytic microglia and macrophages in brain injury and repair

Fang Yu1,2| Yangfan Wang1,2| Anne R. Stetler1,2| Rehana K. Leak3|Xiaoming Hu1,2| Jun Chen1,2This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.1Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA2Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA3Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USACorrespondenceJun Chen, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, University Drive, Pittsburgh, PA 15261, USA.Email: chenj2@upmc.eduFunding informationNIH, Grant/Award Number: NS0105430; VA, Grant/Award Number: 821-RC- NB- 30556, I01BX003377, I01BX003651, I01BX005290 and I01BX005589 

Abstract

 

Aims:  

Phagocytosis is the cellular digestion of extracellular particles, such as patho-gens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed—but viable—neurons.

 Discussion:  

Microglia/macrophages help mediate intercellular communication and react quickly to the “find- me” signals expressed by dead/dying neurons. The acti-vated microglia/macrophages then migrate to the injury site to initiate the phago-cytic process upon encountering “eat- me” signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing “do not- eat- me” signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro- inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage-induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process.

 Conclusion: 

 Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage.

 KEYWORDS

acute brain injury, brain repair, microglia/macrophage, phagocytosis

Factors influencing infarct growth including collateral status assessed using computed tomography in acute stroke patients with large artery occlusion

Will you stop trying to predict stroke severity and just simply stop the 5 causes of the neuronal cascade of death in the first week that would result in vastly less dead and damaged neurons. This is pretty much useless for survivor recovery to 100%. I'm sure there are more than these 5 causes but since I don't have minions or a stroke association to add the additional ones I've found, you'll just have to deal with your incompetent doctor not knowing of these and having nothing to stop that neuronal cascade of death. Hope you are pleased with your doctors' service.  My next stroke will be a screaming match with my stroke 'professionals'. 'What did you do 1/5/10 years ago when your patients did not get to 100% recovery?' 'If you did nothing, I want a new doctor, you're fired!'  Doctors who depend on collaterals for YOU to have a less damaging stroke are worthless.  Doctors can control the neuronal cascade of death if they were responsible and smart enough a decade ago to enlist researchers to solve that problem. Not smart enough or not responsible, YOU are the recipient of that incompetency, vastly more dead and damaged neurons than should have occurred. In my 90 minutes before tPA blew out my clot.

In each minute,
1.9 million neurons die
14 billion synapses die
12 km (7.5 miles) of myelinated fibers die
brain ages 3.6 years each hour without treatment

Day 1,: first 90 minutes:
171 million dead neurons 
1.260 trillion dead synapses
675 miles of dead myelinated fibers
Brain aged 5.4 years
Days 2-3; 1/2 the rate of day 1
So 1440 minutes a day * 2days * 950000 = 2,736,000,000  or 2.7 billion  dead neurons
  1440 minutes a day *2days * 7,000,000,000syn = 20,160,000,000,000     20.2 trillion        dead synapses
1440 * 2days * 3.75mi = 10800 mi  dead myelinated fibers
Brain aged - 2 years, a guess

Days 4-7; 1/4 the rate of day 1

So 1440 minutes a day * 4 days * 475000 = 2,736,000,000  or 2.7 billion dead neurons
  1440 minutes a day *4 days * 3,500,000,000syn = 20,160,000,000,000 20.2 trillion    dead synapses
1440 * 4days * 1.875mi = 10800 mi  dead myelinated fibers
Brain aged - 2 years, a guess 
This is one hell of a lot of damage to recover from. Especially since we don't know how to move functions from dead locations to new ones.  Or know how to usefully get neurogenesis to work.
Totals:
5.571 billion dead neurons
4.041260 trillion dead synapses
 22,275 miles dead myelinated fibers
Brain aged -  9.4 years

If I had just lost neurons in those first 90 minutes I would be completely recovered by now.

If your hospital isn't measuring your neuronal death, then nothing will ever improve.  This set of statistics should be required for every hospital to provide.

“What's measured, improves.” So said management legend and author Peter F. Drucker

 

 

 

Factors influencing infarct growth including collateral status assessed using computed tomography in acute stroke patients with large artery occlusion 

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Bin Jiang, Robyn L Ball, Patrik Michel, ...

First Published May 17, 2019 Case Report

https://doi.org/10.1177/1747493019851278

Article information

Abstract

In major ischemic stroke caused by a large artery occlusion, neuronal loss varies considerably across individuals without revascularization. This study aims to identify which patient characteristics are most highly associated with this variability. Demographic and clinical information were retrospectively collected on a registry of 878 patients. Imaging biomarkers including Alberta Stroke Program Early CT score, noncontrast head computed tomography infarct volume, perfusion computed tomography infarct core and penumbra, occlusion site, collateral score, and recanalization status were evaluated on the baseline and early follow-up computed tomography images. Infarct growth rates were calculated by dividing infarct volumes by the time elapsed between the computed tomography scan and the symptom onset. Collateral score was graded into four levels (0, 1, 2, and 3) in comparison with the normal side. Correlation of perfusion computed tomography and noncontrast head computed tomography infarct volumes and infarct growth rates were estimated with the nonparametric Spearman's rank correlation. Conditional inference trees were used to identify the clinical and imaging biomarkers that were most highly associated with the infarct growth rate and modified Rankin Scale at 90 days. Two hundred and thirty-two patients met the inclusion criteria for this study. The median infarct growth rates for perfusion computed tomography and noncontrast head computed tomography were 11.2 and 6.2 ml/log(min) in logarithmic model, and 18.9 and 10.4 ml/h in linear model, respectively. Noncontrast head computed tomography and perfusion computed tomography infarct volumes and infarct growth rates were significantly correlated (rho=0.53; P < 0.001). Collateral status was the strongest predictor for infarct growth rates. For collateral=0, the perfusion computed tomography and noncontrast head computed tomography infarct growth rate were 31.56 and 16.86 ml/log(min), respectively. Patients who had collateral >0 and penumbra volumes>92 ml had the lowest predicted perfusion computed tomography infarct growth rates (6.61 ml/log(min)). Collateral status was closely related to the diversity of infarct growth rates, poor collaterals were associated with a faster infarct growth rates and vice versa.

Keywords Ischemic stroke, computed tomography, perfusion imaging, collateral

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Resistance training after stroke improves strength but not necessarily function

Muscle weakness is not my problem, it is the ability to move muscles at all. Caused by dead motor cortex neurons or spasticity. What the hell is there out there to solve my problems? 
https://motorimpairment.neura.edu.au/resistance-training-after-stroke/
Muscle weakness is the largest cause of disability after stroke (Canning et al 2004). Stroke survivors have levels of muscle strength that are about half of that of people who have not had a stroke (Dorsch et al 2016; Horstman et al 2008). Thus, it is important to identify interventions that can improve muscle strength in stroke survivors.
The most proven method for improving muscle strength is progressive resistance training. Progressive resistance training involves lifting a load 8 to 15 times to the point of muscle fatigue and then progressively increasing the intensity of the exercise over the course of an intervention. Progressive resistance training has been shown to be effective at increasing muscle strength in people without stroke, but it is unclear how effective it is at improving muscle strength and physical function in stroke patients.
In our recent paper (Dorsch et al. 2018), we reviewed data from 11 clinical trials that used progressive resistance training to try to improve strength and function in people with stroke. Our review included trials in which study participants were stroke survivors at any time after stroke, and the trials also needed to include an intervention group that performed progressive resistance training and a control or placebo group that did not perform the training. We looked at the changes in muscle strength and function in these studies. In general, studies that involved training of leg muscles, function was measured with walking speed, and studies that involved training of arm muscles involved functional tests of the arms.

WHAT DID WE FIND?

We found that progressive resistance training is effective at increasing muscle strength in people with stroke. The average increase in strength is 50% in muscles that are specifically targeted by training. However, this large increase in strength does not consistently reduce disability. That is, the improvement in strength does not always carryover directly to better walking or better use of the affected arm in functional tasks.

SIGNIFICANCE AND IMPLICATIONS

In stroke survivors, progressive resistance training increases muscle strength. However, this does not necessarily improve arm function or the ability to walk. This finding suggests that if stroke survivors are strong enough to participate in resistance training then muscle weakness is not their main impairment, and training should target other impairments, such as loss of coordination. However, if a patient has very weak muscles – too weak to move against small resistances or against gravity – then increasing strength should still be a priority.

PUBLICATION REFERENCE

Dorsch S, Ada L, Alloggia D. Progressive resistance training increases strength after stroke but this may not carry over to activity: a systematic review. J Physiother 64:84-90, 2018.

KEY REFERENCES

Canning CG, Ada L, Adams R, O’Dwyer NJ. Loss of strength contributes more to physical disability after stroke than loss of dexterity. Clin Rehabil 18:300-308, 2004.
Dorsch S, Ada L, Canning CG. Lower limb strength is significantly impaired in all muscle groups in ambulatory people with chronic stroke: a cross-sectional study. Arch Phys Med Rehabil 97:522-527, 2016.
Horstman AM, Beltman MJ, Gerrits KH, Koppe P, Janssen TW, Elich P, deHaan A. Intrinsic muscle strength and voluntary activation of both lower limbs and functional performance after stroke. Clin Physiol Funct Imaging 28:251-261, 2008.

How much better off would I be if only 171 million neurons died during my stroke?

Your doctor should give you this exact same calculation, then you could sue for any damage beyond delivery of tPA.  This calculation proves the fucking failures of our stroke associations. our doctors and stroke hospitals. Money might be the only way to change this, professional responsibility and the Hippocratic Oath are not working. They are doing nothing to solve this neuronal cascade of death. 

1 million dollars per dead neuron sounds like a good amount to ask for.  

This is over the top but unless you don't want change to occur we have to impress upon the medical world how incompetent they are.

Approximate death rates; Your doctor will know exactly.

In each minute,

1.9 million neurons die

14 billion synapses die

12 km (7.5 miles) of myelinated fibers die

brain ages 3.6 years each hour without treatment

I got to the  hospital in 30 minutes, 60 more minutes until I got tPA, no other treatment at all.  I'll be conservative and estimate that for the next two days that the neuronal cascade of death was proceeding at half the normal rate, and days 3-7 at one quarter rate. A medical person could chime in here with research pointing to death rates of the penumbra during the first week.

Day 1,: first 90 minutes:
171 million dead neurons 
1.260 trillion dead synapses
675 miles of dead myelinated fibers
Brain aged 5.4 years
Days 2-3
So 1440 minutes a day * 2days * 950000 = 2,736,000,000  or 2.7 billion  dead neurons
  1440 minutes a day *2days * 7,000,000,000syn = 20,160,000,000,000     20.2 trillion        dead synapses
1440 * 2days * 3.75mi = 10800 mi  dead myelinated fibers
Brain aged - 2 years, a guess

Days 4-7
So 1440 minutes a day * 4days * 475000 = 2,736,000,000  or 2.7 billion dead neurons
  1440 minutes a day *4days * 3,500,000,000syn = 20,160,000,000,000 20.2 trillion    dead synapses
1440 * 4days * 1.875mi = 10800 mi  dead myelinated fibers
Brain aged - 2 years, a guess 
This is one hell of a lot of damage to recover from. Especially since we don't know how to move functions from dead locations to new ones.  Or know how to usefully get neurogenesis to work.
Totals:
5.571 billion dead neurons
4.041260 trillion dead synapses
 22,275 miles dead myelinated fibers
Brain aged -  9.4 years
The brain contains 80 billion neurons, I only lost 6.96375% of my brain.  
My charge would be $5.57100000E+15, whatever that is in real terms, beyond my calculators capacity.

The brain needs to 'clean itself up' so that it can 'sort itself out'

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question. 

The brain needs to 'clean itself up' so that it can 'sort itself out'

A piece of research led by the Achucarro Basque Center for Neuroscience, the University of the Basque Country (UPV/EHU), and the Ikerbasque Foundation has revealed how the brain’s cleaning up mechanisms function in neurodegenerative diseases.
When neurons die, their remains need to be eliminated quickly so that the surrounding brain tissue can continue functioning. A type of highly specialised cell known as microglia is responsible for this process which is called phagocytosis (derived from the Greek “phagein”, to eat, and “kitos”, cell). These tiny cells have numerous branches that are constantly on the move inside the brain and are specially equipped to detect and destroy any foreign element, including dead neurons. Or that is what has been believed until now.
In this study, which has just been published by the journal Public Library of Science (PLoS) Biology, the process of neuronal death and microglial phagocytosis in the diseased brain has been studied for the first time. To do this, brain samples taken from epilepsy patients at the University Hospital of Cruces and from epileptic mice were used.
Neurons are known to die during the convulsions associated with epilepsy. But contrary to expectations, in this condition the microglia are “blind” and incapable of either finding them or destroying them. Their behaviour is abnormal. And the dead neurons that cannot be eliminated build up and damage the neighbouring neurons further, which leads to an inflammatory response by the brain which harms and damages it even further.
This discovery opens up a new channel for exploring therapies that could palliate the effects of brain diseases. In fact, the research group that authored this work is right now exploring the development of drugs to encourage this cleaning up process, phagocytosis, that could help in the treatment of epilepsy patients.
The study was led by Dr Amanda Sierra, head of the Glial Cell Biology laboratory of the Achucarro Basque Center for Neuroscience, and the experimental work was conducted mainly by the researchers Oihane Abiega, Sol Beccari and Irune Díaz-Aparicio. Other Achucarro and UPV/EHU researchers such as Juan Manuel Encinas, Jorge Valero, Víctor Sánchez-Zafra and Iñaki París also participated in it.
This piece of international research was coordinated from the Basque Country and had the participation of research groups from CIC bioGUNE (Derio), the University of Bordeaux (France), the University of Southampton (UK), Université Laval (Canada), and the Baylor College of Medicine (USA).

• Full bibliographic informationO Abiega et al. "Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling" PLoS Biol 14(5): e1002466. doi:10.1371

The brain needs cleaning to stay healthy

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question.
http://medicalxpress.com/news/2016-05-brain-healthy.html

Research led by the Achucarro Basque Center for Neuroscience, the University of the Basque Country (UPV/EHU), and the Ikerbasque Foundation has revealed the mechanisms that keep the brain clean during neurodegenerative diseases.

When neurons die, their debris need to be quickly removed in order for the surrounding brain tissue to continue to function properly. Elimination of the neuron corpses, in a process called phagocytosis, is carried out by highly specialized cells in the brain called microglia. These small cells have many ramifications that are in constant motion and are specially equipped to detect and destroy any foreign element, including dead neurons. Or so it was thought until now.
This study, publishing May 26, 2016 in PLOS Biology, investigates, for the first time, the process of neuronal death and microglial phagocytosis in the diseased brain. To this end, scientists collected brain samples from epilepsy patients at University Hospital of Cruces and from epileptic mice.
It is known that during epilepsy-associated seizures, neurons die. However, contrary to what happens in the healthy brain, during epilepsy, microglia seem to be "blind" and unable to find the dead neurons and to destroy them. Their behavior is abnormal. Therefore, dead neurons cannot be eliminated and accumulate, spreading the damage to neighboring neurons and triggering an inflammatory response that worsens the brain injury.
This discovery opens a new avenue to explore therapies that could alleviate the effects of brain diseases. In fact, the research group that undertook these studies is currently developing drugs, hoping to boost this cleaning process -phagocytosis- and help in the treatment of epilepsy.

Explore further: Epilepsy has been found to reduce the generation of new neurons

More information: Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Layé S, Leyrolle Q, et al. (2016) Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling. PLoS Biol 14(5): e1002466. DOI: 10.1371/journal.pbio.1002466

Journal reference: PLoS Biology
Provided by: Public Library of Science

Researchers create functional human capillaries from adult stem cells

We need this applied to our dead brain areas so when we get neuronal stem cells injected into our brains they will have nourishment.
http://www.stemcellsfreak.com/2013/04/adult-stem-cells-form-human-capillaries.html
One of the biggest problems faced by scientists who try to grow organs in the lab, is forming blood vessel networks that nurish and keep the tissues alive. Today, researchers from the University of Michigan (UM) announced some very promising findings that may help overcome this obstacle. The study also has implications in the treatment of conditions that affect the circulatory system, like diabetes.

Andrew Putnam, chief author of the study, explains why the ability to form functional blood vessels is so important tissue engineering:

"If you don't nourish it with blood by vascularizing it, it's only going to be as big as the head of a pen."

Currently, there are two main approaches that researchers use to grow new capillaries, the smallest blood vessels our body has (5-10 μm in diameter), with their main role being to exchange water, oxygen, carbon dioxide, and other nutrients and waste chemical substances between blood and surrounding tissues like muscles and organs.


More at link.

Advances in Neuronal Destruction

Not that I think that destroying neurons  is a good thing but this blogger points out some research identifying how many neurons can be destroyed for a specific task and still keep the task going. Should be fascinating followups for stroke researchers to determine correlation  and identify  patches of dead brain cells and their resulting deficits.  The end result should be a mapping of dead brain areas to deficits.
http://cellularscale.blogspot.com/2012/07/advances-in-neuronal-destruction.html

The Brain's Bat Signal

Mo Costandi writes on cleanup in the brain.
Microglia are the brain's resident security guards, surveilling the organ for damage and then crawling to the injury site to engulf dead neurons. Exactly how they detect problems was unclear, but researchers now show that they respond to an SOS signal from dying cells that is relayed throughout the brain. The finding may have implications for the treatment of Alzheimer's and other neurodegenerative diseases. 
Rest of article here with cool video;
http://news.sciencemag.org/sciencenow/2012/05/the-brains-bat-signal.html?ref=hp
His blog here with more on injured neurons;
 http://www.guardian.co.uk/science/neurophilosophy/2012/may/26/1