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Alzheimer’s Bone, Brain Link!; Significant Increase in Bone Formation; Cost of Preoperative Interventions

Elizabeth Hofheinz, M.P.H., M.Ed. • Wed, December 14th, 2016

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Bone, Brain Link in Alzheimer’s Found!

Could bone density be a biomarker for risk of Alzheimer's disease (AD)?

Yes, say researchers at Northeast Ohio Medical University (NEOMED). The team, led by Christine Dengler-Crish, Ph.D., found a connection between areas of the brainstem—the ancient area that controls mood, sleep and metabolism—and changes to bone in a preclinical model of AD. Dr. Dengler-Crish is assistant professor of pharmaceutical sciences, and anatomy and neurobiology at NEOMED.

The study, titled "Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease, " will be published in the upcoming issue of the Journal of Alzheimer's Disease.

Dr. Dengler-Crish commented to OTW, “Many years ago as a neuroscience graduate student at Vanderbilt University, I became very interested in bone biology. I was studying sensory systems of very unique species of mammal called naked mole-rats, which are small, mouse-sized rodents. Naked mole-rats live incredibly long, healthy lives (30 years with no cancer or brain atrophy) and any females that become reproductively active over their lifespan experience significant lengthening of the bones in their spine. My research in this area would eventually show that female mole-rats actually lived longer with every pregnancy they had!”

“After graduate school, I began researching neurodegenerative disease and along the way, stumbled across some interesting clinical studies where orthopedists and other physicians were noting an unusually high prevalence of Alzheimer’s patients with osteoporosis or low bone density.”

“Our group characterized BMD [bone mineral density] in a transgenic strain of mice called ‘htau mice’ that selectively develop increasing tau or ‘tangle’ pathology in their brains with age—similar pathologies seen in human Alzheimer’s disease. This was important because we specifically wanted to study tau pathology—not amyloid beta, which is the ‘plaque’ pathology also seen in Alzheimer’s disease because amyloid beta can leave the brain and actually be present in bone tissue—tau cannot.”

“That way we were able to conclude that any changes we saw in BMD would most likely be related damage to brain circuits that maintain bone health. We used a bone densitomer (DEXA) to measure BMD in our mice monthly as they aged from 2-6 months of age and even at some points beyond this. We compared these longitudinal BMD measurements with age- and sex- matched a) transgenic siblings who did not have the same mutation and b) normal mice. We examined brain tissue from separate groups of these mice at 4 and 6 months of age to determine whether tau pathology was present in the brainstem raphe nuclei, which are part of the central serotonin circuit that regulates adult bone health.”

“We also quantified the amount of tryptophan hydroxylase (an enzyme critical to serotonin production)in this region to determine if there were any global deficiencies in serotonin in our htau mice that could account for their compromised BMD.”

“In aging patients, reduced BMD or osteoporosis in the presence of other risk factors for Alzheimer’s disease such as depression, appetite changes, and sleep disturbances may be an early signal that a disease process in the brain is beginning, and that these patients might be at risk for Alzheimer’s disease.”

“As we develop new treatments that could potentially alter the course of this devastating disease (unfortunately, we currently have NONE that do this), this could provide an early and critical intervention point for applying such a therapy. In the meantime, physicians could use reduced BMD as a screening tool so that they can continue to monitor these patients for the emergence of any cognitive deficits.”

“Additionally, if we look at this from the opposite angle, physicians should screen any dementia patients they see for low BMD and osteoporosis since these folks are at increased risk for bone loss. This way, orthopedists could help their patients with dementia (and their caregivers) employ strategies that protect against falls and fractures, which dramatically decrease the quality of life and life-expectancy of persons with Alzheimer’s disease.”

“It is interesting that the classic serotonin-producing brain structures involved in regulating bone growth, appetite, sleep, and mood (i.e., the dorsal raphe nuclei of the brainstem) showed evidence of Alzheimer’s-like pathology very early on in our htau mice, along with deficits in serotonin!”

“So much of Alzheimer’s disease research is focused on looking at structures involved in learning and memory because in its essence, AD is a disease that critically injures cognition. However, my research team and I believe that learning and memory deficits are a much later stage in the disease, and that the earliest damage may occur in brain areas researchers in this field don’t often think to look at—such as these serotonin-producing raphe nuclei. Finding the earliest source of damage in this disease and designing new treatments that protect or restore function in these areas might help slow down or even stop the progress of AD before too much damage to memory is done.”

“We have only just begun our work in this area, and we are planning several studies that look at how using drugs that change the activity of certain types of serotonin receptors might restore serotonin balance in these brain regions and potentially improve bone health and even slow the progress of AD-related tau pathology throughout the brain. We are also interested in understanding the mechanism of how tau pathology, which directly affects how neurons function, causes problems in serotonin brain signaling that eventually leads to bone loss far from the brain. There is so much to do, and we are excited to keep working on these important research questions.”

MSC’s and Their Role in Bone Formation

New tissue engineering work is highlighting the delicate complexity of interactions between bone and the vascular networks that surround it. A multi-institutional study has found, according to the December 1, 2016 news release, that: “A bone tissue engineering approach that exposed human stem cells in the laboratory to both growth factors that promote formation of a vascular network and to mechanical stimuli at the same time led to a significant increase in bone formation. However, neither vascular-promoting signals nor cyclic tensile strain alone enhanced osteogenesis.”

The article “Mechanical and Vascular Cues Synergistically Enhance Osteogenesis in Human Mesenchymal Stem Cells, ” is co-authored by Andrew Steward, Ph.D., Jacqueline Cole, Ph.D., Frances Ligler, D.Phil., D.Sc., and Elizabeth Loboa, Ph.D., University of North Carolina-Chapel Hill and North Carolina State University, Raleigh, and University of Missouri, Columbia.

Dr. Loboa, Dean and Professor of Bioengineering at the University of Missouri, Columbia, told OTW, “Functional tissue engineering, which incorporates the creation and use of biomimetic materials and mechanical stimuli to regenerate new tissues, is a significant focus of research in my lab. A major barrier to success in tissue engineering is the ability to create vascularized tissues. We have previously shown that 10% cyclic tensile strain leads to a robust osteogenic response in both human bone marrow derived mesenchymal stem cells (hMSCs) and human adipose derived stem cells (hASCs). In this study, we wanted to test our hypothesis that the application of this mechanical environment (10% cyclic tensile strain) to a co-culture of hMSCs with human endothelial cells (hECs) would promote greater osteogenesis and new bone formation that either co-culture or tensile strain alone. We found that the application of 10% cyclic tensile strain to an MSC-EC co-culture resulted in a significant increase in calcium accretion and mineral deposition by the MSC relative to non-strained MSC-EC co-cultures, indicating that co-culture and strain synergistically enhance osteogenesis.”

“New approaches to develop and maintain a vascular network are paramount for achieving clinical success in the creation of tissue-engineered bone constructs. Specifically, the ability to create and maintain a vascular network while promoting new bone formation is critical to successful bone tissue engineering. In this study we have shown that 10% cyclic tensile strain, applied to an MSC-EC co-culture, significantly increased osteogenesis and bone formation relative to MSC-EC co-cultures not exposed to tensile strain.”

“In preparing to perform this research, we performed an extensive evaluation of previous literature in the field. Interestingly, we found that there was a great lack of consensus on conditions for MSC-EC co-culture, limited information about how specific conditions were chosen, and lack of agreement on optimal media conditions. As such, we performed extensive pilot studies to determine media conditions and the approaches we utilized.”

“For our study, the most interesting and exciting outcome is that the application of a mechanical stimulus (10% cyclic tensile strain) that we know promotes osteogenesis of hASC and hMSC has a synergistic effect along with MSC-EC co-culture to significantly enhance new bone formation. The maintenance of endothelial cells in this system bodes well for vascularized constructs.”

“More research is needed to determine optimal culture media components to promote both osteogenesis and angiogenesis of MSCs and ECs in co-culture. Further investigation of biomaterial optimization to promote both osteogenesis and angiogenesis in MSC-EC co-culture systems is another exciting area for future work.”

TKA: Cost of Preoperative Interventions

New research from the University of Southern California (USC) is adding to our knowledge of interventions prior to total knee arthroplasty, (TKA) as well their costs.

Jay R. Lieberman, M.D., professor and chairman of the Department of Orthopaedic Surgery at the Keck School of Medicine at USC, told OTW, “There is a dearth of information in the literature on the cost of preoperative interventions. My colleagues and I were interested in learning the cost of care for two years prior to TKA because there have been few studies in this area. Most of the focus on costs has been related to the procedure itself.”

“We examined the records of 35, 596 Medicare patients and 47, 064 UnitedHealthcare patients who underwent TKA from 2009 to 2011. In the two-year period prior to TKA, the average charge per Medicare patient was $3, 545; for United patients it was $3, 281. We found that a significant percentage of costs occur three months prior to TKA. In certain patients it may be more cost-effective to proceed with surgery rather than performing injections and ordering physical therapy (PT) that does not delay the procedure. Payers need to reevaluate ‘medical necessity’ because it may be leading to unnecessary costs and treatments in certain patients.”

“At least one-third of the MRIs were ordered within three months of the surgery; from the database we cannot tell who ordered the MRI. It has yet to be determined if these tests are cost effective or clinically relevant to patients.”

“Clinicians need more training with respect to understanding the appropriate indications for ordering a MRI of the knee. However, patients also need more education because patients often demand a MRI even when a simple plain X-ray is all that is needed to make a diagnosis.”

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