We have previously shown in small studies that full brain Transcranial Radiofrequency Wave Treatment (TRFT) to subjects with Alzheimer’s Disease could stop and reverse their cognitive decline. An 8-emitter head device, the “MemorEM”, was used in these studies to provide TRFT at 915 MHz frequency and power level of 1.6 W/kg Specific Absorption Rate (SAR) during daily 1-hour treatments. Although no deleterious side effects during up to 2.5 years of treatment were reported, it is important to rule out the possibility that brain heating will occur during TRFT in humans at a higher power level of 4.0 W/kg SAR, which is anticipated for future clinical testing in order to increase treatment intensity/efficacy to deep sub-cortical areas. To examine if brain heating occurs during a single 1-hour treatment at 4 W/kg SAR, a hollow human head phantom filled with brain-analogous gel and with an attached MemorEM head device was utilized. Brain temperatures were taken at 64 specific coordinates within the brain gel before and immediately following one-hour of TRFT. Results revealed none of the 64 sites having a temperature increase after TRFT of 1 °C or more. Indeed, 45 of the 64 sites exhibited a temperature rise of less than 0.5 °C, with just three sites exhibiting an increase between 0.75 and 0.9 °C. These results demonstrate that TRFT in a human head phantom that mimics the electromagnetic properties of the human head, does not appreciably increase brain temperature (i.e., is non-thermal) at 915 MHz frequency and 4 W/kg SAR power level. Thus, TRFT would appear to be safe at 4 W/kg for long-term daily treatments.

There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers through three disease-modifying mechanisms. Transcranial Radiofrequency Wave Treatment (TRFT) is non-thermal, non-invasive and self-administered in-home to safely provide radiofrequency waves to the entire human brain. Since TRFT has already been shown to stop and reverse the cognitive decline of Alzheimer’s Disease in small studies, evidence is provided that three key mechanisms of TRFT action, alone or in synergy, could effectively treat brain cancers: (1) enhancement of brain meningeal lymph flow to increase immune trafficking between the brain cancer and cervical lymph nodes, resulting in a robust immune attack on the brain cancer; (2) rebalancing of the immune system’s cytokines within the brain or brain cancer environment to decrease inflammation therein and thus make for an inhospitable environment for brain cancer growth; (3) direct anti-proliferation/antigrowth affects within the brain tumor microenvironment. Importantly, these mechanisms of TRFT action could be effective against both visualized brain tumors and those that are yet too small to be identified through brain imaging. The existing animal and human clinical evidence presented in this perspective article justifies TRFT to be clinically tested immediately against both primary and metastatic brain cancers as monotherapy or possibly in combination with immune checkpoint inhibitors.

Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered—meningeal lymphatic vessels (mLVs)—which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer’s disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable “baseline” VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF’s actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT’s reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.

Most diseases of older age have as their common denominator a dysfunctional immune system, wherein a low, chronic level of inflammation is present due to an imbalance of pro-inflammatory cytokines over anti-inflammatory cytokines that develops during aging (“inflamm-aging”). A gerotherapeutic that can restore the immune balance to that shared by young/middle-aged adults and many centenarians could reduce the risk of those age-related diseases and increase healthy longevity. In this perspectives paper, we discuss potential longevity interventions that are being evaluated and compare them to a novel gerotherapeutic currently being evaluated in humans—Transcranial Electromagnetic Wave Treatment (TEMT). TEMT is provided non-invasively and safety through a novel bioengineered medical device—the MemorEM—that allows for near complete mobility during in-home treatments. Daily TEMT to mild/moderate Alzheimer’s Disease (AD) patients over a 2-month period rebalanced 11 of 12 cytokines in blood back to that of normal aged adults. A very similar TEMT-induced rebalancing of cytokines occurred in the CSF/brain for essentially all seven measurable cytokines. Overall inflammation in both blood and brain was dramatically reduced by TEMT over a 14–27 month period, as measured by C-Reactive Protein. In these same AD patients, a reversal of cognitive impairment was observed at 2 months into treatment, while cognitive decline was stopped over a 2½ year period of TEMT. Since most age-related diseases have the commonality of immune imbalance, it is reasonable to postulate that TEMT could rebalance the immune system in many age-related diseases as it appears to do in AD. We propose that TEMT has the potential to reduce the risk/severity of age-related diseases by rejuvenating the immune system to a younger age, resulting in reduced brain/body inflammation and a substantial increase in healthy longevity.

Background: There is currently no therapeutic that can stop or reverse the progressive memory impairment of Alzheimer's disease (AD). However, we recently published that 2 months of daily, in-home transcranial electromagnetic treatment (TEMT) reversed the cognitive impairment in eight mild/moderate AD subjects. These cognitive enhancements were accompanied by predicted changes in AD markers within both the blood and cerebrospinal fluid (CSF). Methods: In view of these encouraging findings, the initial clinical study was extended twice to encompass a period of 2½ years. The present study reports on the resulting long-term safety, cognitive assessments, and AD marker evaluations from the five subjects who received long-term treatment. Results: TEMT administration was completely safe over the 2½-year period, with no deleterious side effects. In six cognitive/functional tasks (including the ADAS-cog13, Rey AVLT, MMSE, and ADL), no decline in any measure occurred over this 2½-year period. Long-term TEMT induced reductions in the CSF levels of C-reactive protein, p-tau217, Aβ1-40, and Aβ1-42 while modulating CSF oligomeric Aβ levels. In the plasma, long-term TEMT modulated/rebalanced levels of both p-tau217 and total tau. Conclusions: Although only a limited number of AD patients were involved in this study, the results suggest that TEMT can stop the cognitive decline of AD over a period of at least 2½ years and can do so with no safety issues.

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://clinicaltrials.gov/ct2/show/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.

Background: Small aggregates (oligomers) of the toxic proteins amyloid-β (Aβ) and phospho-tau (p-tau) are essential contributors to Alzheimer’s disease (AD). In mouse models for AD or human AD brain extracts, Transcranial Electromagnetic Treatment (TEMT) disaggregates both Aβ and p-tau oligomers, and induces brain mitochondrial enhancement. These apparent “disease-modifying” actions of TEMT both prevent and reverse memory impairment in AD transgenic mice. Objective: To evaluate the safety and initial clinical efficacy of TEMT against AD, a comprehensive open-label clinical trial was performed. Methods: Eight mild/moderate AD patients were treated with TEMT in-home by their caregivers for 2 months utilizing a unique head device. TEMT was given for two 1-hour periods each day, with subjects primarily evaluated at baseline, end-of-treatment, and 2 weeks following treatment completion. Results: No deleterious behavioral effects, discomfort, or physiologic changes resulted from 2 months of TEMT, as well as no evidence of tumor or microhemorrhage induction. TEMT induced clinically important and statistically significant improvements in ADAS-cog, as well as in the Rey AVLT. TEMT also produced increases in cerebrospinal fluid (CSF) levels of soluble Aβ1-40 and Aβ1-42, cognition-related changes in CSF oligomeric Aβ, a decreased CSF p-tau/Aβ1-42 ratio, and reduced levels of oligomeric Aβ in plasma. Pre- versus post-treatment FDG-PET brain scans revealed stable cerebral glucose utilization, with several subjects exhibiting enhanced glucose utilization. Evaluation of diffusion tensor imaging (fractional anisotropy) scans in individual subjects provided support for TEMT-induced increases in functional connectivity within the cognitively-important cingulate cortex/cingulum. Conclusion: TEMT administration to AD subjects appears to be safe, while providing cognitive enhancement, changes to CSF/blood AD markers, and evidence of stable/enhanced brain connectivity.

We have demonstrated in multiple studies that daily, long-term electromagnetic field (EMF) treatment in the ultra-high frequency range not only protects Alzheimer's disease (AD) transgenic mice from cognitive impairment, but also reverses such impairment in aged AD mice. Moreover, these beneficial cognitive effects appear to be through direct actions on the AD process. Based on a large array of pre-clinical data, we have initiated a pilot clinical trial to determine the safety and efficacy of EMF treatment to mild-moderate AD subjects. Since it is important to establish the safety of this new neuromodulatory approach, the main purpose of this review is to provide a comprehensive assessment of evidence supporting the safety of EMFs, particularly through transcranial electromagnetic treatment (TEMT). In addition to our own pre-clinical studies, a rich variety of both animal and cell culture studies performed by others have underscored the anticipated safety of TEMT in clinical AD trials. Moreover, numerous clinical studies have determined that short- or long-term human exposure to EMFs similar to those to be provided clinically by TEMT do not have deleterious effects on general health, cognitive function, or a variety of physiologic measures-to the contrary, beneficial effects on brain function/activity have been reported. Importantly, such EMF exposure has not been shown to increase the risk of any type of cancer in human epidemiologic studies, as well as animal and cell culture studies. In view of all the above, clinical trials of safety/efficacy with TEMT to AD subjects are clearly warranted and now in progress.

Transcription factors are involved to varying extents in the health and survival of neurons in the brain and a better understanding of their roles with respect to the pathogenesis of Alzheimer's disease (AD) could lead to the development of additional treatment strategies. Sp1 is a transcription factor that responds to inflammatory signals occurring in the AD brain. It is known to regulate genes with demonstrated importance in AD, and we have previously found it upregulated in the AD brain and in brains of transgenic AD model mice. To better understand the role of Sp1 in AD, we tested whether we could affect memory function (measured with a battery of behavioral tests discriminating different aspects of cognitive function) in a transgenic model of AD by pharmaceutical modulation of Sp1. We found that inhibition of Sp1 function in transgenic AD model mice increased memory deficits, while there were no changes in sensorimotor or anxiety tests. Aβ42 and Aβ40 peptide levels were significantly higher in the treated mice, indicating that Sp1 elevation in AD could be a functionally protective response. Circulating levels of CXCL1 (KC) decreased following treatment with mithramycin, while a battery of other cytokines, including IL-1α, IL-6, INF-γ and MCP-1, were unchanged. Gene expression levels for several genes important to neuronal health were determined by qRT-PCR, and none of these appeared to change at the transcriptional level.

La presente invention concerne des dispositifs, procedes, et systemes pour aider a la prevention (ou pour la prevention) ou au traitement de troubles cerebraux et/ou corporels. Des modes de realisation comportent une fonctionnalite pour l'amelioration de la fonction cognitive lors du vieillissement. L'invention utilise la stimulation electromagnetique (EMS) qui peut fournir une gamme de parametres et de modalites de stimulation electromagnetique. La stimulation electromagnetique peut etre utilisee conjointement avec des capteurs physiologiques qui peuvent fournir une retroaction pour des modifications possibles de la stimulation electromagnetique.

Traumatic brain injury (TBI) has become a signature wound of the wars in Iraq and Afghanistan. Many American soldiers, even those undiagnosed but likely suffering from mild TBI, display Alzheimer's disease (AD)-like cognitive impairments, suggesting a pathological overlap between TBI and AD. This study examined the cognitive and neurohistological effects of TBI in presymptomatic APP/PS1 AD-transgenic mice. AD mice and non-transgenic (NT) mice received an experimental TBI on the right parietal cortex using the controlled cortical impact model. Animals were trained in a water maze task for spatial memory before TBI, and then reevaluated in the same task at two and six weeks post-TBI. The results showed that AD mice with TBI made significantly more errors in the task than AD mice without TBI and NT mice regardless of TBI. A separate group of AD mice and NT mice were evaluated neurohistologically at six weeks after TBI. The number of extracellular beta-amyloid (Aβ)-deposits significantly increased by at least one fold in the cortex of AD mice that received TBI compared to the NT mice that received TBI or the AD and NT mice that underwent sham surgery. A significant decrease in MAP2 positive cells, indicating neuronal loss, was observed in the cortex of both the AD and NT mice that received TBI compared to the AD and NT mice subjected to sham surgery. Similar changes in extracellular Aβ deposits and MAP2 positive cells were also seen in the hippocampus. These results demonstrate for the first time that TBI precipitates cognitive impairment in presymptomatic AD mice, while also confirming extracellular Aβ deposits following TBI. The recognition of this pathological link between TBI and AD should aid in developing novel treatments directed at abrogating cellular injury and extracellular Aβ deposition in the brain.

Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APP(sw) showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A(2a) and A₁ adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APP(sw) transgenic mouse and cell models of Alzheimer's disease.

Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25–1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21–27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD.

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.

The universal failure of pharmacologic interventions against Alzheimer's disease (AD) appears largely due to their inability to get into neurons and the fact that most have a single mechanism-of-action. A non-invasive, neuromodulatory approach against AD has consequently emerged: transcranial electromagnetic treatment (TEMT). In AD transgenic mice, long-term TEMT prevents and reverses both cognitive impairment and brain amyloid-β (Aβ) deposition, while TEMT even improves cognitive performance in normal mice. Three disease-modifying and inter-related mechanisms of TEMT action have been identified in the brain: 1) anti-Aβ aggregation, both intraneuronally and extracellularly; 2) mitochondrial enhancement; and 3) increased neuronal activity. Long-term TEMT appears safe in that it does not impact brain temperature or oxidative stress levels, nor does it induce any abnormal histologic/anatomic changes in the brain or peripheral tissues. Future TEMT development in both AD mice and normal mice should involve head-only treatment to discover the most efficacious set of parameters for achieving faster and even greater cognitive benefit. Given the already extensive animal work completed, translational development of TEMT could occur relatively quickly to "proof of concept" AD clinical trials. TEMT's mechanisms of action provide extraordinary therapeutic potential against other neurologic disorders/injuries, such as Parkinson's disease, traumatic brain injury, and stroke.

The pathogenesis of Alzheimer's disease (AD) remains controversial but it clearly involves the loss of neuronal homeostasis and synaptic activity with subsequent deficits in cognitive functions. Previous groups have reported that AD patients have decreased blood and CSF levels of melatonin. Lower CSF levels of melatonin have been strongly correlated with progression of AD neuropathology, and preclinical AD subjects already have decreased CSF melatonin levels. Several epidemiologic and case studies have also suggested that melatonin treatment provides cognitive benefit to MCI and AD patients. In our recent studies (Olcese et al., 2009; Dragicevic et al. 2011), we evaluated the neuroprotective effects of long-term melatonin administration in transgenic APPswe+PS1 mice. Our results revealed that transgenic AD mice given melatonin treatment were cognitively protected in a spectrum of tasks and cognitive domains, brain beta-amyloid (Aβ) deposition was dramatically reduced, and soluble Aβ levels were elevated in blood, suggesting improved clearance. Brain mitochondrial membrane potential, respiratory rates and ATP levels were also preserved in AD mice that had received melatonin. In our on-going studies, we are assessing protein expression of a variety of genes involved in synaptic integrity and neuronal function in the cortex of melatonin-treated and non-treated AD mice. Tg and NT mice treated with melatonin or vehicle from age 2 months. Cognitive testing begun at age 7 months and sacrifice, collection of samples at age 9 months. Homogenization of saline perfused frontal cortex with standard HEPES protein extraction buffer, Thermo Scientific Halt™ phosphatase inhibitor cocktail, and Roche cOmplete™ protease inhibitor cocktail. Immunoblotting was performed according to manufacturer's protocol for each antibody. Proteins were either detected on x-ray film using enhanced chemiluminscent reagents from Pierce, or detected via the LICOR Odyssey™ infrared imaging system with secondary antibodies sensitive to 685 and 785 excitation wavelengths. Significant increase in synapsin and spinophilin expression in melatonin-treated AD animals as compared to samples from AD mice not treated. Phosphorylated MAP2 as well as phospho-tau is significantly lower in melatonin-treated AD mouse brain.