The Effects of Ischemic Conditioning in Individuals With Parkinson's Disease

Parkinson Disease Clinical Trial

Official title:

The Chronic Effect of Ischemic Conditioning on Motor Function, Cognitive Performance, and Immune System in Individuals With Parkinson's Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06293118
• Other study ID #: 71055423.3.0000.0071
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 1, 2024
• Est. completion date: January 15, 2028

Study information

• Verified date: February 2024
• Source: Hospital Israelita Albert Einstein
• Contact: SAMUEL AMORIM DE SOUZA, Master
• Phone: 11983331912
• Email: samuel.amorim.s[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Ischemic conditioning (IC) is a promising therapy that can mimic the physiological effects of physical exercise. IC consists of using a cuff to measure blood pressure and calibrate 200 mmHg on the upper or lower limb. Thus, at alternating intervals of 5 minutes, ischemia or reperfusion occurs, depending on whether the cuff is inflated or deflated. IC induces changes in spinal cord excitability for the last reflex reactions of recruited motoneurons with improved balance control in healthy young people and improved learning in the elderly. The objective of the present study is to evaluate the chronic effect of IC on the motor function and cognitive performance of patients with Parkinson's disease. Furthermore, the investigators will evaluate secondary outcomes such as mobility, quality of life, and immunological responses.

Description:

Parkinson's disease (PD) is a neurodegenerative disorder that causes a variety of motor and non-motor symptoms. Typically, patients with PD suffer from disabilities and secondary complications even when the disease is optimally treated, and many patients still have sedentary lifestyles, which in turn result in higher rates of mortality and comorbidity. Physical activity is an essential element in maintaining daily functional capabilities and quality of life. However, patients with PD have motor and non-motor deficits that can prevent or limit physical exercise, such as running or resistance exercise. Ischemic conditioning (IC) is a promising therapy that can mimic the physiological effects of physical exercise. IC consists of using a cuff to measure blood pressure, calibrated between 180 and 200 mmHg on the upper or lower limb. Thus, at alternating intervals of 5 minutes, ischemia or reperfusion occurs, depending on whether the cuff is inflated or deflated. IC induces changes in spinal cord excitability for the last reflex reactions of recruited motoneurons with improved balance control in healthy young people and improved learning in the elderly. Recently, IC has been shown to improve cognitive performance in neurological patients with stroke, subcortical ischemia, and vascular dementia. However, there are no studies that have evaluated the effect of IC on motor and cognitive performance in patients with PD. The objective of the present study is to evaluate the chronic effect of IC on the motor and cognitive performance of patients with PD. Furthermore, the investigators intend to evaluate other secondary outcomes such as mobility, quality of life, and immunological responses.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 34
• Est. completion date: January 15, 2028
• Est. primary completion date: April 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 90 Years

Eligibility

Inclusion Criteria:

• PD patients aged 40 years or older;
• Diagnosis of PD without cognitive complaints or with complaints, but without impact on daily activities;

Exclusion Criteria:

• Patients with uncontrolled diabetes mellitus or peripheral neuropathy;
• Uncontrolled arterial hypertension (BP>160/100mmHg);
• Uncontrolled diabetes (Fasting glucose > 250mg/dl, peripheral retinopathy or diabetic ketoacidosis);
• Uncontrolled dyslipidemia (total chol > 220mg/dL);
• Pre-existing autoimmune diseases;
• Infectious conditions for less than 1 month;
• Neurological problems that prevent training from being carried out;
• History of anemia, cerebral vascular disease, myocardial infarction in the last 6 months;
• Previous deep vein thrombosis;
• Smoking < 6 months;
• Symptomatic peripheral arterial obstructive disease;
• Cognitive dysfunction: Moca < 24.

Related Conditions & MeSH terms

• Parkinson Disease

Intervention

Device:
• Ischemic conditioning group
The ischemic conditioning protocol will consist of a period of 12 weeks (24 sessions) with a frequency of 2 weekly sessions lasting between 15 and 20 minutes each. Therapy will be performed bilaterally on the upper limbs. The ischemic conditioning group will perform 4 times, 8 cycles with 30 seconds of ischemia (80 - 200 mmHg) with 5 seconds of reperfusion in each cycle. Ischemia cycles are controlled by a device (KAATSU C3 - KAATSU GLOBAL / USA) with customized ischemia programs, partially restricting blood flow through special pressure cuffs that are internally valved, providing greater comfort and safety for these patients who typically have stiffness in the affected limb and localized muscle pain. In the first cycle, participants will be subjected to pressures of 80 to 150 mmHg. In the 3 subsequent cycles, pressures from 130 to 200 mmHg will be applied.
• Sham group
Participants in the control group (Sham) will perform 4 cycles of 5 minutes of ischemia (30 mmHg) with 4 subsequent cycles of reperfusion (rest) bilaterally in the arms with a sphygmomanometer

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Israelita Albert Einstein

References & Publications (17)

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Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 2009 Dec;8(12):1150-7. doi: 10.1016/S1474-4422(09)70238-8. Erratum In: Lancet Neurol. 2010 Feb;9(2):140. Lancet Neurol. 2010 Jan;9(1):29. — View Citation

Guo ZN, Guo WT, Liu J, Chang J, Ma H, Zhang P, Zhang FL, Han K, Hu HH, Jin H, Sun X, Simpson DM, Yang Y. Changes in cerebral autoregulation and blood biomarkers after remote ischemic preconditioning. Neurology. 2019 Jul 2;93(1):e8-e19. doi: 10.1212/WNL.0000000000007732. Epub 2019 May 29. Erratum In: Neurology. 2019 Sep 24;93(13):608. — View Citation

He Z, Xu N, Qi S. Remote ischemic preconditioning improves the cognitive function of elderly patients following colon surgery: A randomized clinical trial. Medicine (Baltimore). 2017 Apr;96(17):e6719. doi: 10.1097/MD.0000000000006719. — View Citation

Kaushik S, Cuervo AM. Proteostasis and aging. Nat Med. 2015 Dec;21(12):1406-15. doi: 10.1038/nm.4001. — View Citation

Liao Z, Bu Y, Li M, Han R, Zhang N, Hao J, Jiang W. Remote ischemic conditioning improves cognition in patients with subcortical ischemic vascular dementia. BMC Neurol. 2019 Aug 23;19(1):206. doi: 10.1186/s12883-019-1435-y. — View Citation

Loukogeorgakis SP, Williams R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ, Yellon DM, Deanfield JE, MacAllister RJ. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation. 2007 Sep 18;116(12):1386-95. doi: 10.1161/CIRCULATIONAHA.106.653782. Epub 2007 Aug 27. — View Citation

Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003 Jul;18(7):738-50. doi: 10.1002/mds.10473. — View Citation

Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x. Erratum In: J Am Geriatr Soc. 2019 Sep;67(9):1991. — View Citation

Poewe et al. Parkinson disease. Nat Rev 2017;3:1-21. doi:10.1038/nrdp.2017.13

Poewe W. Clinical measures of progression in Parkinson's disease. Mov Disord. 2009;24 Suppl 2:S671-6. doi: 10.1002/mds.22600. — View Citation

Post B, Merkus MP, de Bie RM, de Haan RJ, Speelman JD. Unified Parkinson's disease rating scale motor examination: are ratings of nurses, residents in neurology, and movement disorders specialists interchangeable? Mov Disord. 2005 Dec;20(12):1577-84. doi: 10.1002/mds.20640. — View Citation

Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017 Jul;18(7):435-450. doi: 10.1038/nrn.2017.62. Epub 2017 Jun 8. Erratum In: Nat Rev Neurosci. 2017 Aug;18(8):509. — View Citation

Strijdom H, Friedrich SO, Hattingh S, Chamane N, Lochner A. Hypoxia-induced regulation of nitric oxide synthase in cardiac endothelial cells and myocytes and the role of the PI3-K/PKB pathway. Mol Cell Biochem. 2009 Jan;321(1-2):23-35. doi: 10.1007/s11010-008-9906-2. Epub 2008 Sep 14. — View Citation

Sutter EN, Mattlage AE, Bland MD, Cherry-Allen KM, Harrison E, Surkar SM, Gidday JM, Chen L, Hershey T, Lee JM, Lang CE. Remote Limb Ischemic Conditioning and Motor Learning: Evaluation of Factors Influencing Response in Older Adults. Transl Stroke Res. 2019 Aug;10(4):362-371. doi: 10.1007/s12975-018-0653-8. Epub 2018 Aug 7. — View Citation

Xu R, He Q, Wang Y, Yang Y, Guo ZN. Therapeutic Potential of Remote Ischemic Conditioning in Vascular Cognitive Impairment. Front Cell Neurosci. 2021 Aug 3;15:706759. doi: 10.3389/fncel.2021.706759. eCollection 2021. — View Citation

Zhou D, Ding J, Ya J, Pan L, Bai C, Guan J, Wang Z, Jin K, Yang Q, Ji X, Meng R. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. Aging (Albany NY). 2019 Jan 28;11(2):634-648. doi: 10.18632/aging.101764. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Motor function	The UPDRS (Unified Parkinson's Disease Rating Scale) is a scale created by the Movement Disorders Society (MDS) and has been the main scale used to assess the severity of PD symptoms through the patient's own report and also from their companions, in addition to observation and clinical examination [40]. The MDS UPDRS consists of 42 items divided into 4 subsections: Part I (non-motor aspects of daily life), Part II (motor aspects of daily life), Part III (motor assessment) and Part IV (motor complications)	Pre and Post 12 weeks
Primary	Cognitive performance	The MoCA consists of a one-page protocol, whose application time is approximately 10 minutes. It assesses six cognitive domains which include several items: 1 and 2. Memory; 3. Executive Function; 4. Languag ; 5. 6. Orientation	Pre and Post 12 weeks
Secondary	PDQ-39	The PDQ-39 questionnaire is self-administered and was developed based on interviews with individuals with PD.	Pre and Post 12 weeks
Secondary	Timed up and go (TUG)	The Timed Up & Go (TUG) is an easy test to perform and is associated with balance and gait speed outcomes[42]. The test consists of getting up from a chair, walking in a straight line 3 meters away at a comfortable and usual pace, turning around, walking back, and sitting down again[43]. The shorter the time used, the better the test performance.	Pre and Post 12 weeks
Secondary	Assessment of cellular and soluble immune response	The patient's peripheral blood will be collected in three EDTA tubes of 5 mL each before and after 12 weeks of application of the ischemic conditioning protocol. From the blood samples, plasma will be obtained for quantification of soluble mediators, followed by the isolation/storage of peripheral blood mononuclear cells (PBMC or Peripheral Blood Mononuclear Cell) for phenotypic characterization of subpopulations of T and B lymphocytes, NK cells, myeloids and monocytes	Pre and Post 12 weeks
Secondary	Quantifications of systemic soluble mediators	Initially, the EDTA tubes containing the blood will be centrifuged for 5 minutes at 400 x g and 20 ºC to separate the plasma. The collected plasma will be aliquoted into cryotubes and stored at -80ºC until the tests are carried out. Quantification of systemic soluble mediators will be performed using the MILLIPLEX® Human Cytokine/Chemokine/Growth Factor Panel A Kit H - Immunology Multiplex Assay (Merck Millipore, Massachusetts, USA). The panel of analytes included chemokines, growth factors, pro-inflammatory cytokines and regulatory cytokines: FGF-2/FGF-basic, G-CSF, GM-CSF, IFNa2,IFNy, IL-1a, IL-1b, IL-1RA , IL-2, IL-4, IL-6, IL-7, IL-8/CXCL8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL -17A/CTLA8, IL-18, IP-10/CXCL10, MCP-1/CCL2, MCP-3/CCL7, M-CSF, MIG/CXCL9, MIP-1a/CCL3, MIP-1b/CCL4, PDGF-AB /BB, RANTES/CCL5, TNFa, TNFb/Lymphotoxin-a, VEGF-A, HIF-1a. The PCR, BNDF, and Irisin proteins will be measured using single-plex assays.	Pre and Post 12 weeks
Secondary	PBMC acquisition and flow cytometry	Finally, a minimum of 100,000 events will be acquired on the BD LSRFortessa™ flow cytometer (BD Biosciences).	Pre and Post 12 weeks