Deans' stroke musings

Changing stroke rehab and research worldwide now.Time is Brain!Just think of all the trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 438 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:

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's quite disgusting that this information is not available from every stroke association and doctors group.
My back ground story is here:

Friday, August 28, 2015

Alzheimer’s disease thought to be accelerated by an abnormal build-up of fat in the brain

What is your doctor doing with this discovery?
What is your doctor doing to prevent your 33% dementia chance post-stroke from an Australian study? ANYTHING AT ALL? Or is your doctor expecting you to figure this out on your own? 

People with Alzheimer’s disease have fat deposits in the brain. For the first time since the disease was described 109 years ago, researchers affiliated with the University of Montreal Hospital Research Centre (CRCHUM) have discovered accumulations of fat droplets in the brain of patients who died from the disease and have identified the nature of the fat.
This breakthrough, published today in the journal Cell Stem Cell, opens up a new avenue in the search for a medication to cure or slow the progression of Alzheimer’s disease. "We found fatty acid deposits in the brain of patients who died from the disease and in mice that were genetically modified to develop Alzheimer’s disease. Our experiments suggest that these abnormal fat deposits could be a trigger for the disease", said Karl Fernandes, a researcher at the CRCHUM and a professor at University of Montreal.
Over 47.5 million people worldwide have Alzheimer’s disease or some other type of dementia, according to the World Health Organization. Despite decades of research, the only medications currently available treat the symptoms alone.
This study highlights what might prove to be a missing link in the field. Researchers initially tried to understand why the brain’s stem cells, which normally help repair brain damage, are unresponsive in Alzheimer’s disease. Doctoral student Laura Hamilton was astonished to find fat droplets near the stem cells, on the inner surface of the brain in mice predisposed to develop the disease. "We realized that Dr. Alois Alzheimer himself had noted the presence of lipid accumulations in patients’ brains after their death when he first described the disease in 1906. But this observation was dismissed and largely forgotten due to the complexity of lipid biochemistry", said Laura Hamilton.
The researchers examined the brains of nine patients who died from Alzheimer’s disease and found significantly more fat droplets compared with five healthy brains. A team of chemists from University of Montreal led by Pierre Chaurand then used an advanced mass spectrometry technique to identify these fat deposits as triglycerides enriched with specific fatty acids, which can also be found in animal fats and vegetable oils.
"We discovered that these fatty acids are produced by the brain, that they build up slowly with normal aging, but that the process is accelerated significantly in the presence of genes that predispose to Alzheimer’s disease", explained Karl Fernandes. In mice predisposed to the disease, we showed that these fatty acids accumulate very early on, at two months of age, which corresponds to the early twenties in humans. Therefore, we think that the build-up of fatty acids is not a consequence but rather a cause or accelerator of the disease."
Fortunately, there are pharmacological inhibitors of the enzyme that produces these fatty acids. These molecules, which are currently being tested for metabolic diseases such as obesity, could be effective in treating Alzheimer’s disease. "We succeeded in preventing these fatty acids from building up in the brains of mice predisposed to the disease. The impact of this treatment on all the aspects of the disease is not yet known, but it significantly increased stem cell activity," explained Karl Fernandes. "This is very promising because stem cells play an important role in learning, memory and regeneration."
This discovery lends support to the argument that Alzheimer’s disease is a metabolic brain disease, rather like obesity or diabetes are peripheral metabolic diseases. Karl Fernandes’ team is continuing its experiments to verify whether this new approach can prevent or delay the problems with memory, learning and depression associated with the disease.

Survivors of Childhood Cancer Have High-Risk of Recurrent Stroke

Once again the fixation on preventing stroke shows up. We should be having a multi-pronged approach. But this isn't going to occur until we get a great stroke association.
1. Replace the 88% failure rate of tPA
2. Solve the neuronal cascade of death.
3. Solve all the problems in stroke.
New evidence suggests that childhood cancer survivors who have experienced a stroke have double the risk of suffering a second stroke, when compared with non-cancer stroke survivors.
The study, published in the online edition of the journal Neurology, found that the main predictors of recurrent stroke were cranial radiation therapy, hypertension, and older age at first stroke -- factors that could help physicians identify high-risk patients.
The findings provide strong evidence for adjusting secondary stroke prevention strategies in these patients, and to aggressively detect and treat modifiable stroke risk factors, such as hypertension.
“We are at a point where more children are surviving cancer because of life-saving interventions,” said Sabine Mueller, MD, Pediatric Brain Tumor Center at the University of California at San Francisco, San Francisco, California. “Now, we are facing long-term problems associated with these interventions.”
The researchers analysed retrospective data from the Childhood Cancer Survivor Study (CCSS), which has followed 14,358 survivors diagnosed between 1970 and 1986 in the United States and Canada to track long-term outcomes of cancer treatment. All of the recruits were diagnosed with cancer before age 21.
To assess stroke recurrence rates, the researchers sent a second survey to participants who had reported a first stroke, asking them to confirm their first stroke and report if and when they had had another. The researchers analysed the respondent demographics and cancer treatments to identify any potential predictors of recurrent strokes.
Of the 271 respondents who reported having had a stroke, 70 also reported a second one. Overall, the rate of recurrence within the first 10 years after an initial stroke was 21%, which is double the rate of the general population of stroke survivors. The rate was even higher -- 33% for patients who had received cranial radiation therapy.
Previous research has shown that radiation therapy targeting the head is a strong predictor of a first stroke. In an earlier study, the authors found that children treated for brain tumours were 30 times more likely to suffer a stroke compared with their siblings. While the exact mechanisms are unclear, the scientists think high-dose radiation causes the blood vessels to constrict and encourage blockage.
“If they have 1 stroke, it’s not actually surprising that they have a high risk of getting another stroke,” said Heather Fullerton, MD, University of California at San Francisco. “You might use aspirin after the first stroke to try to reduce blood clots, but you’re not making those diseased blood vessels go away.”
The findings have significant implications for medical follow-up in childhood cancer patients. The authors said that current survivor screening guidelines do not recommend checking for diseased blood vessels, even though the signs are visible in standard MRIs.
“The radiologists are so focused on looking in the brain area where the tumour used to be that they’re not looking at the blood vessels,” said Dr. Fullerton.
Based on the findings, the University of California San Francisco has updated protocols for monitoring patients to include screening for both blood vessel injury and modifiable stroke risk factors, but it is not required on a national level.
“If we could identify high-risk patients, we could recommend they be followed by a paediatric stroke specialist,” said Dr. Mueller. “That will be huge in providing effective follow-up care for these children.”
SOURCE: University of California, San Francisco

Thursday, August 27, 2015

Regulation of Intracellular Structural Tension by Talin in the Axon Growth and Regeneration

We need axon growth so DEMAND your doctor run a clinical trial to see if this would work in humans and what the dosing would be.
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Intracellular tension is the most important characteristic of neuron polarization as well as the growth and regeneration of axons, which can be generated by motor proteins and conducted along the cytoskeleton. To better understand this process, we created Förster resonance energy transfer (FRET)-based tension probes that can be incorporated into microfilaments to provide a real-time measurement of forces in neuron cytoskeletons. We found that our probe could be used to assess the structural tension of neuron polarity. Nerve growth factor (NGF) upregulated structural forces, whereas the glial-scar inhibitors chondroitin sulfate proteoglycan (CSPG) and aggrecan weakened such forces. Notably, the tension across axons was distributed uniformly and remarkably stronger than that in the cell body in NGF-stimulated neurons. The mechanosensors talin/vinculin could antagonize the effect of glial-scar inhibitors via structural forces. However, E-cadherin was closely associated with glial-scar inhibitor-induced downregulation of structural forces. Talin/vinculin was involved in the negative regulation of E-cadherin transcription through the nuclear factor-kappa B pathway. Collectively, this study clarified the mechanism underlying intracellular tension in the growth and regeneration of axons which, conversely, can be regulated by talin and E-cadherin.

Effects of Ginko biloba leaf extract on the neurogenesis of the hippocampal dentate gyrus in the elderly mice

Don't start on this just because it works on mice. Ask your doctor to run a clinical trial on this. No pharma company is going to sponsor such research.

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Aging is associated with reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. We assessed the effect of Ginkgo biloba (Gb) on hippocampal neurogenesis in elderly male mice using immunohistochemistry. We used anti-caspase-3 as a marker of apoptosis, anti-GFAP as a marker of neural stem cells, anti-Ki-67 as a specific marker for cellular proliferation and anti-doublecortin (DCX) to detect newly born neurons in the hippocampal dentate gyrus (DG) of aged male mice. The 24-month-old male mice were divided into two groups: a control group treated with distilled water and a group fed with Gb at a dose of 100 mg/kg once daily for 28 days. A sharp decrease in apoptotic cells in Gb-treated compared to nontreated mice was observed by anti-csapase-3 immunostaining. A large number of GFAP+ve cells was found in the subgranular zone of the DG of Gb-treated mice, suggesting an increase in the pool of neural stem cells by Gb treatment. There was also an increase in Ki-67 immunoreactive cells, indicating increased cell proliferation in the DG in the Gb-treated compared to nontreated group. A significant increase in newborn DCX+ve neurons with well-developed tertiary dendrites was also found in the Gb-treated compared to nontreated group. Using Western blot analysis, the expression of DCX protein in the Gb group was also significantly increased compared to the control. The results support a beneficial role of Gb on hippocampal neurogenesis in the context of brain aging.

Wednesday, August 26, 2015

St. Luke’s Baptist Hospital Receives Comprehensive Stroke Center Certification from DNV GL Healthcare - San Antonio, Texas

You'll notice that nowhere in here do they refer to RESULTS.  We don't give a shit about care, care and processes doesn't solve any of the problems in stroke. Call that hospital CEO(Graham Reeve, President and CEO) and demand to know what the RESULTS are; tPA efficacy, 30 day deaths, 100% recovery. Accreditation means nothing here, except it looks good on paper.
Big f*cking  Whoopee.
The puffery piece here:

Considerations for the optimization of induced white matter injury preclinical models

It should be a simple matter to calculate how much white matter was damaged during your stroke.
1. Locate the epicenter
2. calculate the radius of gray matter damage from the regular scans, after the neuronal cascade of death is finished.
3. extrapolate that radius into the white matter.
This is not rocket science, Considering the large radius of my infarct, my white matter damage must be massive. Yet, there is absolutely no intervention or protocol for recovering from such damage. What should be occurring is using interventions that;
1. accelerate dendritic branching and
2.  axon pathfinding.
If I remember correctly I've written 17 posts on dendritic branching and 15 posts on axon pathfinding.
Your doctor, if any good at all, should know of all of these and have created stroke protocols for them.
imageAbdullah Shafique Ahmad1†, imageIrawan Satriotomo1†, imageJawad Fazal1, imageStephen E. Nadeau2,3 and imageSylvain Doré1,2,3,4,5,6,7,8*
  • 1Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA
  • 2Research Service, Brain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA
  • 3Department of Neurology, University of Florida, Gainesville, FL, USA
  • 4Department of Neuroscience, University of Florida, Gainesville, FL, USA
  • 5Department of Neurology, University of Florida, Gainesville, FL, USA
  • 6Department of Pharmaceutics, University of Florida, Gainesville, FL, USA
  • 7Department of Psychology, University of Florida, Gainesville, FL, USA
  • 8Department of Psychiatry, University of Florida, Gainesville, FL, USA
White matter (WM) injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in imaging technologies in the field of stroke have confirmed that WM injury plays an important role in the prognosis of stroke and suggest that WM protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of WM injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective WM injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective WM ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly, the ratio of WM to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general WM injury in animal models (stroke and non-stroke related) and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury.


The human brain comprises both gray matter and white matter (WM), with the latter constituting roughly 60% of the total volume. Gray matter consists of neuronal cell bodies, their dendrites and axons, glial cells, and blood vessels (1). On the other hand, WM consists of myelinated and unmyelinated axons that connect various gray matter areas of the brain and support communication between neurons, as well as convey information among the network of efferent and afferent axonal fibers. Disruption of these conduction pathways may cause motor and sensory dysfunction, neurobehavioral syndromes, and cognitive impairment (24). In clinical settings, WM injury can occur at any time in the life span, such as with the development of periventricular leukomalacia due to hypoxic ischemic injury in infants, cardiac arrest and stroke in adults, and vascular dementia in the elderly (58). WM injury is the major cause of paresis in all types of stroke (9). Most obviously this is true for lacunar infarcts, which comprise about 25% of all strokes, and for lower extremity paresis in large vessel distribution strokes (except in the rare circumstance that the anterior cerebral artery territory is involved). However, because anterior circulation large vessel strokes are almost always due to clots embolizing or propagating to the carotid T-junction or the proximal middle cerebral artery, and because infarcts in both locations cause ischemia in the posterior periventricular WM, through which corticospinal and corticobulbar pathways pass, ischemic WM injury also accounts for most upper extremity paresis in large vessel distribution strokes. Furthermore, the site of periventricular WM lesions that cause paresis is also the site of crossing callosal fibers. Damage to these may contribute to apraxia after left brain stroke and may interfere with language recovery after stroke.
Thus, the extent to which WM injuries contribute to neurological impairment after stroke and the frequency with which WM damage contributes to other neurologic disorders highlights the need for therapeutic intervention strategies aimed at ameliorating WM damage or promoting WM recovery, as well as the need to dissect the molecular mechanisms involved in the pathophysiology of this injury. This review focuses essentially on techniques reported to induce WM injury. For other topics such as WM injury induced by traumatic brain injury, the pathophysiology of WM injury, WM hypersensitivity, and genetics variants leading to stroke and WM injury, which are beyond the scope of this paper, see reviews (1017) and original research articles (1820).

Lots more to read.

Improvement in touch sensation after stroke is associated with resting functional connectivity changes

I don't give a shit what your conclusions are, you should not have any stroke research funded without coming up with a translational plan to put your results into a stroke protocol. Worthless crap.
imageLouise C. Bannister1,2,3, imageSheila G. Crewther2, imageMaria Gavrilescu1,4 and imageLeeanne M. Carey1,3,5*
  • 1Neurorehabilitation and Recovery, Stroke Division, Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
  • 2School of Psychology and Public Health, College of Science, Health and Engineering, La Trobe University, Melbourne, VIC, Australia
  • 3Occupational Therapy, School of Allied Health, College of Science, Health and Engineering, La Trobe University, Melbourne, VIC, Australia
  • 4Defence Science and Technology Organisation, Melbourne, VIC, Australia
  • 5Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia
Background: Distributed brain networks are known to be involved in facilitating behavioral improvement after stroke, yet few, if any, studies have investigated the relationship between improved touch sensation after stroke and changes in functional brain connectivity.
Objective: We aimed to identify how recovery of somatosensory function in the first 6 months after stroke was associated with functional network changes as measured using resting-state connectivity analysis of functional magnetic resonance imaging (fMRI) data.
Methods: Ten stroke survivors underwent clinical testing and resting-state fMRI scans at 1 and 6 months post-stroke. Ten age-matched healthy participants were included as controls.
Results: Patients demonstrated a wide range of severity of touch impairment 1 month post-stroke, followed by variable improvement over time. In the stroke group, significantly stronger interhemispheric functional correlations between regions of the somatosensory system, and with visual and frontal areas, were found at 6 months than at 1 month post-stroke. Clinical improvement in touch discrimination was associated with stronger correlations at 6 months between contralesional secondary somatosensory cortex (SII) and inferior parietal cortex and middle temporal gyrus, and between contralesional thalamus and cerebellum.
Conclusion: The strength of connectivity between somatosensory regions and distributed brain networks, including vision and attention networks, may change over time in stroke survivors with impaired touch discrimination. Connectivity changes from contralesional SII and contralesional thalamus are associated with improved touch sensation at 6 months post-stroke. These functional connectivity changes could represent future targets for therapy.


Somatosensory impairment is common after stroke, occurring in 50–80% of stroke survivors (1, 2). However, investigations of the neural correlates of clinical somatosensory improvement after stroke are scarce (3). In particular, knowledge of how brain networks are interrupted is limited, but is critical to better understand the nature of the clinical deficit and post-stroke recovery (4).
Stroke impacts not only the focal lesion site but also on remote brain regions (5, 6). Lesions have important remote effects on the function of connected neural networks that are structurally intact, i.e., physiological changes in distant but functionally related brain areas (4, 7, 8). These remote effects contribute significantly to the observed behavioral deficits and recovery potential (4, 8). Further, changes in brain networks (across both hemispheres and function-specific networks) have been shown to be important in recovery of motor and attention functions (4, 6). A significant challenge is to identify the brain networks and processes that mediate functional improvement so that rehabilitation strategies can be aimed at the appropriate targets (9).
Only a few studies have investigated changes in the brain over time in association with somatosensory recovery (3, 1013). These studies have primarily involved identification of brain regions associated with task-related brain activation. A few studies have reported that somatosensory recovery is associated with patterns of activation in primary somatosensory (SI) cortex that resembles those seen in healthy controls. For example, return of ipsilesional SI activation has been shown to be associated with improved somatosensory perception (1012). Staines et al. (12) found that enhanced primary somatosensory cortex activation using functional MRI in the stroke-affected hemisphere occurred in conjunction with improved touch detection in four patients with thalamocortical strokes. Likewise, Wikström et al. (10) reported that increased amplitude of early somatosensory evoked fields in the ipsilesional SI in response to median nerve simulation was associated with recovery of two-point discrimination (the ability to discern that two nearby objects touching the skin are truly two distinct points, not one) in stroke patients.
While relative “normalization” of brain activity in primary and secondary (SII) somatosensory regions in both hemispheres seems to underlie good clinical recovery, patients with more severe impairments have been shown to recruit attention and multisensory brain regions to a greater degree than that seen in healthy controls, in order to accomplish successful task performance (3, 11, 1417). In an early positron emission tomography (PET) study of five patients after subcortical stroke, Weder et al. (14) reported activation across bilateral sensorimotor cortex and distributed regions, such as premotor cortex and cerebellum, with worse performance on a tactile shape discrimination task found to correlate with bilateral sensorimotor cortex activation. Tecchio et al. (16) used magnetoencephalography (MEG) to study 18 patients at the acute (5 days) and post-acute (6 months) stages after stroke. They reported that excessive interhemispheric asymmetry correlated with a greater degree of clinical improvement over time in those patients who showed partial recovery. Taskin et al. (15) reported reduced activation of ipsilesional SI with preserved responsiveness of SII in six patients who had suffered thalamic strokes. More recently, in 19 patients, a study into the relationship between touch impairment and interruption to cortical and subcortical somatosensory areas revealed that the neural correlates of touch impairment in patients with interruption to subcortical somatosensory areas (e.g., thalamus), involved a distributed network of ipsilesional SI and SII, contralesional thalamus, and attention-related frontal and occipital regions (3).
Use of task-based brain activation paradigms can be challenging for stroke patients who may have difficulty performing a given task, and inability to perform the task may impact on the validity of the results (18). Resting-state functional connectivity analysis of functional magnetic resonance imaging (fMRI) data has more recently been employed as a way of assessing activity in the brain over time and across different networks of the brain (19, 20). Resting-state functional connectivity reveals intrinsic, spontaneous networks that elucidate the functional architecture of the human brain at rest (task-independent). Functional connectivity is defined as the statistical association (or temporal correlation) among two or more anatomically distinct regions (21). Data are analyzed for coherence across the whole brain and/or in relation to particular regions of interest (ROIs). Evidence suggests that this measure is indicative of behaviorally relevant brain networks without requiring task performance (22). Consistent resting-state networks, with sharp transitions in correlation patterns, are reliably detected in individual and group data (23, 24).
In stroke patients, use of this technique has revealed disruption of functional connectivity of brain networks, even within structurally intact brain regions (6, 25, 26). Changes in functional connectivity have been described in motor recovery under resting-state and task-related conditions (27). Further, changes in functional connectivity over time have been found to occur in conjunction with behavioral change, both in healthy individuals (22) and in stroke patients (7, 25). For example, He and colleagues (25) reported that in patients with spatial neglect, dorsal attention network connectivity was disrupted early after stroke, but appeared to have improved to similar levels as controls by 9 months post-stroke, in conjunction with behavioral improvement. This supports the interpretation that different networks or areas of the brain may dynamically change and assume different roles to allow behavior to occur.
The aim of the current study was to identify longitudinal changes in functional connections of the somatosensory network in stroke patients with somatosensory impairment, and to establish if and how these correlations are associated with improvement in touch discrimination.
The importance of interhemispheric functional connectivity in behavioral performance and recovery has been highlighted from studies using resting-state fMRI (rsfMRI) with animal and human stroke populations (7, 25, 28). The most consistent finding is of changes in interhemispheric functional connectivity between homotopic areas, such as ipsilesional and contralesional primary motor cortex (7). Longitudinal changes have also been reported. Decreased interhemispheric functional connectivity of the ipsilesional sensorimotor cortex has been reported early after stroke, with return to more normal levels during the recovery process (7, 29, 30). These findings are not surprising given that interhemispheric connections are implicated in sensory (31) and cognitive processing (32) and in models of motor and somatosensory recovery (3337). Thus, changes in interhemispheric functional connectivity in stroke patients and associations between these changes and behavioral improvement are expected. We hypothesized that over time, stroke patients would exhibit return to a more “typical” pattern of interhemispheric functional connectivity between homologous cortical somatosensory regions, and that stronger interhemispheric resting-state functional correlations between homologous SI and SII regions at 6 months than at 1 month post-stroke would be associated with clinical improvement.
Increased connectivity with distributed networks has also been reported in recovery after stroke. First, the visual system drives human attention and planning (38, 39), and a rich history of evidence for cross-modal plasticity between the visual and somatosensory systems exists (40). Recruitment of visual areas has been reported in previous studies of motor recovery after stroke (30, 41) as well as in patients with somatosensory impairment after stroke (3). Second, greater recruitment of attention systems is known to be necessary (42) to compensate for the impairment of function-specific brain areas due to aging or injury (43, 44). In stroke patients, increased attention has been shown to be required to accomplish previously simple tasks, such as walking, and attention skills have been shown to predict outcome after stroke (42, 45). Increased activation of frontoparietal attention areas, such as inferior parietal cortex (IPC), has been reported to occur in recovering stroke patients with motor problems (4648). Thus, greater functional connections with frontoparietal attention networks could be expected in stroke patients with somatosensory impairment. As such, we predicted that stronger thalamocortical and cortico-cortical functional correlations with frontoparietal visual attention networks at 6 months post-stroke would be associated with clinical improvement.

More at link, not that it will help any survivor.

Image more to save more

The only thing I can think of here is that the researchers are basically recommending that they cherry pick the patients to a vast extent to make sure their clinical trials succeed. You will need to make sure you have the 'correct' stroke so that the interventions available actually work. Rather than working with real-life strokes and figuring out how to solve them. Lazy bastards. What do you expect when you don't have stroke survivors running the strategy and research teams?
  • 1Department of Neurology, Mount Sinai Comprehensive Stroke Center, New York, NY, USA
  • 2University of California Los Angeles Comprehensive Stroke Center, Los Angeles, CA, USA
  • 3University of California San Diego Comprehensive Stroke Center, San Diego, CA, USA
Recent successful endovascular stroke trials have provided unequivocal support for these therapies in selected patients with large-vessel occlusive acute ischemic stroke. In this piece, we briefly review these trials and their utilization of advanced neuroimaging techniques that played a pivotal role in their success through targeted patient selection. In this context, the unique challenges and opportunity for advancement in current stroke networks’ routine delivery of care created by these trials are discussed and recommendations to change current national stroke system guidelines are proposed.
Recent clinical trials have endorsed a variety of advanced neuroimaging approaches to reiterate the now unequivocal superiority of combined thrombolytic and endovascular therapy for improving outcomes in acute ischemic stroke (AIS) patients with large-vessel occlusion (LVO). Heralding a new era, this momentous advance in treatment has, on the one hand, created a novel challenge to current routine clinical practice and, on the other, a tremendous opportunity to modernize current stroke systems of care: the necessary and inevitable incorporation of advanced imaging techniques into acute stroke. Such integration and utilization, as these trials have demonstrated, holds the key for stroke care providers to save more brain and more stroke patients.
Advanced imaging, specifically vascular imaging, was an essential component of the recent landmark clinical trials and their success. Multicenter Randomized Clinical Trial of Endovascular treatment for AIS in the Netherlands (MR CLEAN), Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE), and Assess the Penumbra System in the Treatment of Acute Stroke (THERAPY) all required imaging evidence of LVO for enrollment (13). Even more selectively, THERAPY limited inclusion to LVOs of at least 8 mm in measured length (3). Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) required not only detection of LVO but also an a priori determined favorable perfusion/ischemic mismatch profile within the affected vascular territory (4). Endovascular treatment for small core and proximal occlusion ischemic stroke (ESCAPE) required presence of LVO and excluded those with poor Alberta Stroke Program Early CT Score (ASPECTS) scores and poor collateral circulation (5, 6). Similarly, Solitaire™ FR as primary treatment for acute ischemic stroke (SWIFT-PRIME) and endovascular revascularization with solitaire device versus best medical therapy in anterior circulation stroke within 8 h (REVASCAT) required presence of LVO and excluded those with unfavorable ASPECTS scores (7, 8).
As a consequence of these trials’ requisite inclusion of vascular imaging, their image profiles reflected a more comprehensive, informative assessment of acute stroke than those obtained in routine clinical practice: one not only of tissue status but also of vascular status. More importantly, because these trials enrolled patients with LVO across a wide range of clinical scenarios, their results demonstrated that acute stroke imaging profiles enhanced with vascular status invaluably expanded eligibility for and established treatment of LVO-AIS in its diverse array of clinical impairment beyond what routine practice has offered.
The notion that imaging which reflects both tissue and vascular status may be of great benefit is not new to the field of stroke. An abundance of evidence has progressively mounted to modernize acute stroke management through approaches that provide such information. For one, ASPECTS scoring is a validated method for assessing tissue status using either CT or MR imaging (9) and indicates the likelihood of a favorable response to treatment (5). Vascular status, although less established, has been shown also to play a significant role in AIS (1012). Collateral flow, in particular, appears to impact acute stroke treatment response: both clinical and radiographic outcomes across all AIS and treatments are better in those with existing collateral flow than in those without (10, 13). As a consequence, the development and utilization of ASPECTS collateral scoring in acute stroke assessment and treatment guidance has been promoted within the stroke community. Furthermore, perfusion-based methods have garnered continued support for assessment of tissue and vascular status in acute stroke (12, 14). Evaluating therapeutic responsiveness for hypoperfusion of an affected territory in LVO, perfusion-based imaging trials have required vascular imaging to determine LVO status for eligibility selection. In fact, EXTEND-IA, where a small ischemic core (<70 cm3), a region of hypoperfusion, and a vascular occlusion were required for entry, demonstrated a high-revascularization rate (4) and the lowest NNT (3) of any of the recent trials, supporting the idea that collateral flow and tissue perfusion remain tightly linked to the success of endovascular therapy (15, 16). Even more importantly, ongoing trials utilizing perfusion- and vascular-based imaging have demonstrated promising early results that further encourage and justify continued investigation of imaging profiles in LVO-AIS that may be most responsive to recanalization therapies (17).
In essence then, advanced stroke imaging has changed how providers can now utilize diagnostic methods to inform treatment decision-making, whereas before it allowed for exclusion of pathology (i.e., hemorrhage) (18), it now allows for active detection of it (i.e., LVO, ischemic changes). This revolution in applicability affords, somewhat paradoxically, the opportunity to deliver more and better care, but only at the expense of improved diagnostic certainty not obtained in routine clinical practice. As a consequence, the modernization of acute stroke through utilization of advancing neuroimaging requires a re-evaluation of acute stroke triage and available diagnostic resources within the hub-and-spoke model.
Current stroke systems of care predominantly implement a hub-and-spoke model that links multiple primary stroke centers (PSCs) with a comprehensive stroke center (CSC) (19). This model provides proven excellence in stroke care for uncomplicated cases at all sites through compliance with established best-care practice, but also allows for a higher level of care for more complicated cases at CSCs when necessary (20). Best-care practice required for PSC designation includes immediate neuroimaging availability for determination of thrombolysis eligibility, largely achieved with non-contrast CT. However, more advanced neuroimaging approaches, such as multimodal CT or MRI to ascertain vascular and perfusion status, are presently not required.
Consequently, these requirements already provide challenge to current consensus positions on early management of LVO-AIS. The 2013 AHA/ASA Guidelines for the Early Management of Patients with AIS include the following recommendations: intracranial vascular imaging when endovascular therapy is considered (Class I, LOE A) and perfusion-based methods for reperfusion therapies when event duration exceeds thrombolytic eligibility windows (Class IIb, LOE B) (19). This challenge is only magnified by the fact that the vast majority of patients receive their initial acute stroke evaluation at PSCs: according to the “Get with the Guidelines” registry data from 2014, over 70%. Furthermore, although LVO comprises only a minority of this population, it carries the highest rates of disability making its rapid identification and treatment crucial (21). As a consequence, efficient triage and selection of LVO-AIS for potential combined or endovascular monotherapy cannot rely on nor succeed with the existing imaging standards of PSCs. Because advanced imaging has now become a key determinant in stroke treatment best-practice, incorporation of such methods, particularly vascular imaging, and their rapid expert interpretation have become a necessity of all designated stroke centers.
Without updating this requirement for PSC designation, the current framework within which stroke care is delivered faces significant challenges. For one, currently designated PSCs without at least vascular imaging capability and vascular neurology expertise available for its interpretation run the grave risk of becoming obsolete. Although these sites can administer thrombolytic therapy and clinically infer presence of LVO, without vascular imaging and its expert evaluation, they can no longer provide a definitive, complete assessment of acute stroke rendering them ineffective within an acute stroke system of care. In fact, a recent analysis of over 11,000 patients in the SITS-International Stroke Thrombolysis Register demonstrated that an NIHSS of 11 was moderately predictive of LVO, though the sensitivity of this measure was only 64.5% (22), in line with prior studies suggesting that this widely used and PSC-certification-required initial triage assessment tool is not adequate to identify all patients with LVO (23). Thus, this handicap will have many downstream effects within acute stroke networks diminishing stroke care delivery overall: a priori bypassing of centers without access to vascular imaging and/or additional transfer to those with it leading to the disuse of certain centers and an overburdening on and stressing of a network’s remaining available sites, services, and resources to accommodate this need.
With these concepts in mind, we suggest that PSC certification (or re-certification) mandate the following new key elements: (1) immediate availability of vascular imaging with either contrast-enhanced CT angiography or time of flight magnetic resonance angiography for all patients presenting with acute stroke; (2) immediate availability of vascular neurology expertise via in-person or telemedicine for clinical and radiologic evaluation of acute stroke; and (3) in-place protocols within acute stroke networks of care for rapid identification, stabilization, and transfer of LVO-AIS patients to CSCs or facilities of equivalence in care.
The colossal efforts to advance acute stroke care have yielded a tremendous opportunity that should not be forsaken. More imaging, incorporating non-invasive angiography and multimodal CT or MRI, beyond the current standard of non-contrast CT at PSCs will facilitate triage of stroke patients for current state-of-the-art therapies to save more brain and to extend this opportunity to more patients at greatest risk of long-term disability. Such modernization of stroke systems of care through incorporation of advanced imaging methods and their timely interpretation in clinical context is not just an opportunity, but an inevitable next step that recent trial success has galvanized with a clear message: we must image more to save more.
Which means even fewer stroke centers will have such ability and only those within a deliverable radius in the correct elapsed time will be helped. We are basically going backwards in helping stroke survivors, eventually these head-in-the sand medical professionals will realize that stopping the neuronal cascade of death will help all survivors. But don't count on that happening for another 50 years.

The dark side of the force – constraints and complications of cell therapies for stroke

So there might actually be a bad side to stem cells as compared to a lot of survivors waiting breathlessly for stem cells to be proven because stem cells will solve all the stroke problems.
I personally think I will never benefit from stem cells and I figure I have 35-40 years left to go.
  • 1Department of Cell Therapy, Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig, Germany
  • 2Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany
  • 3Division of MR Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • 4Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA
  • 5Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
Cell therapies are increasingly recognized as a promising option to augment the limited therapeutic arsenal available to fight ischemic stroke. During the last two decades, cumulating preclinical evidence has indicated a substantial efficacy for most cell treatment paradigms and first clinical trials are currently underway to assess safety and feasibility in patients. However, the strong and still unmet demand for novel stroke treatment options and exciting findings reported from experimental studies may have drawn our attention away from potential side effects related to cell therapies and the ways by which they are commonly applied. This review summarizes common and less frequent adverse events that have been discovered in preclinical and clinical investigations assessing cell therapies for stroke. Such adverse events range from immunological and neoplastic complications over seizures to cell clotting and cell-induced embolism. It also describes potential complications of clinically applicable administration procedures, detrimental interactions between therapeutic cells, and the pathophysiological environment that they are placed into, as well as problems related to cell manufacturing. Virtually each therapeutic intervention comes at a certain risk for complications. Side effects do therefore not generally compromise the value of cell treatments for stroke, but underestimating such complications might severely limit therapeutic safety and efficacy of cell treatment protocols currently under development. On the other hand, a better understanding will provide opportunities to further improve existing therapeutic strategies and might help to define those circumstances, under which an optimal effect can be realized. Hence, the review eventually discusses strategies and recommendations allowing us to prevent or at least balance potential complications in order to ensure the maximum therapeutic benefit at minimum risk for stroke patients.


Therapeutic stem cell research represents one of the most vibrant fields in regenerative medicine. Embryonic, fetal, and adult stem cells are believed to exert multiple therapeutic actions. These range from potential tissue regeneration over the support of local endogenous repair attempts to the beneficial modulation of systemic immune responses. The still ongoing discovery of this tremendous therapeutic potential has fueled the imagination of researchers and clinicians to develop novel therapeutic strategies and to treat disorders, which have been considered untreatable for decades. Among those, ischemic stroke plays a primary role. Stroke is a worldwide predominant cause of death and acquired disability in adulthood (1). The only currently available treatment is thrombolysis, being restricted by a narrow time window (2) and a number of contraindications (3). Together, these limitations exclude the majority of patients from successful and causal treatment. On the other hand, numerous scientific reports corroborated the therapeutic benefit provided by stem cell populations in stroke. This is exemplified by the improvement of neurofunctional deficits (4), reduction of infarct volume, an extension of the time windows for intervention (5, 6), pro-regenerative cerebral reorganization (7), and potentially even limited tissue restoration (8), as well as mitigation of post-stroke neuroinflammation (9). Consequently, first early stage clinical studies are underway to confirm safety and to collect evidence for the therapeutic benefit of stem cell-based treatments in human stroke patients (10).
However, the well-founded enthusiasm for cell therapies and the urgent need for novel therapeutic approaches seem to have drawn our attention away from possible complications of stem cell applications in stroke. Since each therapeutic intervention comes at the risk of undesirable side effects, such side effects would not generally compromise the overall value of stem cell therapies. They could, however, significantly limit the safety, efficacy, as well as successful translation of stem cell-based experimental treatment concepts into clinically available therapies. We therefore argue that potential side effects deserve a closer and more thorough look. Moreover, some side effects might be specific to stroke because important pathophysiological aspects such as blood brain barrier (BBB) breakdown, perilesional hyperexcitability, systemic immunodepression and others differ from those in the other central nervous system (CNS) pathologies. This review summarizes current preclinical and clinical evidence for risks arising from therapeutic use of stem cell populations and the means by which the therapies are commonly applied. It also describes major translational hurdles, which arise from undesirable interactions between the cell transplant and its local pathophysiological environment.

Lots more at link.

Differential effects of parietal and cerebellar stroke in response to object location perturbation

This is a worthless piece of research unless someone takes it and translates it into a useful stroke protocol. That is exactly what a great stroke association would do, except we don't have one.

  • 1School of Psychology, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, UK
  • 2School of Health Sciences, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
  • 3Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia
Background: The differential contributions of the cerebellum and parietal lobe to coordination between hand transport and hand shaping to an object have not been clearly identified.
Objective: To contrast impairments in reach-to-grasp coordination, in response to object location perturbation, in patients with right parietal and cerebellar lesions, in order to further elucidate the role of each area in reach-to-grasp coordination.
Method: A two-factor design with one between subject factor (right parietal stroke; cerebellar stroke; controls) and one within subject factor (presence or absence of object location perturbation) examined correction processes used to maintain coordination between transport-to-grasp in the presence of perturbation. Sixteen chronic stroke participants (eight with right parietal lesions and eight with cerebellar lesions) were matched in age (mean = 61 years; standard deviation = 12) and hand dominance with 16 healthy controls. Hand and arm movements were recorded during unperturbed baseline trials (10) and unpredictable trials (60) in which the target was displaced to the left (10) or right (10) or remained fixed (40).
Results: Cerebellar patients had a slowed response to perturbation with anticipatory hand opening, an increased number of aperture peaks and disruption to temporal coordination, and greater variability. Parietal participants also exhibited slowed movements, with increased number of aperture peaks, but in addition, increased the number of velocity peaks and had a longer wrist path trajectory due to difficulties planning the new transport goal and thus relying more on feedback control.
Conclusion: Patients with parietal or cerebellar lesions showed some similar and some contrasting deficits. The cerebellum was more dominant in controlling temporal coupling between transport and grasp components, and the parietal area was more concerned with using sensation to relate arm and hand state to target position.


Successful control of reach-to-grasp requires coordination, “an ability to maintain a context-dependent and phase-dependent cyclical relationship between different body segments or joints in both spatial and temporal domains” (Krasovsky and Levin, 2010) of various body segments including the arm with the trunk, the shoulder with the elbow, and the hand with the arm. Studies in healthy adults have suggested hand and arm function are controlled as a single coordinated unit (Jeannerod, 1984; Wallace et al., 1990) demonstrated by significant correlations between reach and grasp components, including between the start time of the opening of the hand and the start time of hand movement toward the object (Jeannerod and Biguer, 1982; Jeannerod, 1984), between the time of maximum hand aperture and the time of peak deceleration (PD) of the hand (Jeannerod, 1984; Castiello et al., 1993), and between time of maximum aperture (TMA) and the time of peak velocity (TPV) of the hand (Wallace et al., 1990). Apart from a few situations (Gentilucci et al., 1991; Kudoh et al., 1997), for example, where correlations between the time of PD and the time of MA are not reliable when transport and grasp were manipulated by the distance and type of grasp (Gentilucci et al., 1991), temporal coupling of these events is a fairly consistent finding across reach-to-grasp tasks.
Stroke can adversely affect reach-to-grasp coordination (Pelton et al., 2012; vanVliet et al., 2013). Spatiotemporal relationships between transport and grasp in a heterogenous group of stroke patients with mild to moderate impairments, were investigated in a study where movements were performed at both fast and preferred speeds and to small and larger objects (vanVliet and Sheridan, 2007). There were significant correlations (p < 0.05) between times of start of hand movement and hand opening and between times of MA and PD in all conditions for both groups, although some of the correlations were numerically small (Pearson product-moment correlation coefficient r for the two groups ranged from 0.3 to 0.71). However, transport and grasp in patients were not as tightly coupled. In the condition which most challenged accuracy (i.e., the fast paced condition with small objects), the two events were less correlated in participants with stroke.
One informative paradigm used to investigate underlying control mechanisms for coordination of reach-to-grasp is to perturb the object location at movement onset in order to examine the resulting temporal adjustments made to the grasp component (Paulignan et al., 1990, 1991a,b), requiring modification of a pre-defined program (Goodale et al., 1986). Typically, the unexpected perturbation in the object produced adjustments to both the transport and grasp components, where the initial wrist acceleration was aborted and a new one started, and the initial grasp aperture was also aborted and reincreased in synchrony (Paulignan et al., 1990, 1991a,b) demonstrating that the two components are coordinated spatiotemporally.
The premise of a tight-coupling between the two components prompted the development of a model for the temporal coordination of transport and grasp (Hoff and Arbib, 1993). The model proposed that neural processes controlling transport and grasp are monitored on-line and adjusted for temporally so that the expected duration of each trajectory to reach the target is matched to the other component according to a consistent enclose time of the hand. The coordinated control of transport-to-grasp with object location perturbation also involves the integration of sensory signals from multiple modalities (principally visual information concerning the object and its relative position; and proprioceptive information about the position of the arm and the hand). It requires the feed-forward selection of perhaps one or two coupled motor commands for transport and grasp together with a forward representation of the desired movement. Smooth movement is dependent upon on-line updating of the initial pattern of muscle activation and detection of error between the actual positions of object relative to the hand. Large errors which are instigated by the introduction of a perturbation require either rapid modification of an ongoing internal forward model or rapid onset of a new internal forward model and cessation of the old forward model.
Two key brain areas responsible for processing of information pertaining to reach-to-grasp coordination are the parietal lobe and the cerebellum. Current theories attribute similar contributions by parietal and cerebellar regions. For example, both areas have been identified as potential areas that integrate the independent motor processes for reach and grasp into one common motor program (Desmurget et al., 1999; Zackowski et al., 2002). Given the specialization of cortical areas, it is unlikely that these areas perform identical roles. Thus, further research is needed to elucidate their exact role in control of reach-to-grasp. It has been pointed out that the two regions may work as a functional loop in estimating the current status of the motor system, since the parietal cortex receives input from the cerebellar dentate nucleus, and there are connections from parietal cortex to cerebellum via the pontine nuclei (Blakemore and Sirigu, 2003; Ramnani, 2012). Below, we review the current knowledge about roles of parietal cortex and cerebellum in control of reach-to-grasp.

More at link.