Umbilical Cord Stem Cell Use in Post-Stroke Recovery

David Chiu, MD, medical director of the Houston Methodist Eddy Scurlock Stroke Center

In a landmark investigation, Houston Methodist is partnering with Duke University, The University of Texas MD Anderson Cancer Center and Emory University in a phase I study of whole umbilical cord blood and its potential role in stroke recovery. Through stem cell therapy, physicians hope to ameliorate this long-term disability.

The treatment of choice for ischemic stroke is administration of tissue plasminogen activator (tPA) if delivered within a narrow therapeutic window. Targeted thrombolytic therapy or mechanical clot removal are common strategies when the option of tPA is no longer viable.

“When a person has a stroke, there’s an injury,” said John J. Volpi, MD, co-director of the Eddy Scurlock Stroke Center and director of the cerebral blood flow lab. “Clot retrieval and tPA help mitigate the cells that have died from not getting blood. But then there’s a second phase of the stroke where cells don’t die but they are very vulnerable and can progress to cell death if not rescued.”

Stem cells are undifferentiated precursors that can develop into any type of cell within the body. With the use of whole umbilical cord blood, researchers and physicians at Houston Methodist seek to rescue brain cells on the threshold of injury from stroke. In the phase I study, umbilical cord blood is infused several days after a stroke has occurred.

“We want to shut down the damaging, inflammatory process in a way that may rescue some of those brain cells and thereby limit disability,” Volpi said. “I think there is a common misunderstanding that somehow the stem cells in the cord blood are going to regrow brain tissue and that’s not what we’re expecting.”

In theory, umbilical cord blood therapy holds a great deal of promise as a regenerative treatment in stroke as well as other brain disorders. The current stroke study is being led by Joanne Kurtzberg, MD, chief scientific and medical officer the Robertson Clinical and Translational Cell Therapy Program (CT2) at the Duke Translational Medicine Institute. Houston Methodist is partnered with MD Anderson Cancer Center for banked allogeneic umbilical cord blood supply, and Duke is partnered with Emory University Hospital Midtown for their umbilical cord blood resources.

“We anticipate this phase I study to be a relatively rapid enrollment. Between the three sites we’ll enroll 10 patients, ideally by the first quarter of next year,” Volpi said. “Then we expect to start a multi-year phase II project, probably in the third quarter of next year.”

Houston Methodist is collaborating with Duke University and Emory University for scientific planning and patient enrollment in this study, which is funded by a grant from The Marcus Foundation, Inc.

The Athersys MultiStem Trial

Reducing long-term disability is the primary goal of stroke rehabilitation. Stem cells may hold a key. The recent phase II Athersys MultiStem trial is the largest randomized clinical trial to date to evaluate stem cell therapy in stroke. Houston Methodist Hospital was one of the lead centers in this study, which enrolled 129 patients with acute ischemic stroke. “The results of this phase II trial suggested lower mortality, fewer medical complications and a signal of improved neurological outcomes in patients treated early,” said David Chiu, MD, medical director of the Houston Methodist Eddy Scurlock Stroke Center. “There is sufficient promise in these results to warrant a pivotal phase III study.”

Participants in the trial will be re-evaluated at one year with MRI scans to determine if those who received stem cell therapy had smaller infarcts after 12 months. Chiu will present the final data at the 2016 European Stroke Organization Conference next May, which will be held in Barcelona.

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The Anatomy of Stuttering

By David B. Rosenfield, MD

Santosh Helekar, MD, PhD, and David Rosenfield, MD, at the Houston Methodist Neurological Institute for Speech and Language Center

Evidence of stuttering is present throughout history. It is found on the clay tablets of ancient Mesopotamians, displayed within Egyptian hieroglyphics (“nit-nit”) and mentioned in the Bible (Moses stuttered), and Holy Koran. Stuttering is a ubiquitous disturbance of speech-motor production that occurs in all cultures and is referenced in all languages.1

Fluency in speech mandates the intricate execution of numerous coordinated and synchronized events. It has been hypothesized that individuals who have developmental stuttering (DS) have an impairment or deficiency in a brain-timing mechanism.2

Researchers have investigated functional and structural connectivity necessary for dynamic interactions within speech-related neural pathways, employing numerous techniques including probabilistic tractography and psychophysiological interaction. Using these methods, Chang et al3 demonstrate a reduction of function in left Brodmann area 44 (BA44) and premotor areas with a correlated increase between homologous regions on the right side.

An additional study of adult stutterers showed decreased functional connectivity between the posterior language area, which is necessary for the perception and decoding of sensory information, and the anterior speech area, which is linked with initiation of speech and motor function. This was associated with increased functional connectivity between both areas and the default mode network with prefrontal areas. However, independent component analyses indicated a decreased functional connectivity in the default motor network with an increase in the sensorimotor network in individuals who stutter.4

At the Houston Methodist Neurological Institute Speech and Language Center, Santosh A. Helekar, MD, PhD, our team and I continue to conduct direct measurements of functional connectivity between Broca’s and Wernicke’s areas of the brain. We initially designed a neuroscience model of stuttering that implicated dysfluency of speech with a momentary instability in a multiloop speech-motor control system.5 This model has been subsequently corroborated by our research on functional connectivity problems between the motor output in Broca’s area within the left frontal lobe and the auditory input in Wernicke’s area of the left superior temporal lobe. The reduced strength between these two regions results in a timing error in the brain of the individual who stutters.

Broca’s area is critically involved in language production with a primary focus on speech-motor output and Wernicke’s area is primarily assigned to language input. In addition, the right supplementary motor cortex hooks into Broca’s area. We have been able to demonstrate in DS the strength of the connection between Broca’s area and Wernicke’s area is inversely related to the connection between Broca’s area and the ipsilateral supplementary motor cortex. In other words, if the connection between Broca’s and Wernicke’s areas is strong, the connection between Broca’s area and the supplementary motor cortex will be weak and vice versa.

We further contend stuttering is not the problem but a response to the problem. We hypothesize that treatment should be aimed at the normalization of this connectivity through the strengthening of the nerve fiber connections between Broca’s and Wernicke’s areas.

To earn CME credit, visit: http://physician.hm.wcea.education/

REFERENCES

1 Rosenfield DB. (2014). Disorders of Fluency and Voice. In Harry Whitaker (Ed.), International Encyclopedia of the Social and Behavioral Science, (second edition). New York: American Elsevier Publishing Company.

2 Etchell AC, Johnson BW, Sowman PF. Behavioral and multimodal neuroimaging evidence for a deficit in brain timing networks in stuttering: a hypothesis and theory. Front Hum Neurosci. 2014;8: 467.

3 Chang SE, Horwitz B, Ostuni J, Reynolds R, Ludlow CL. Evidence of left inferior frontal-premotor structural and functional connectivity deficits in adults who stutter. Cereb Cortex. 2011;21(11): 2507-2518.

4 Xuan Y, Meng C, Yang Y, Zhu C, Lang W, et al. Resting-state brain activity in adult males who stutter. PLoS One. 2012;7(1): e30570. Available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030570
Accessed November 10, 2015.

5 Nudelman HB, Herbrich KE, Hoyt BD, Rosenfield DB. A neuroscience model of stuttering. J Fluency Disord. 1989;14(6): 399-427.

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Viral-Based Gene Immunotherapy to Treat Glioblastoma



Glioblastoma multiforme carries a median survival of 15 months when treated with the current standard of care that includes surgery, radiotherapy and chemotherapy. At the Kenneth R. Peak Center for Brain and Pituitary Tumor Treatment and Research, David S. Baskin, MD, director of the center, heads an extensive research program with a number of basic and clinical research programs to study and treat this most aggressive and common form of malignant primary brain tumors.

Matt Futer is a patient who has benefited from these efforts. Futer, aged 44, initially presented with a five-inch mass in his brain with tumor that infiltrated even further. Complete surgical resection was not possible due to the tumor’s critical location in the speech and language area of the brain. In fact, only about 25 percent of the tumor could be removed.

Baskin elected to remove only the portion of the tumor that was safe to excise and administer a two-pronged treatment that had recently demonstrated good results in a phase I clinical trial.

Baskin elected to remove only the portion of the tumor that was safe to excise and administer a two-pronged treatment that recently demonstrated good results in a phase I clinical trial. Called gene-mediated cytotoxic immunotherapy (GMCI), the first component requires injection of a virus into the resection bed. In this instance, Futer was given a non-replicating adenovirus with the herpes simplex virus thymidine kinase (AdV-Tk) gene sequence within it. This was followed by oral valacyclovir, which targeted the AdV-TK-infected glioma cells.

“As the tumor dies, tumor-associated antigens are released,” said Baskin. “As the antigens are released and uptake occurs in antigen-presenting cells, cell mediated immunity is boosted, producing killer T-Cells that seek out the tumor. In addition, we know that the cytotoxic nucleotide analog that is made when thymidine kinase combines with valacyclovir has separate pro-inflammatory effects, acting like a super antigen protein. This releases a number of substances including IL-2 and IL-12, giving a very powerful systemic immune response.┬áThe therapy therefore has a one-two punch, stimulating both cell mediated and humoral immunity.” Results from the phase II study were presented by Baskin at the 2015 American Society of Clinical Oncology (ASCO) annual meeting.

At Futer’s one-year follow-up, imaging showed his tumor had diminished by one-third. His second-year visit showed the original tumor at half its original size. Today, nine years after the original therapy, Futer is tumor-free, based on findings on a recent MRI of the brain. This year, Futer was diagnosed with renal cancer, unrelated to his glioblastoma. Surgical removal of the tumor was successful and Futer is now completely cancer-free.

A critical part of the basic science research forming the basis of this clinical trial was done at Houston Methodist Hospital by Brian Butler, MD, and Bin Teh, MD, from radiation oncology. Robert Grossman, MD, former chairman of the department of neurosurgery, was instrumental in helping to start the trial, and Todd Trask, MD, from neurosurgery, also participated and entered patients. The results are very favorable and a phase III clinical trial with some important additions will begin next year.

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Advancements in Neuro-Ophthalmology

An astronaut with two long-duration exposures to microgravity showed development of more widespread choroidal folds and new onset of optic disk edema.

More than half the brain is dedicated to vision-related activities. The critical subspecialty of neuro-ophthalmology provides essential information on neurologic disorders that initially manifest in the eye, optic nerves, ocular motor or visual pathway. At the Houston Methodist Blanton Eye Institute, neuro-ophthalmologists continue a legacy of research to further broaden understanding of the physiologic and pathologic connections between the eye and the brain.

The Effect of Prolonged Space Orbit on Ocular Orbits

Ophthalmic abnormalities associated with astronauts who spend extended periods of time in a microgravity environment have been documented in studies performed by physicians and researchers at Houston Methodist and the National Aeronautics and Space Medicine’s (NASA) Space Medicine Division. Several neuro-ophthalmic findings, including disk edema, globe flattening, choroidal folds and hyperopic shifts have been documented. In a 2011 article published in the journal, Ophthalmology, Andrew G. Lee, MD, Houston Methodist chair of the department of ophthalmology, and other team members hypothesized that ocular changes could result from shifts in cephalad fluid caused by a gravity-altered environment. The authors stated that these findings may represent a range of ocular and cerebral fluctuations that could result from extended periods in a microgravity habitat, such as the International Space Station.

“What’s not known is how much damage will occur if we let humans remain in that environment for long durations,” Lee said. “We have new data that was not available at the time of the original publication on repeat flyers — astronauts who have gone up once and then gone up again.”

A specific case study of an astronaut with two long-duration exposures to microgravity showed development of more widespread choroidal folds and a new onset of optic disk edema after the second flight. In addition, at five months during the space mission, a remotely guided funduscopic examination performed at the International Space Station indicated a loss of spontaneous venous pulsations (SVPs) in the eye with optic disk edema. The lack of SVPs persisted at 21 months post flight, suggesting a continued pathologic process within the optic nerve sheath that had not abated.

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New Findings in the Neurophysiology of Executive Dysfunction

By Mario F. Dulay, PhD

“Executive function” is a broad term used to define a series of complex processes (mental control, multitasking, planning, problem-solving, etc.) that require coordination within the brain to achieve specific goals.1 Depending on the location and the size of damage, up to 75 percent of individuals who suffer a stroke may have some type of executive impairment that can severely impede and devastate everyday life. 2

Historically, executive dysfunction — commonly known as “dysexecutive syndrome” — has been largely associated with damage to the prefrontal cortex.3 Recent advances in the understanding of neuroanatomy, however, have demonstrated that localizing executive functions to the frontal lobe may be oversimplifying the neuropathology of dysexecutive syndrome. For example, in Parkinson’s disease patients, similar neuropsychological deficits implicate striatal structures in the conciliation of executive processes.4

At the Houston Methodist Neurological Institute, The Houston Institute for Neuropsychological Knowledge (THINK) laboratory studies the neurobiological basis of human behavior. With the use of neuroimaging and human lesion studies, we have identified subcortical and brain stem regions that are also essential as part of a network of executive functioning skills.

In a novel and potentially landmark study, we examined four separate areas of the brain (frontal lobe, cerebellum, thalamus and pons) in four distinct patient groups with post-stroke damage in these specific areas. We looked at different types of executive functioning and compared the severity and frequency of a dysexecutive syndrome after suffering a focal unilateral stroke. Prior murine lesion and neuroimaging studies have hypothesized the presence of a feedforward mechanism consisting of a fronto-pontocerebellar loop with a feedback cerebello-thalamo-frontal loop.5 We questioned what percentage of patients actually incurred executive difficulties when these areas of the brain were damaged.

We tested 84 individuals an average of four months after stroke and found that individuals with damage to the frontal lobe, cerebellum and thalamus demonstrated similar rates of executive impairment. Approximately half of the patients who had suffered a stroke to the aforementioned feedforward-feedback looped network demonstrated a dysexecutive syndrome.

Our conclusion is that any damage or disruption that occurs within this complex and interdependent brain network has the potential to result in a dysexecutive disconnection syndrome. Further study is required to fully understand the neurocognitive and neuropsychiatric anatomy post stroke and thereby provide education and guidance to both patients and their families about prognosis and optimization of recovery.

We have been invited to give a talk on our findings at the 2016 International Neuropsychological Society’s 44th annual meeting next February in Boston.

To earn CME credit, visit: http://physician.hm.wcea.education/

REFERENCES

1 Alvarez J. Emory E. Executive function and the frontal lobes: a meta-analytic review. Neuroopsychol Rev. 2006;16: 17-42.

2 Chung CS, Pollock A, Campbell T, Durward BR, Hagen S. Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult non-progressive acquired brain damage. Cochrane Database Syst Rev. 2013;4: 1-76.

3 Funahashi S. Neuronal mechanisms of executive control by the prefrontal cortex. Neurosci Res. 2001;39(2):147-165.

4 O’Callaghan C, Bertoux M, Hornberger M. Beyond and below the cortex: the contribution of striatal dysfunction to cognition and behavior in neurodegeneration. J Neurol Neurosurg Psychiatry. 2014;85: 371-378.

5 Middleton F, Strick P. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science. 1994;266: 458-461

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