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SURF  |   June 2019
Osteopathic Cranial Manipulative Medicine and the Blood-Brain Barrier: A Mechanistic Approach to Alzheimer Prevention
Author Notes
  • From the Rowan University School of Osteopathic Medicine in Stratford, New Jersey. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to Lauren J. Crispino, OMS II, Rowan University School of Osteopathic Medicine, 1 Medical Center Dr, Stratford, NJ 08084-1500. Email: crispinol2@rowan.edu
     
Article Information
Geriatric Medicine / Neuromusculoskeletal Disorders / Preventive Medicine
SURF   |   June 2019
Osteopathic Cranial Manipulative Medicine and the Blood-Brain Barrier: A Mechanistic Approach to Alzheimer Prevention
The Journal of the American Osteopathic Association, June 2019, Vol. 119, e25-e28. doi:https://doi.org/10.7556/jaoa.2019.070
The Journal of the American Osteopathic Association, June 2019, Vol. 119, e25-e28. doi:https://doi.org/10.7556/jaoa.2019.070
Abstract

Recent studies have demonstrated that blood-brain barrier (BBB) dysfunction may be implicated in the pathogenesis of Alzheimer disease, thus establishing a link between disease manifestation and compromised neurovasculature. The authors identify relationships between Alzheimer disease and BBB breakdown, the response of the BBB to increased cerebral blood flow and shear stress, and the impact of osteopathic cranial manipulative medicine on cerebrovascular hemodynamics. They propose and review a rationale for future research to evaluate osteopathic cranial manipulative medicine as a preventive treatment for patients with illnesses of neurovascular origin.

More than 4.7 million people in the United States currently live with Alzheimer disease (AD), and it is anticipated that the majority of these people will experience loss of independence and death within 4 to 8 years after diagnosis.1 As the sixth leading cause of death in the United States,2 more than 64,000 people aged 65 to 74 years, 173,000 people aged 75 to 84 years, and 243,000 people aged 85 years or older receive a diagnosis of AD each year.3 The mortality rate from AD increased by 123% from 2000 to 2015, a telling reminder that the success rate of drug development for treatment and prevention of AD remains inadequate4; therefore, increased emphasis must be placed on novel approaches to manage and prevent this condition.5 Studies have demonstrated that blood-brain barrier (BBB) dysfunction may be implicated in AD pathogenesis, thus establishing a link between AD and compromised neurovasculature.6,7 
Based on this literature review, we propose the novel idea that although osteopathic manipulative treatment (OMT) has not traditionally been considered a preventive treatment modality for neurologic disorders, osteopathic cranial manipulative medicine (OCMM) should be evaluated as a potential preventive treatment for patients with illnesses with neurovascular origin, such as AD. 
Literature Review
Current literature about OMT was identified by means of a literature search, with particular emphasis given to the OCMM compression of the fourth ventricle (CV-4) technique. Relevant publications relating to the pathogenesis and management of AD prompted additional searches to identify the relationship between AD and BBB breakdown, the response of the BBB to increased cerebral blood flow (CBF) and shear stress, and the impact of OCMM on cerebrovascular hemodynamics. PubMed search keywords included OCMM, compression of the 4th ventricle, Alzheimer disease, cerebral blood flow, shear stress, and blood brain barrier. 
Literature Findings
Osteopathic Cranial Manipulative Medicine
Osteopathic manipulative medicine uses a variety of manual techniques to enhance range of motion, improve lymphatic flow, and reduce pain associated with musculoskeletal and visceral dysfunction.8 Currently, OMT is used to promote patient self-healing capabilities and to address somatic dysfunction, defined as “impaired or altered function of related components of the somatic system: skeletal, arthrodial and myofascial structures related to neural and/or vascular elements that might underlie pathophysiologic conditions.”9 One subset of osteopathic techniques, OCMM, has its basis in the idea that respiratory motion triggers the movement of brain mass, dural membranes, cerebrospinal fluid, and cranial bones, which manifest as a detectable cranial rhythmic impulse (CRI).10 One common OCMM technique, CV-4, modulates cerebrovascular hemodynamics and may mediate sympathetic and parasympathetic autonomic activity. To perform this technique, the physician cradles the patient's head such that the physician's thenar eminences are in direct contact with the squamous area of the patient's occipital bone. While applying medial pressure on the lateral angles of the occiput, the physician evaluates the flexion and extension of the cranial bones while monitoring for the CRI.11 This technique reduces the volume of the fourth ventricle and redistributes the cerebrospinal fluid within it, ultimately leading to a downstream increase in CBF.12 
Link Between AD and the BBB
Studies strongly suggest a positive link between a decrease in cerebrovascular integrity and the development of AD and dementia.13 The literature on postmortem findings of atherosclerotic plaques in the circle of Willis, which tend to be markedly more severe in patients with AD or vascular dementia, indicates a direct association between poor cardiovascular health, brain vascular perfusion, and cognitive decline.14 Additionally, the findings of the Rotterdam study15 established proportionality between cognitive decline and reduced CBF velocity. 
The blood is a major reservoir for amyloid ß (Aß) peptides, proteins associated with AD that deposit within the hippocampus, cerebral cortex, and basal forebrain.16 Postmortem examination of human sera and AD brains has also found a widespread presence of autoantibodies to aggregated Aß protein.17 These Aß peptides and their antibodies must cross the BBB to infiltrate the brain, strongly suggesting that BBB deterioration plays a key role in the manifestation of AD. 
These findings imply that taking measures to strengthen the integrity of the BBB may reduce the risk of AD.18 
BBB Response to Increased Flow and Shear Stress
The major function of the BBB is to protect neural tissue from harmful substances in the circulatory system, a role critical to the maintenance of neural tissue homeostasis.19 The integrity of the barrier is maintained by brain endothelial cells, strongly bonded by a series of tight and adherens junctions.19 In addition, the junctional proteins platelet endothelial cell adhesion molecule and vascular endothelial cadherin (VE-cadherin) act as sensors to surrounding mechanical stimuli.20 Activation of these mechanoreceptors influences intra- and intercellular signaling cascades that work to modulate vascular permeability. 
Cucullo et al21 explain that circulating blood constantly exposes brain endothelial cells to shear stress. This stress has an effect on the arrangement of brain endothelial cells in the vascular wall, inducing functional remodeling of the BBB. Specifically, shear stress from increased CBF upregulates mRNA expression of critical junction proteins, such as claudins 3 to 5, zona occludens-1, and N- (neural), P- (placental), and VE-cadherins.21 A study by Walsh et al22 further strengthens the case for flow-dependent modification and stabilization of the BBB by explaining that VE-cadherin facilitates a Tiam1/Rac1 mechanotransduction pathway that leads to a downstream reduction in phosphorylated tyrosine residues on junction proteins. The inverse relationship between this reduction and barrier permeability suggests that activation of these mechanotransduction pathways strengthens the BBB.23 
These findings support the idea that increased shear stress aids in preserving cerebrovascular health and that modulating shear stress by increasing CBF velocity could strengthen BBB integrity. 
Impact of OCMM on Cerebrovascular Hemodynamics
Literature on OCMM is limited, and few studies have been done to determine the impact of the CV-4 technique on cerebrovascular hemodynamic parameters. However, specific downstream effects of the CV-4 technique are outlined in a review of studies by Z˙urowska et al.24 Of note, Nelson et al11 showed correlation between blood flow velocity and patient CRI after CV-4 treatment. A laser transcutaneous blood flowmeter was used to measure blood flow velocity during the CV-4 procedure. A Fourier transform analysis was then performed to isolate the Traube-Hering velocity component of the complex Traube-Hering-Mayer oscillation. The results revealed a posttreatment increase in both the patient's Traube-Hering waveform and CRI, suggesting a potential role for CV-4 in amplification of blood flow velocity. Although the observed changes in blood pressure and heart rate did not achieve statistical significance, this finding may have been largely attributable to study limitations, and future studies may yield improved results.24 
Discussion
Based on the literature reviewed and the epidemiologic severity of AD, we strongly believe that the CV-4 technique should be explored as a means of prevention in persons with a family history of or predisposition to the disease. We hypothesize that over time, routine OCMM has the potential to upregulate CBF and trigger an increase in shear stress, which could lead to functional remodeling of the BBB, resulting in decreased autoantibody and Aß peptide access to brain parenchyma. This approach may reduce the likelihood of AD or another disease with comparable cause developing in vulnerable persons. Our primary outcome of interest is that OCMM, particularly the CV-4 technique, may help to preserve the cerebrovascular integrity of the BBB with the important potential secondary outcome of delaying the onset of AD. Braskie et al25 showed that enhanced functional activity on magnetic resonance imaging in the fusiform and middle temporal gyri of apolipoprotein E4+ participants may indicate long-term progression to AD. It is hoped that using such imaging techniques in patients with a known genetic risk of AD could be used to quantify the role of CV-4 with regard to the progression to disease. 
Although we hope that our findings encourage research into the use of OCMM to prevent diseases with neurovascular origin, we foresee potential obstacles to effective study design. For example, “number of visits” would present a confounding variable because the experimental group would presumably require more physician contact than the control group. Another potential challenge would be the difficulty of finding a definitive sample population that would have developed AD without the intervention. Also, technique variability among physicians and uncertainty about the optimal time per OCMM treatment to provide a therapeutic effect would need to be considered. 
Possible avenues for future research include investigation of additional OMT techniques to inhibit BBB degeneration, as well as their potential use as a preventive strategy for other conditions. In the long term, our proposed use of OCMM, along with overall promotion of general health and exercise, may offer an important key to preventing neurovascular autoimmune diseases such as AD. In the short term, it may be possible to use a basic science approach to gather data that support this clinical approach. For example, microvessels have been formed in vitro after seeding a co-culture of vascular pericytes and cerebral microvascular endothelial cells within a collagen and hyaluronan 3-dimensional composite scaffold.26 After several days in culture, the resulting microvessels exhibited tight junctions and low permeability values characteristic of an intact BBB. In the context of this review, this in vitro system more directly tests the effects of modulation of fluid flow and shear stress in these vessels and monitors and measures the influence of these parameters on BBB permeability directly.26 This important and feasible proof of principle step could provide the necessary preliminary data as a foundation for funding the much-needed OCMM studies in humans. 
Acknowledgments
We thank Robert G. Nagele, PhD, Danielle L. Cooley, DO, Gary S. Goldberg, PhD, and Lisa M. Price, MSLIS, for their mentorship and review of this manuscript. 
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