|Year : 2019 | Volume
| Issue : 4 | Page : 89-93
Remote ischemic conditioning of the brain in dementia patients: protocol for a crossover non-pharmaceutical intervention study
1st Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
|Date of Submission||08-Oct-2019|
|Date of Decision||12-Oct-2019|
|Date of Acceptance||22-Nov-2019|
|Date of Web Publication||13-Jan-2020|
1st Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki
Source of Support: None, Conflict of Interest: None
Background and objectives: Brain ischemia is one of the mechanisms causing dementia; this refers to vascular dementia, however its involvement in other forms of dementia cannot be excluded. We will study the potential neuroprotection of ischemia/reperfusion of a peripheral organ or tissue against cerebral I/R injury in people with mild cognitive impairment (percondition) and early and middle stage dementia (postcondition).
Subjects and methods: This crossover study will be held with individuals suffering from peripheral arteriopathy that can cause intermittent claudication after structured exercise, thus inducing extensive transient leg’s ischemia. The level of cerebral function will be checked at baseline and after the intervention with cognitive tests, electroencephalography, magnetic resonance imaging, blood tests, immunological examinations, Event Related Potentials and level of proteins of cerebrospinal fluid (only at baseline). We will examine the possible slowing of progression or the improvement of the disease (dementia), we will suggest or exclude possible biomarkers that are transmitted to the process as well as the intracellular mode of action in the target organs, with a study comprising independent samples and comparison groups. Patient recruitment will begin in January 2020, the analysis of primary outcome measures will be completed in August 2021, and the study will finish in December 2021. The study was approved by the Ethical Committee of the “Greek Association of Alzheimer’s Disease and Related Disorders” (Alzheimer Hellas) (Pr Nr 250 / 2019 AI) on November 8, 2019.
Outcome measures: Participants’ cognitive function will be assessed by cognitive scales (primary outcome measure), electroencephalography, magnetic resonance imaging, blood tests and immunological examinations, and cognitive induced potentials (secondary outcome measure) at the beginning and at the end of the study.
Discussion: This is the first time in the literature that protection of the human brain from dementia of different stages by remote conditioning is investigated. Also innovating is the method that the remote organ ischemia is achieved. The above mentioned strategy of cerebral protection from the initiation or the development of dementia is safe and costless.
Trial registration: ClinicalTrials.gov NCT04168021 registered on November 18, 2019.
Keywords: cognitive impairment; dementia; ischemic conditioning; neuroprotection; perconditioning; postconditioning; remote ischemia
|How to cite this article:|
Voucharas C. Remote ischemic conditioning of the brain in dementia patients: protocol for a crossover non-pharmaceutical intervention study. Clin Trials Degener Dis 2019;4:89-93
|How to cite this URL:|
Voucharas C. Remote ischemic conditioning of the brain in dementia patients: protocol for a crossover non-pharmaceutical intervention study. Clin Trials Degener Dis [serial online] 2019 [cited 2020 Apr 2];4:89-93. Available from: http://www.clinicaltdd.com/text.asp?2019/4/4/89/274076
| Introduction|| |
Tolerance of an organ or tissue to ischemia/reperfusion injury is an endogenous phenomenon that can be provoked by preceded nonfatal ischemia. Ischemic preconditioning is the first discovered form of tolerance to ischemia; it occurs widely in many animal species and in humans and in various organs including the brain and spinal cord.,
Brain ischemia is postulated as a main reason for vascular dementia; moreover it plays a significant role in all other forms of dementia.
Ischemic conditioning (IC) refers to repetitive, transient and sublethal series of ischemia/reperfusion (I/R) bursts that can trigger endogenous protection and tolerance against subsequent ischemic threats.,
Remote ischemic conditioning (RIC) that is a brief, repetitive and sublethal I/R injury applied to an organ or tissue far from the target organ, may benefit multiple organs of the body at the same time, such as heart, brain, spinal cord, kidney, lung, liver and skin. RIC has advantage over classic IC since it does not compromise vital organs such as the myocardium or the brain. Remote conditioning of the brain regarding transient ischemia/reperfusion caused to another organ or tissue far from the cerebrum, has advantage over classic ischemic conditioning, since it does not compromise the brain with irreversible neuronal damage. The brain’s protection by remote condition can be ahead of (preconditioning) or during (perconditioning) or following (postconditioning) the influence of the harmful stimulus., It seems to be a promising non-pharmaceutical and non-invasive therapy for preventing and treating age-related systemic vascular diseases such as combined lesions in the brain and also arteriosclerosis-induced neurodegenerative disorders.
The possible underlying mechanisms are correlated with several aspects, mainly including neuronal, humoral and immune-inflammatory (complement reaction) pathways, all of which also display inseparable interactions with each other. The role of epigenetics remains to be clarified.
There are three methods of RIC intervention based on timing of RIC in relation to I/R injury, including remote ischemic preconditioning (RIPreC, initiated before I/R injury), remote ischemic perconditioning (RIPerC, initiated during ischemia continuation) and remote ischemic postconditioning (RIPostC, initiated after ischemia has been established). The three methods of IC correspond to the three human subgroups experiencing a) normal cognitive function, b) mild cognitive impairment and c) mild or moderate dementia, accordingly.
Previous experimental work in humans applied pressure cuff on the upper limp in order to induce ischemia of a remote organ. The method carries a lot of disadvantages such as discomfort for the individual, risk for deep vein thrombosis, not extended ischemia, controversy relating to the degree, the duration and the number of the pressure cycles. In fact there is a paucity of clinical data comparing the effectiveness of different RIC protocols, and no convincing evidence of the most favorable conditioning strategy has been established.
Peripheral arteriopathy leading to intermittent claudication is frequently seen in the older adults as a result of progressive atherosclerosis, diabetes mellitus, coronary and great vessels of the neck insufficiency.
Limp ischemia caused by promoting exercise to the point of claudication guaranties extended ischemia of one or even both limps. Not only is the exercise completely harmless for the individual suffering from lower limp arteriopathy, but it is highly recommended by the angiologists as well. We have designed our investigation to include individuals with potential claudication, who usually avoid the discomfort of muscular cramps and pain in everyday life, encouraging them to follow a structured physical exercise program.
The incidence of RIC has already been investigated in acute ischemic stroke,, chronic cerebral ischemia,,,, subarachnoid hemorrhage,,,,,, carotid endarterectomy and stenting,, cerebral small-vessel disease,, and traumatic brain injury.
Whether RIC is efficient enough against cerebral I/R injury is controversial and further research will expand our knowledge in the field of cerebral protection.,,, Our investigation institutes the first time worldwide that RIC will be studied in different stages of dementia.
| Methods/Design|| |
The individuals that will be enrolled in this crossover study will be chosen among the “Alzheimer Hellas” association’s cohort (https://www.alzheimer-hellas.gr/index.php/en/), approximately 10,000 people that are under the association’s attention and care [Figure 1]. The protocol design is based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [Additional file 1] [Additional file 1].
The whole study will be under the supervision of the 1st Neurology Department of the Aristotle University of Thessaloniki and the “Alzheimer Hellas” (Head - Professor Magda Tsolaki, ORCID 0000-0002-2072-8010).
People with severe peripheral arteriopathy can potentially experience intermittent claudication after structured aerobic exercise. They all will be subjects of Fontaine’s stage IIb or Rutherford’s category 3 of chronic arteriopathy., This means they will experience claudication in less than 200 meters walking distance. Severe dementia patients are excluded the design because they cannot follow the exercise program (postconditioning group).
Individuals that will not be able to follow the exercise program for more than 2 days for any reason will also be excluded.
The considered subgroups will be built as below:
Group A, patients with arteriopathy and mild cognitive dysfunction, 30 individuals (perconditioning);
Group B, patients with arteriopathy and mild dementia, 30 individuals (postconditioning);
Group C, patients with arteriopathy and moderate dementia, 30 individuals (postconditioning).
Each of the groups A, B and C will be compared to each self from the baseline to the end of the investigation. Additional examination will be held 6 months later to examine if the potent result is permanent or is lost.
Only the psychologists that will carry out the cognitive scales will be blinded; unblinding is not permissible.
A full medical history as well as duplex ultrasonography of the lower extremity vessels will be used to document the peripheral arteriopathy. The level of cerebral function will be checked at baseline with cognitive tests, electroencephalography, magnetic resonance imaging, blood tests, immunological examinations, event-related potentials and level of proteins of cerebrospinal fluid.
Duplex ultrasonography of the lower extremity vessels as well as the vessels of the neck will be used to document the peripheral arteriopathy. People with arteriopathy will be encouraged to exercise everyday for a month’s duration to the extent of claudication appearance. All three groups have to transact the same scheduled exercise. They have to walk to the extent of maximum 200 meters distance or equivalent, with a rhythm relating to their physical situation or concomitant disorders. All participants are supposed to have severe peripheral arteriopathy, so they easily experience claudication on exercise. In case of experiencing any discomfort due to fatigue, myocardial ischemia, insufficient cerebral perfusion (chest pain or dizziness), they have to terminate the walking effort. If claudication does not appear, the exercise should be stopped after 200 meters walking distance.
Primary outcome measure is the change in cognitive function from the baseline to the end of the study, which will be assessed by cognitive scales (at least three different tests will confirm the documentation, Mini Mental State Examination, Change Test and Global Deterioration Scale).
Secondary outcome measures are electroencephalography, magnetic resonance imaging (white matter hyperintensities volume), blood tests (plasma total cholesterol, triglyceride, low density lipoprotein, homocysteine) and immunological examinations (including DNA methylation), cognitive induced potentials and cerebrospinal fluid examination (only at baseline), at the beginning and at the end of the study. All patients will be over the age of 65, since dementia is rare in younger ages. A complete medical history of every person participating in the study will be kept and all co-morbidities will be recorded.
The assessment schedule is shown in [Table 1].
Data collection, management, and monitoring
We will collect demographic data including patient’s name, gender, and age. Case report form (CRF) will be written in a unified format, including patient’s details, personal history, physical examination, special examination, laboratory examination, and patient signature. Data will be input into a computer database. All participant data will maintain personal privacy. The full names of the subjects will not be present in records or documents. Only their abbreviated names will be displayed. Clinical trial data will include written data and electronic data; all data will be accessible only by the author (administrator).
For each of the three groups we will use a two-tailed test. We will accept a P < 0.05 as acceptable and a study with 80% power. The standard deviation in the common population variance is approximately 0.7. The intervention is expected (hypothesis) to improve cognitive function by 60% at minimum. According to the calculation the sample size for each group should be at least 21 individuals.,
Mental test scores will be expressed as the mean ± SEM. Two-tailed unpaired t-test will be used to compare the values before and after the procedure. Data in every separate group will have to pass normality test and differences between SEMs in compared groups (raw data) will have to be due to random sampling. A difference will be considered statistically significant if P < 0.05. The results of the remaining tests will confirm the potent statistic differences.
Ethics and dissemination
All individuals will be informed about the design and the purpose of the study and will be given informed consent [Additional file 2] [Additional file 2]. The study was approved by the Ethical Committee of the “Greek Association of Alzheimer’s Disease and Related Disorders” (Alzheimer Hellas) (Pr Nr 250 / 2019 AI) on November 8, 2019 [Additional file 3] [Additional file 3].
This study will conduct in accordance with the Declaration of Helsinki, formulated by the World Medical Association. The findings of this study will be submitted to an open-access peer-reviewed journal.
| Discussion|| |
The aim of our study is to determine whether there is a beneficial effect after applying remote ischemic conditioning to individuals with different stages of dementia. Our investigation does not intent to suggest methods of provoking remote transient ischemia; in fact a small proportion of the elderly has intermittent claudication; however if evidence exists that RIC is effective, and the mechanism is not mild or ambiguous, then the scientists efforts will focus mainly in a way to achieve remote ischemia; for example an invasive or a non invasive technique that could temporarily obstruct the iliac or the femoral artery.
As the average human lifespan has increased markedly over the past decades, the mounting incidence of ageing-related disorders in the elderly and the related economic and social burden urge scientists all over the world to develop novel strategies to slow down or prevent these disorders. More well designed and comprehensive experimental work or clinical trials are warranted in future research to confirm whether RIC could be utilized as a non-invasive, inexpensive and efficient adjunct therapeutic intervention method for dementia confrontation.
We are going to introduce a novel strategy to induce efficient limp ischemia in humans. This kind of ischemia not only does avail the limp of the individual and provokes neo-angiogenesis, but it induces ischemic preconditioning to many organ of the body as well. We study an endogenous mechanism in humans (IC) that is costless and easily applicable. We hope that remote ischemic conditioning applies successfully to prevention or deceleration of dementia.
| Trial Status|| |
Patient recruitment will begin in January 2020. Cognitive status and peripheral arterial disease estimation will begin in March 2020. Structured exercise will begin in May 2020. The post intervention cognitive status estimation will begin in June 2020. The late cognitive status estimation will begin in September 2020. The analysis of primary outcome measures will be completed in August 2021, and the study will finish up to December 2021 (dissemination of the results).
Additional file 1: SPIRIT checklist.
Additional file 2: Model consent form.
Additional file 3: Ethical approval documentation.
Study concept and design, manuscript drafting: VC. The author gave final approval for publication.
Conflicts of interest
Institutional review board statement
The study was approved by the Ethical Committee of the “Greek Association of Alzheimer’s Disease and Related Disorders” (Alzheimer Hellas) (Pr Nr 250 / 2019 AI) on November 8, 2019.
Declaration of patient consent
The author certify that all appropriate patient consent forms will be obtained. In the forms the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This manuscript was prepared according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.
The statistical methods of this study were reviewed by the biostatistician of Aristotle University of Thessaloniki, Greece.
Copyright license agreement
The Copyright License Agreement has been signed by the author before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices) will be shared. Study protocol and informed consent form will also be available. Data will be available (start and end dates) immediately following publication, no end date, with investigations whose proposed use of the data has been approved by an independent review committee identified for this purpose, and for any purpose types of analysis. Proposals should be directed to firstname.lastname@example.org. To gain access, data requestors will need to sign a data access agreement.
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| References|| |
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation
Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med
Voucharas C, Lazou A, Triposkiadis F, Tsilimingas N. Remote preconditioning in normal and hypertrophic rat hearts. J Cardiothorac Surg
Zhou D, Ding J, Ya J, et al. Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection. Aging (Albany NY)
Pan J, Li X, Peng Y. Remote ischemic conditioning for acute ischemic stroke: dawn in the darkness. Rev Neurosci
Hess DC, Blauenfeldt RA, Andersen G, et al. Remote ischemic conditioning – a new paradigm of self-protection in the brain. Nat Rev Neurol
Johnsen J, Pryds K, Salman R, Løfgren B, Kristiansen SB, Bøtker HE. The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. Basic Res Cardiol
Hougaard KD, Hjort N, Zeidler D, et al. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Stroke
England TJ, Hedstrom A, O’Sullivan S, et al. RECAST (Remote Ischemic Conditioning After Stroke Trial): A pilot randomized placebo controlled phase II trial in acute ischemic stroke. Stroke
Meng R, Ding Y, Asmaro K, et al. Ischemic conditioning is safe and effective for octo- and nonagenarians in stroke prevention and treatment. Neurotherapeutics
Meng R, Asmaro K, Meng L, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology
Hou C, Duan J, Luo Y, et al. Remote limb ischemic conditioning treatment for intracranial atherosclerotic stenosis patients. Int J Stroke
Khan MB, Hoda MN, Vaibhav K, et al. Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment. Transl Stroke Res
Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke
Bilgin-Freiert A, Dusick JR, Stein NR, Etchepare M, Vespa P, Gonzalez NR. Muscle microdialysis to confirm sublethal ischemia in the induction of remote ischemic preconditioning. Transl Stroke Res
Gonzalez NR, Hamilton R, Bilgin-Freiert A, et al. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. Acta Neurochir Suppl
Gonzalez NR, Connolly M, Dusick JR, Bhakta H, Vespa P. Phase I clinical trial for the feasibility and safety of remote ischemic conditioning for aneurismal subarachnoid hemorrhage. Neurosurgery
Nikkola E, Laiwalla A, Ko A, et al. Remote ischemic conditioning alters methylation and expression of cell cycle genes in aneurysmal subarachnoid hemorrhage. Stroke
Laiwalla AN, Ooi YC, Liou R, Gonzalez NR. Matched cohort analysis of the effects of limb remote ischemic conditioning in patients with aneurismal subarachnoid hemorrhage. Transl Stroke Res
Walsh SR, Nouraei SA, Tang TY, Sadat U, Carpenter RH, Gaunt ME. Remote ischemic preconditioning for cerebral and cardiac protection during carotid endarterectomy: results from a pilot randomized clinical trial. Vasc Endovascular Surg
Zhao W, Meng R, Ma C, et al. Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis before carotid artery stenting: a proof-of-concept, randomized controlled trial. Circulation
Mi T, Yu F, Ji X, Sun Y, Qu D. The interventional effect of remote ischemic preconditioning on cerebral small vessel disease: a pilot randomized clinical trial. Eur Neurol
Wang Y, Meng R, Song H, et al. Remote ischemic conditioning may improve outcomes of patients with cerebral small-vessel disease. Stroke
Joseph B, Pandit V, Zangbar B, et al. Secondary brain injury in trauma patients: the effects of remote ischemic conditioning. J Trauma Acute Care Surg
Zhou G, Li MH, Tudor G, Lu HT, Kadirvel R, Kallmes D. Remote ischemic conditioning in cerebral diseases and neurointerventional procedures: recent research progress. Front Neurol
Vinciguerra A, Cuomo Ornella, Cepparulo P, et al. Models and methods for conditioning the ischemic brain. J Neurosci Methods
Zhao W, Che R, Li S, et al. Remote ischemic conditioning for acute stroke patients treated with thrombectomy. Ann Clin Transl Neurol
Doeppner TR, Zechmeister B, Kaltwasser B, et al. Very delayed remote ischemic post-conditioning induces sustained neurological recovery by mechanisms involving enhanced angioneurogenesis and peripheral immunosuppression reversal. Front Cell Neurosci
Hardman RL, Jazaeri O, Yi J, Smith M, Gupta R. Overview of classification systems in peripheral artery disease. Semin Intervent Radiol
Tegos TJ, Mavrophoros D, Sabetai MM, et al. Types of neurovascular symptoms and carotid plaque ultrasonic textural characteristics. J Ultrasound Med
Kadam P, Bhalerao S. Sample size calculation. Int J Ayurveda Res
Hickey GL, Grant SW, Dunning J, Siepe M. Statistical primer: sample size and power calculations-why, when and how? Eur J Cardiothorac Surg