Researchers at HSE University and the Russian Academy of Sciences Institute of Molecular Biology have proposed investigating the response of the blood-brain barrier (BBB), the brain's natural filter that becomes disrupted by the disease, to transcranial brain stimulation. Understanding how the BBB changes during stimulation can, in theory, enhance treatment by facilitating more effective delivery of medications to the brain in the early stages of the disease, and by providing therapeutic support for brain function in the latter stages. The study has been published in Communications Biology.
Dementia, or acquired cognitive impairment, is characterized by a gradual decline in the brain's cognitive functions, including thinking, memory, attention, and coordination, as well as emotional and behavioural changes that lead to a disintegration of personality. According to WHO estimates, over 55 million people worldwide are affected by dementia, with an additional 10 million new cases emerging every year. This number is likely to increase, since the main risk factor for the disease is ageing, and the proportion of the elderly population on the planet is growing.
The most common form of dementia is Alzheimer's disease, accounting for 60% to 70% of cases. The hallmarks of Alzheimer's disease are beta-amyloid and tau proteins — molecules that form extracellular and intracellular aggregates, leading to neuron death and subsequent loss of cognitive functions. There is no cure for the disease, and the patient's condition will gradually worsen over 7-10 years. They will experience problems with memory, speech and thinking, and lose the ability to recognize loved ones, to control emotions, to navigate their surroundings, and to take care of themselves.
Researchers are continuing to search for a cure or, at the very least, ways to mitigate the symptoms of the disease. A team which included HSE researchers conducted a systematic review of approximately 40 papers on the topic published over the past 20 years. Based on their findings, the team suggested that brain stimulation can influence the integrity of the blood-brain barrier.
Disruption of the BBB is one of the markers of Alzheimer's, occurring prior to the onset of symptoms. The BBB system normally functions as a filter, preventing toxic substances from entering the nervous tissue from the bloodstream, while allowing essential nutrients to pass through. With Alzheimer's disease, the BBB's functioning is disrupted, enabling pathogens to enter the brain and accumulate there.
Non-invasive brain stimulation techniques, primarily transcranial magnetic stimulation and transcranial direct current stimulation can be used to modulate BBB permeability. The magnetic stimulation procedure relies on the rhythmic action of a magnetic field, while the direct current stimulation employs a weak electric current.
The authors suggest that the alteration in BBB integrity resulting from stimulation can be used to enhance the effectiveness of drug delivery in the early stages. However, in advanced stages, such stimulation should be applied with caution, as the potential disruption of the BBB could exacerbate the disease.
The impact of stimulation on cognitive functions is being actively studied, which is particularly crucial for patients with Alzheimer's disease. However, the potential variability in the effects of stimulation depending on BBB integrity is often overlooked. We maintain that investigating the effects of BBB stimulation in Alzheimer's disease can enhance the efficacy of its pharmacological treatment. In addition to this, further research is essential for a better understanding of the safety of stimulation in advanced stages of the disease, when the BBB condition deteriorates dramatically.
No systematic analysis of the effect of stimulation on Alzheimer's-related factors in endothelial cells has yet been conducted, but some data on neurons and glial cells is available. According to a study by Chinese researchers, repetitive transcranial magnetic stimulation can have a neuroprotective effect. In particular, the expression of the IL-10 gene acting as an anti-inflammatory mediator increased in astrocyte cell culture after exposure to pulses with a frequency of 10 Hz.
Conversely, in another set of studies, stimulation resulted in the opening of the BBB. This approach can be beneficial for drug delivery in cases of illness. Magnetic stimulation was found to increase the BBB permeability in rats and also in a group of human patients with malignant brain tumours. More recently, while testing the potential for opening the BBB in an animal model, repetitive low-frequency transcranial stimulation was applied to the right hemisphere of rats, resulting in an 18% increase in BBB permeability after just 15 minutes of stimulation.
However, at the time of writing, no studies have examined the impact of stimulating the BBB endothelium in Alzheimer's models. To enhance the reproducibility of studies involving brain stimulation, it is essential to translate the effects from cellular to animal to human models. Studies conducted on cellular and animal models can demonstrate how brain cell stimulation, depending on the parameters used, impacts their functioning. However, further detailed research is needed to determine how it specifically affects the BBB in patients with Alzheimer's disease.
In order to extrapolate the findings from in vitro and in vivo animal studies to humans, it is necessary to investigate the effects of stimulation on key components of Alzheimer's pathology. This includes studying changes in extracellular and intracellular ion concentrations, as well as alterations in beta-amyloids and tau proteins. We believe that further studies should address the effects of BBB stimulation in both Alzheimer's disease and healthy aging. Considering that a large pool of cerebral blood vessels is located on the surface of the cortex and is readily accessible for stimulation, this approach can serve as a relatively straightforward and informative method.
Чтобы экстраполировать результаты исследований на животных in vitro и in vivo на людей, необходимо изучить влияние стимуляции на ключевые компоненты патологии Альцгеймера, такие как изменения концентрации вне- и внутриклеточных ионов, бета-амилоидов и тау-белка. Мы считаем, что исследования должны рассмотреть влияние стимуляции на ГЭБ как при болезни Альцгеймера, так и при здоровом старении. Учитывая, что большая часть мозговых кровеносных сосудов расположена на поверхности коры и хорошо доступна для стимуляции, это относительно простой и информативный метод.
* At the time of paper preparation