Virginia Research Day 2021

PILOT STUDY: NOVEL THERAPEUTIC STRATEGIES FOR TREATMENT OF ALZHEIMER’S DISEASE

William Moles, OMS III, Curtis McInnis, OMS II, Allison Savon, OMS II, Hope Tobey, DO. Edward Via College of Osteopathic Medicine-Virginia Campus, Blacksburg, Virginia.

Abstract

Methods

Discussion

References This study is designed to take place in the clinic, under real world conditions, once data is collected and analyzed we hope to be able to make a conclusion of the effectiveness of OMT including OCMM on symptoms of Alzheimer’s disease. Despite our best efforts, this study does have some limitations. A small sample size along with a single provider conducting the study could impact the results. While a single provider will be able to provide consistent treatment, it is not as feasible to treat as many patients and we can not show reproducibility of results among multiple providers. A potential lack of follow up from patients may also be a concern. Lastly, the duration of treatment (8 weeks) is previously untested and may be too short to show significant results. In future experiments, we would aim for increased providers to allow the sample size to be increased and we would like different treatment groups with with varied treatment schedules to determine the optimal frequency of OMT treatment. OCMM involves manipulation of the primary respiratory mechanism 10 and in the future it may be beneficial to look at other specific OCMM techniques to determine their effectiveness. It is worth noting that there are current studies that shows thoracic lymphatic techniques inhibiting the growth of certain microbes in lung 11 , and although the MOA has not yet been determined, this may be an area to explore independently to see if it aids in improving optimal waste clearance in the brain glymphatics, which is believed to be a primary mechanism in the pathogenesis of Alzheimer’s. 1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 Census. Neurology 2013;80(19):1778-83. 2. Louveau A, Smirnov I, Keyes T et al. Structural and functional features of central nervous system lymphatic vessels. Nature doi:10.1038/nature14432, 2015; 523; 337-353 3. Bordoni B, Zanier E. Sutherland’s legacy in the new millennium: the osteopathic cranial model and modern osteopathy. Adv Mind Body Med. 2015;29(2):15-21 4. Tobey H, Lucas T, Bledsdoe D, et al Effect of Osteopathic Cranial Manipulative Medicine on an Aged Rat Model of Alzheimer Disease. The Journal of the American Osteopathic Association. 2019; 119(11); 712-723 5. Nakada T. Virchow-Robin space and aquaporin-4: new insight on an old friend. Croat Med J. 2014;55(4): 328-336. doi:10.3325/cmj.2014.55.328 6. Ozdemir MB, Akdogani E, Yonguc N. Three dimensional (3D) reconstruction of the rat ventricles. Neuroanatomy 4: 49 –51, 2005. 7. McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA. The Translational Significance of the Neurovascular Unit. J Biol Chem. 2017 Jan 20;292(3):762-770. doi: 10.1074/jbc.R116.760215. Epub 2016 Dec 5. PMID: 27920202; PMCID: PMC5247651. 8. Weyer G, Erzigkeit H, Kanowski S, Ihl R, Hadler D (1997). Alzheimer's Disease Assessment Scale: reliability and validity in a multicenter clinical trial. 9. Kaufer D, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, Lopez OL, DeKosky ST (2000). Validation of the NPI-Q, a Brief Clinical Form of the Neuropsychiatric Inventory 10. Jakel A, Hauenschild P. Therapeutic Effects of Cranial Osteopathic Manipulative Medicine: A Systematic Review. The Journal of the American Osteopathic Association. 2011; 111; 685-693 11. Creasy C, Schander A, Orlowski A, Hodge L. Thoracic and abdominal lymphatic pump techniques inhibit the growth of S. pneumoniae bacteria in the lungs of rats. Lymphatic Research and Biology 2013 Sep;11(3):183-6. doi: 10.1089/lrb.2013.0007. Epub 2013 Sep 11. PMID: 24024572 PMCID: PMC3780326

Alzheimer’s Disease affects 5.8 million Americans today, making it the sixth leading cause of death in the United States 1 . It has been well established that the accumulation of metabolic waste products including plaques of abnormally folded amyloid beta and tau neurofibrillary tangles contribute to the pathogenesis of brain tissue degeneration in Alzheimer’s Disease. Currently, management of this disease includes medications that inhibit the reuptake of Acetylcholine and promote the action of N-methyl D-aspartate (NMDA), but do not likely target the true underlying pathology of the disease. It has recently been discovered that the central nervous system (CNS) has a unique lymphatic system with vessels that clear metabolic waste products. This finding opens an unprecedented capability to increase clearance of macromolecules like amyloid beta by facilitating lymphatic drainage from the CNS 2 . To assess methods of facilitating CNS lymphatic drainage, we are performing a pilot study to determine the impact of Osteopathic Cranial Manipulation Medicine (OCMM) on patients with Alzheimer’s Disease. OCMM comprises a set of gentle, non-invasive techniques aimed at facilitating CNS lymphatic and CSF circulation. The efficacy of OCMM in this setting will be assessed by both an Alzheimer’s Disease cognitive assessment scale (ADAS-cog) looking for improvement over several cognitive domains, and a caregiver burden scale (NPI-Q) looking for a reduction in caregiver distress. Using these scales, we will determine if there is a significant difference between pre-treatment and post- treatment symptomatic burden in patients with Alzheimer’s Disease who receive OCMM in addition to their standard medical therapy. Given that current medical therapy for Alzheimer’s Disease is at a stalemate, knowing how OCMM affects the cognitive function of patients with the disease may lead to improvement in heath care outcomes for this patient population as well as pave the way for future studies in osteopathic cranial medicine at large. • Alzheimer’s Disease (AD) kills 1 in 3 seniors with a prevalence of 5.8 million Americans and currently costs the nation $290 billion 1 • Recently, it has been discovered that the CNS has a lymphatic system that clears the metabolic waste products. The recent discovery of the waste-clearing CNS lymphatic system opens the door for new non-invasive treatment options for patients with AD. • Osteopathic Cranial Manipulative Medicine (OCMM) is gentle, non-invasive and throughout the years has been hypothesized to improve lymphatic and blood flow to and from the brain. The basis for OCMM is in the inherent motion and mobility of all the anatomic components of the cranium (dural membrane, cerebral spinal fluid, sacrum and the cranial bones) which is termed the primary respiratory mechanism 3 • It has been shown in rat models of AD that OCMM led to improved spatial learning and memory, decreased amyloid beta levels on PET scan 4 , increased astrocyte markers, and increased expression of AQP4 channels 5 . The anatomy of the dural and ventricular system in rats has also been shown to be similar to that of humans which allows us to hypothesize that we may be able to see similar physiologic effects when using OCMM in humans 6 . Introduction

Men and women ages 50 and above were recruited from neurology and psychiatry offices in rural south-western Virginia. Inclusion and exclusion criteria is listed in Figure 2. Figure 2: Study Criteria

Inclusion Criteria

Exclusion Criteria

Age >50 (men and women)

Patients with clinically significant comorbid cardiovascular disease Patients with history of traumatic brain injury Patients with history of alcohol abuse Patients receiving concomitant psychoactive medications that are not considered part of standard Alzheimer’s Disease medication therapy Patients who underwent any major surgeries in the past year Patients receiving concurrent musculoskeletal therapies such as: osteopathic manipulation therapy, chiropractic therapy, massage therapy, physical therapy

Diagnosis of Probable Alzheimer’s Disease according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)

Figure 3: OMT Techniques Used Study Design: This study has a before-after design. Participants will receive one OMT treatment per week for eight consecutive weeks. The OMT treatment protocol is listed in Figure 3. The total treatment time is 30 minutes per patient. The treatment protocol will be discontinued if the principle investigator deems that continuation poses a medical risk to the participant, or if the patient declines further participation. Any participants who withdraw are asked to complete an end-point assessment. 1. Thoracic inlet myofascial release (1-2 min) 2. Thoracic diaphragm myofascial release (1-2 min) 3. Pelvic diaphragm myofascial release (1-2 min) 4. Lymphatic drainage of anterior and posterior cervical chains (1-2 min) 5. Thoracic lymphatic pump (1-2 min_ 6. Variable techniques to treat clinically significant somatic dysfunction (5 min) Outcome Measures: The primary efficacy variables are the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), and the Neuropsychiatric Inventory Questionnaire (NPI-Q). The ADAS-cog consists of tasks that measure the disturbances of memory, language, praxis, attention, and several other cognitive parameters which are thought the be the core symptoms of Alzheimer’s Disease 8 . This test will be administered to each participant prior to the study, and then at each subsequent treatment visit. The NPI-Q evaluates caregiver distress in relation to the various symptom domains of Alzheimer’s Disease. It is a retrospective caregiver interview measuring symptom burden in 12 different neuropsychiatric domains. The caregiver rates the severity of each symptom with regards to the patient, and the distress experienced by the caregiver due to that symptom 9 . The NPI-Q will be administered to each of the participant’s caretakers prior to the study, and then at each subsequent treatment visit. 7. Cranial balances membranous tension (5 min) 8. Compression of the fourth ventricle (5 min)

Figure 1 Perivascular clearance of extracellular fluids and solutes in the brain parenchyma 7

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