Transcranial Electromagnetic Treatment "Rebalances" Blood and Brain Cytokine Levels in Alzheimer's Patients: A New Mechanism for Reversal of Their Cognitive Impairment

Chuanhai Cao, Haitham Abulaban, Rob Baranowski, Yanhong Wang, Yun Bai, Xiaoyang Lin, Ning Shen, Xiaolin Zhang, Gary W Arendash, Chuanhai Cao, Haitham Abulaban, Rob Baranowski, Yanhong Wang, Yun Bai, Xiaoyang Lin, Ning Shen, Xiaolin Zhang, Gary W Arendash

Abstract

Background: The immune system plays a critical role in the development and progression of Alzheimer's disease (AD). However, there is disagreement as to whether development/progression of AD involves an over-activation or an under-activation of the immune system. In either scenario, the immune system's cytokine levels are abnormal in AD and in need of rebalancing. We have recently published a pilot clinical trial (https://ichgcp.net/clinical-trials-registry/NCT02958930) showing that 2 months of daily in-home Transcranial Electromagnetic Treatment (TEMT) was completely safe and resulted in reversal of AD cognitive impairment.

Methods: For the eight mild/moderate AD subjects in this published work, the present study sought to determine if their TEMT administration had immunologic effects on blood or CSF levels of 12 cytokines. Subjects were given daily in-home TEMT for 2 months by their caregivers, utilizing first-in-class MemorEM™ devices.

Results: For eight plasma cytokines, AD subjects with lower baseline cytokine levels always showed increases in those cytokines after both a single treatment or after 2-months of daily TEMT. By contrast, those AD subjects with higher baseline cytokine levels in plasma showed treatment-induced decreases in plasma cytokines at both time points. Thus, a gravitation to reported normal plasma cytokine levels (i.e., a "rebalancing") occurred with both acute and long-term TEMT. In the CSF, TEMT-induced a similar rebalancing for seven measurable cytokines, the direction and extent of changes in individual subjects also being linked to their baseline CSF levels.

Conclusion: Our results strongly suggest that daily TEMT to AD subjects for 2-months can "rebalance" levels for 11 of 12 cytokines in blood and/or brain, which is associated with reversal of their cognitive impairment. TEMT is likely to be providing these immunoregulatory effects by affecting cytokine secretion from: (1) blood cells traveling through the head's vasculature, and (2) the brain's microglia/astrocytes, choroid plexus, or neurons. This rebalancing of so many cytokines, and in both brain and systemic compartments, appears to be a remarkable new mechanism of TEMT action that may contribute substantially to it's potential to prevent, stop, or reverse AD and other diseases of aging.

Keywords: Alzheimer’s disease; Transcranial Electromagnetic Treatment; brain and blood; cytokines; immunoregulation.

Conflict of interest statement

The University of South Florida has a financial interest in NeuroEM Therapeutics, a company that provided all of the financial support for this clinical trial. The interest has been reviewed and managed by the University in accordance with its Institutional Conflict of Interest policy. GA has a financial interest in NeuroEM Therapeutics as a common shareholder and has received a salary at times as CEO of the company. RB, as an employee of Left Coast Engineering, has received consulting and manufacturing fees from NeuroEM for a variety of services related to the MemorEM device and patent applications. He also owns common shares in NeuroEM. CC, XL, NS, and XZ were employed by the company MegaNano Biotech, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Cao, Abulaban, Baranowski, Wang, Bai, Lin, Shen, Zhang and Arendash.

Figures

FIGURE 1
FIGURE 1
(A) A MemorEM™ device being worn by a subject. The control panel/battery box is worn on the upper arm and wired via a cable to eight electromagnetic emitters in the head cap. (B) Position of the eight electromagnetic emitters (four on each size of the head) embedded between the device’s two-layered head cap. Emitters collectively provide full forebrain TEMT via rapid sequential activation. (C) FDTD brain simulation of electric field showing penetration and distribution from a single emitter at a SAR power level of 1.6 W/kg. The head/emitter interface is the thin blue margin below the bow tie-like electric field generated by the emitter.
FIGURE 2
FIGURE 2
The significant inverse correlation between plasma baseline GCSF levels and baseline ADAS-cog scores in individual AD subjects. Lower baseline GCSF levels were evident in individual AD subjects having poorer (higher) baseline ADAS-cog scores (Group 1, red-filled circles), while higher baseline GCSF levels were found in individual AD subjects with better (lower) baseline ADAS-cog scores (Group 2, green-filled points). This inverse correlation was present for seven of the eight cytokines measures in plasma.
FIGURE 3
FIGURE 3
Effects of 2-months of daily TEMT on plasma levels of eight cytokines in AD subjects. As can be seen for all eight cytokines, if baseline plasma levels were low (below the horizontal “convergence” dashed line), TEMT resulted in increased blood levels after 2-months of treatment (red lines). Conversely, if baseline cytokine levels were high, TEMT resulted in decreased blood levels after 60 days of treatment (green lines). Both red and green data points after 2 months of TEMT largely gravitate to at or near the horizontal “convergence” dashed line. These results suggest a clear ability of TEMT to re-balance or attempt to rebalance plasma cytokine levels to normal.
FIGURE 4
FIGURE 4
Means and SEMs for the individual subjects shown in Figure 3 for IL-17α and IL-18. As is evident for both cytokines, the response to TEMT is dependent on baseline levels, with TEMT inducing convergence (rebalancing) of both IL-17α and IL-18 toward aged normal levels (horizontal dashed line).
FIGURE 5
FIGURE 5
From the individual subject results presented in Figure 3, summarized means of TEMT-induced changes for Group 1 (red; lower baseline levels) and Group 2 (green; higher baseline levels). When comparing Group 1 to Group 2, the direction of plasma cytokine response to 2 months of TEMT is universally opposite for all eight cytokines. The difference is frequently significant (p-value) and there is a substantial Effect Size (clinically important effect) for all eight cytokines. For Group 1 vs. Group 2 significance: *p < 0.05, **p < 0.02, ***p < 0.001. For Group 1 vs. Group 2 Effect Size: L, large; VL, very large; H, huge.
FIGURE 6
FIGURE 6
Effects of a single 1-h TEMT treatment on plasma levels of four cytokines in AD subjects. For all four cytokines, if baseline blood levels were low (red points and lines), 1-h of TEMT induced an increase in plasma levels in samples taken several hours thereafter on Day 1. Conversely, if baseline cytokine levels were high (green points and lines), 1-h of TEMT resulted in decreased blood levels shortly thereafter on Day 1.
FIGURE 7
FIGURE 7
(A–C) For five cytokines in CSF, 2 months of TEMT increased their CSF levels if lower levels were present at baseline, and just the opposite for higher CSF levels at baseline. Three examples of the significant correlations resulting from this rebalancing of CSF cytokine levels by TEMT are presented. Thus, baseline CSF levels of at least five cytokines determine the direction and extent of cytokine response to TEMT. (D) Baseline ADAS-cog scores correlated strongly with the response of GCSF in CSF to TEMT.
FIGURE 8
FIGURE 8
Three-dimensional model of the cerebral arterial tree showing the location of four emitters on the surface of the head’s right side for the MemorEM device. The emitters (blue disks) are in close proximity to affect all blood components within the cerebrovascular tree including arteries/arterioles and most importantly capillaries, where the velocity of blood cells and plasma is at its slowest for maximal EMF exposure.

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