Transcranial Photobiomodulation to treat dementia and Alzheimer´s disease
Results of the latest studies, the role of the glymphatic system, and other mechanisms.
Bottom line
Transcranial PBM is a new and very promising approach to treating dementia and specifically its most common type Alzheimer´s disease. A review of preclinical and clinical studies as well as additional human studies consistently concluded significant beneficial clinical outcomes. Caregivers can also benefit from the improved independence of patients. This article provides brief summaries of some of these studies. It also looks at underlying mechanisms of action and specifically explains how PBM can improve the function of the glymphatic system and thereby the clearance of beta-amyloid protein aggregations which are a pathological hallmark of Alzheimer’s disease.
Introduction: Brief facts about dementia and Alzheimer´s disease
In my last post, I summarized the most important mechanisms of transcranial photobiomodulation therapy. Let´s now take a deep dive into one of its best-established applications; dementia and Alzheimer´s disease.
The WHO estimated that over 55 million people worldwide lived with dementia in 2020. There are more than 10 million new cases per year, which equals one new case every 3 seconds and leads to an estimated 78 million cases by 2030 and 139 million by 2050 [1].
Dementia itself is not a specific disease but rather an umbrella term that includes a variety of symptoms, such as
- declined memory,
- declined reasoning, judgment, and thinking skills
- changes in behavior and the ability to use language
- decreased attention and focus.
The social burden of dementia becomes even more evident when we consider that the disease not only affects the actual patients, but also many people in their social environment.
The term Alzheimer´s disease is often used as a synonym for dementia, while it in fact just describes one specific type of dementia. However, it is the most common type and may contribute to 60-70% of all dementia cases [1]. Compared to other types of dementia, it is characterized by two specific features: The accumulation of beta-amyloid plaques and the tangling of tau protein.
Current dementia and Alzheimer´s treatments focus on improving symptoms such as memory loss and problems with reasoning, but they do not stop the underlying decline and death of brain cells and thus do not stop the disease progression.
Against this background, it seems obvious that additional interventions are urgently needed to tackle one of society´s biggest health challenges. Transcranial photobiomodulation is precisely that, a promising new intervention to treat dementia in general and Alzheimer´s disease in particular. Let´s have a look at the studies that are already out there.
Review of preclinical and clinical PBM- studies for dementia (2021)
A review published in 2021 in the “Journal of Alzheimer´s Disease” reviews 36 published articles, out of which nine were conducted on cell cultures, seventeen on animals, and ten on humans. Remarkably, all these studies concluded beneficial clinical results. On top of that, they highlighted that the intervention was free of side effects and “remarkably” easy to use [2].
Further human studies since 2021
Since 2021, more human studies have been published.
A trial in “aging and disease” [3] compared the effects of tPBM therapy administered twice daily for 6 minutes during eight weeks vs. sham therapy with a sham device. After already seven days, the study group patients reported improved sleep quality. After 2-3 weeks, study group patients reported less anxiety, improved mood and energy and cognitive functions, and more positive daily routines. These findings can be considered significant clinical effects and also highlight that results can be achieved rapidly if the treatment is administered with high frequency. Worth being mentioned, the daily interventions were conducted conveniently in the homes of the elderly patients, without any side effects being reported.
A randomized clinical trial published in “Photobiomodulation, photomedicine, and laser surgery” on 32 dementia patients reported significantly improved cognitive functions of patients who received tPBM (measured by the minimental state examination and clinical dementia rating tests), as compared to a control group [4]. The improved cognitive functions went along with improved quality of life and improved independence in daily lives, thus also helping family caregivers by decreasing their burden.
A double-blind, randomized trial on 53 Alzheimer´s disease patients reported the effects of 40 tPBM-treatments within eight weeks, with each treatment lasting 25 minutes. Besides improved general cognitive functions, the study group patients in particular showed lower task execution times, longer attention spans, and were – remarkably – “highly compliant” with the therapy (92,5% of patients were able to maintain the therapy as planned) [5]. This highlights the feasibility of the approach for Alzheimer´s disease patients, which is not automatically given for all treatments.
Two other human studies looked specifically, under EEG validation, at the effects of tPBM on neural oscillations and subsequently its impact on dementia and Alzheimer´s [6,7]. Read a bit more about the rationale of this approach below.
How does tPBM work on dementia / Alzheimer´s disease? A deeper dive into the glymphatic system
My last post explained how tPBM can work in general and we can transfer this knowledge to our understanding of how some of the typical hallmarks of dementia and Alzheimer´s can be treated by PBM. These include
- brain vascular compromise,
- neuroinflammation,
- impaired mitochondrial function,
- oxidative damage,
- as well as the loss of dendrites, synapses, and neurons [8].
Specific pathological hallmarks of Alzheimer’s disease are the occurrence of neurofibrillary tangles and abnormal levels of beta-amyloid protein accumulations which are neurotoxic and disrupt cell function. This ultimately leads to memory loss and cognitive decline.
While beta-amyloid protein occurs naturally and is also found in healthy people, its abnormally high levels seem to cause the onset of Alzheimer´s disease. In a healthy brain, the glymphatic system removes enough of the beta-amyloid protein from the body. In Alzheimer´s patients, the glymphatic system seems to have lost its ability to clear the protein to a sufficient extent.
Here, I want to take a deeper dive into how tPBM can help clear beta-amyloid protein through the glymphatic system (the lymphatic system of the brain. The “g” is added as a reference to “glia cells”; the supporting cells of the nervous system).
To give you some background, here is how the glymphatic system works: Cerebrospinal fluid passes through the perivascular spaces surrounding the arteries. Via a water channel protein called aquaporin-4, it is from there passed on into the brain´s interstitial space where it picks up all sorts of metabolic waste products to clear the brain from materials that could inhibit homeostasis. From the interstitial area, it is then pushed into the perivascular space surrounding the veins. The whole process is driven by arterial pulsations. The fluid then leaves the brain via a series of lymphatic vessels within the meninges and is drained into the cervical lymph nodes [9].
According to a recent review [10], there are four mechanisms by which PBM can improve the natural function of the glymphatic system and thereby lead to improved removal of beta-amyloid protein:
- PBM can stimulate the cerebrospinal fluid's flow by changing the water molecules' structure, making the fluid less viscous and letting it flow more freely.
- PBM can break down protein aggregations (specifically beta-amyloid aggregations).
- PBM can increase the permeability of the aquaporin-4 water channels, thereby allowing more fluid flow through the brain.
- PBM can widen lymphatic vessels, presumably because of the release of nitric oxide as a consequence of the photon absorption in cytochrome c oxidase.
Consistent with these proposed mechanisms, three studies on mice in Alzheimer´s disease mouse models already showed PBM-induced stimulation of beta-amyloid-clearance from the brain [11-13]. Feel free to check the literature below for an even deeper dive.
What other mechanisms might be at play?
In addition to the importance of the glymphatic system, research also focuses on the connection between photobiomodulation and neural oscillations. There is now solid evidence that applying different wavelengths can significantly change the oscillatory activity in neurons [14]. Dementia and Alzheimer´s disease are often associated with dysrhythmic gamma waves [15]. Accordingly, treatment parameters that increase gamma amplitudes may be effective interventions in such cases. Indeed, light of 810nm, pulsed at 40Hz, could already successfully enhance gamma waves in an exploratory pilot study on humans that was published in Nature [16].
A brief summary and outlook
The study results that were published so far are consistently positive and not only include beneficial effects for the actual patients, but also suggest that caregivers can benefit from the improved independence of the patients. However, the results are limited by the relatively small sample sizes and it is not yet clear which stages of disease progression can be treated effectively. More research is already on the way and I personally believe that this treatment will evolve into standard care for dementia and Alzheimer´s patients over the next few years.
How to obtain more information?
Simply make contact with me - best through LinkedIn or email - to obtain more information about all the above.
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Disclaimer
I’m not a medical professional and the above is not meant as medical advice, I’m merely sharing my personal understanding of the subject.
Literature
[1] https://www.who.int/news-room/fact-sheets/detail/dementia
[2] Salehpour, F., Khademi, M., & Hamblin, M. R. (2021). Photobiomodulation Therapy for Dementia: A Systematic Review of Pre-Clinical and Clinical Studies. Journal of Alzheimer's disease : JAD, 83(4), 1431–1452.
https://pubmed.ncbi.nlm.nih.gov/33935090/
[3] Nizamutdinov, D., Qi, X., Berman, M. H., Dougal, G., Dayawansa, S., Wu, E., Yi, S. S., Stevens, A. B., & Huang, J. H. (2021). Transcranial Near Infrared Light Stimulations Improve Cognition in Patients with Dementia. Aging and disease, 12(4), 954–963.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219492/
[4] Kheradmand, A., Donboli, S., Tanjani, P. T., Farhadinasab, A., Tabeie, F., Qutbi, M., & Kordmir, T. (2022). Therapeutic Effects of Low-Level Laser Therapy on Cognitive Symptoms of Patients with Dementia: A Double-Blinded Randomized Clinical Trial. Photobiomodulation, photomedicine, and laser surgery, 40(9), 632–638.
https://pubmed.ncbi.nlm.nih.gov/36126290/
[5] Blivet, G., Relano-Gines, A., Wachtel, M., & Touchon, J. (2022). A Randomized, Double-Blind, and Sham-Controlled Trial of an Innovative Brain-Gut Photobiomodulation Therapy: Safety and Patient Compliance. Journal of Alzheimer's disease : JAD, 90(2), 811–822.
https://pubmed.ncbi.nlm.nih.gov/36189591/
[6] Spera, V., Sitnikova, T., Ward, M. J., Farzam, P., Hughes, J., Gazecki, S., Bui, E., Maiello, M., De Taboada, L., Hamblin, M. R., Franceschini, M. A., & Cassano, P. (2021). Pilot Study on Dose-Dependent Effects of Transcranial Photobiomodulation on Brain Electrical Oscillations: A Potential Therapeutic Target in Alzheimer's Disease. Journal of Alzheimer's disease : JAD, 83(4), 1481–1498.
https://pubmed.ncbi.nlm.nih.gov/34092636/
[7] Vrankic, M., Vlahinić, S., Šverko, Z., & Markovinović, I. (2022). EEG-Validated Photobiomodulation Treatment of Dementia-Case Study. Sensors (Basel, Switzerland), 22(19), 7555.
https://pubmed.ncbi.nlm.nih.gov/36236654/
[8] Bathini, M., Raghushaker, C. R., & Mahato, K. K. (2022). The Molecular Mechanisms of Action of Photobiomodulation Against Neurodegenerative Diseases: A Systematic Review. Cellular and molecular neurobiology, 42(4), 955–971.
https://pubmed.ncbi.nlm.nih.gov/33301129/
[9] Valverde, A., Hamilton, C., Moro, C., Billeres, M., Magistretti, P., & Mitrofanis, J. (2023). Lights at night: does photobiomodulation improve sleep?. Neural regeneration research, 18(3), 474–477.
[10} Salehpour, F., Khademi, M., Bragin, D. E., & DiDuro, J. O. (2022). Photobiomodulation Therapy and the Glymphatic System: Promising Applications for Augmenting the Brain Lymphatic Drainage System. International journal of molecular sciences, 23(6), 2975.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8950470/
[11] Zinchenko, Ekaterina & Klimova, Maria & Mamedova, Aysel & Agranovich, Ilana & Blokhina, Inna & Antonova, Tatiana & Terskov, Andrey & Shirokov, Alexander & Navolokin, Nikita & Morgun, A. & Osipova, Elena & Boytsova, Elizaveta & Yu, Tingting & Zhu, Dan & Kurths, Juergen & Semyachkina-Glushkovskaya, Oxana. (2020). Photostimulation of Extravasation of Beta-Amyloid through the Model of Blood-Brain Barrier. Electronics. 9. 1056. 10.3390/electronics9061056.
[12] Semyachkina-Glushkovskaya O., Klimova M., Iskra T., Bragin D., Abdurashitov A., Dubrovsky A., Khorovodov A., Terskov A., Blokhina I., Lezhnev N., et al. Transcranial Photobiomodulation of Clearance of Beta-Amyloid from the Mouse Brain: Effects on the Meningeal Lymphatic Drainage and Blood Oxygen Saturation of the Brain. Adv. Exp. Med. Biol. 2021;1269:57–61. doi: 10.1007/978-3-030-48238-1_9.
[13] Zinchenko E., Navolokin N., Shirokov A., Khlebtsov B., Dubrovsky A., Saranceva E., Abdurashitov A., Khorovodov A., Terskov A., Mamedova A., et al. Pilot study of transcranial photobiomodulation of lymphatic clearance of beta-amyloid from the mouse brain: Breakthrough strategies for non-pharmacologic therapy of Alzheimer’s disease. Biomed. Opt. Express. 2019;10:4003–4017. doi: 10.1364/BOE.10.004003.
[14] Liebert, A., Capon, W., Pang, V., Vila, D., Bicknell, B., McLachlan, C., & Kiat, H. (2023). Photophysical Mechanisms of Photobiomodulation Therapy as Precision Medicine. Biomedicines, 11(2), 237.
https://pubmed.ncbi.nlm.nih.gov/36830774/
[15] Mably, A.J.; Colgin, L.L. Gamma oscillations in cognitive disorders. Curr. Opin. Neurobiol. 2018, 52, 182–187.
[16] Zomorrodi, R., Loheswaran, G., Pushparaj, A. et al. Pulsed Near Infrared Transcranial and Intranasal Photobiomodulation Significantly Modulates Neural Oscillations: a pilot exploratory study. Sci Rep 9, 6309 (2019).
Good to understand combined with the necessary background. I imagine this information could be very helpful for people in such a situation. This article should definitely be more spread!