Dementia is thought to occur when proteins called amyloid-β, tau, and α-synuclein accumulate in the brain and form oligomers. A research group from the Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, had previously shown in a study using mice that the antibiotic rifampicin removes oligomers from the brain and improves cognitive function.
However, the drug has been associated with side effects such as liver damage. Resveratrol, a naturally occurring antioxidant in plants, is used as a supplement in Europe and the United States. “To combat the negative side effects of the existing drug rifampicin, we thought of combining it with the hepatoprotective effects of resveratrol,” illustrates Professor Takami Tomiyama, who acted as lead investigator for the current study.
This time, the research group administered a fixed dose combination of rifampicin and resveratrol intranasally five days a week for a total of four weeks to mice models of Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies, and observed their cognitive functions and brain pathology. The results showed that the combination significantly improved the cognitive function of the mice, inhibited the accumulation of oligomers, and restored synaptophysin levels – presynaptic proteins that facilitate synapses. Additionally, blood levels of liver enzymes, a marker of hepatic damage that normally increases with rifampicin, remained normal in the fixed-dose combination. Furthermore, increased levels of brain-derived neurotrophic factor (BDNF) expression were observed in the hippocampus, which was not seen with rifampicin alone. These results indicate that this fixed-dose combination is superior to rifampicin alone in terms of both safety and efficacy.
The results of this study were published online in the Swiss scientific journal Frontiers in Neuroscience on December 13, 2021.
“The number of patients with dementia has been increasing all over the world, with some sources predicting a doubling of patients every 20 years. However, there is still no effective treatment for the disease,” states Specially Appointed Lecturer Tomohiro Umeda, first author of the study. “Recent studies have shown that abnormalities begin to appear in the brains of dementia patients more than 20 years before the onset of the disease.” By investigating new therapeutic purposes with existing drugs in a process called drug repositioning, the research team hopes to diagnose and prevent dementia before the neurons start dying.
Furthermore, based on the team’s previous research experience, nasal administration of a fixed dose combination of rifampicin and resveratrol would increase drug transferability to the brain and further enhance both safety and medicinal effects. The dosage used in this study was 0.02 mg of rifampicin per mouse per day, or 1 mg/kg/day assuming a mouse weight of 20g. “Converted to a human dosage based on body surface area, it becomes 0.081 mg/kg/day,” states Prof. Tomiyama, “currently, rifampicin is prescribed at 10 mg/kg/day as an antibiotic, and compared to this, we confirmed an effect at a much lower dosage.”
The development of a fixed-dose combination of rifampicin and resveratrol nasal spray is currently being carried out by Medilabo RFP, a venture company originating from the research team’s laboratory. Following the publication of this paper, Medilabo RFP has begun preparations for global clinical trials. In November 2021, with the support of the Japan External Trade Organization (JETRO), Medilabo RFP has established a subsidiary in Massachusetts, USA.
Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — to such an extent that it interferes with a person’s daily life and activities. Some people with dementia cannot control their emotions, and their personalities may change. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person’s functioning, to the most severe stage, when the person must depend completely on others for basic activities of living.
Dementia is more common as people grow older (about one-third of all people age 85 or older may have some form of dementia) but it is not a normal part of aging. Many people live into their 90s and beyond without any signs of dementia.
There are several different forms of dementia, including Alzheimer’s disease. A person’s symptoms can vary depending on the type.
What are the signs and symptoms of dementia?
Signs and symptoms of dementia result when once-healthy neurons, or nerve cells, in the brain stop working, lose connections with other brain cells, and die. While everyone loses some neurons as they age, people with dementia experience far greater loss.
The symptoms of dementia can vary and may include:
- Experiencing memory loss, poor judgment, and confusion
- Difficulty speaking, understanding and expressing thoughts, or reading and writing
- Wandering and getting lost in a familiar neighborhood
- Trouble handling money responsibly and paying bills
- Repeating questions
- Using unusual words to refer to familiar objects
- Taking longer to complete normal daily tasks
- Losing interest in normal daily activities or events
- Hallucinating or experiencing delusions or paranoia
- Acting impulsively
- Not caring about other people’s feelings
- Losing balance and problems with movement
People with intellectual and developmental disabilities can also develop dementia as they age, and recognizing their symptoms can be particularly difficult. It’s important to consider a person’s current abilities and to monitor for changes over time that could signal dementia.
What causes dementia?
The causes of Alzheimer’s and related dementias can vary, depending on the types of brain changes that may be taking place. While research has found that some changes in the brain are linked to certain forms of dementia, in most cases, the underlying causes are unknown. Rare genetic mutations may cause dementia in a relatively small number of people.
What are the different types of dementia?
Various disorders and factors contribute to the development of dementia. Neurodegenerative disorders result in a progressive and irreversible loss of neurons and brain functioning. Currently, there are no cures for these diseases.
The five most common forms of dementia are:
- Alzheimer’s disease, the most common dementia diagnosis among older adults. It is caused by changes in the brain, including abnormal buildups of proteins, known as amyloid plaques and tau tangles.
- Frontotemporal dementia, a rare form of dementia that tends to occur in people younger than 60. It is associated with abnormal amounts or forms of the proteins tau and TDP-43.
- Lewy body dementia, a form of dementia caused by abnormal deposits of the protein alpha-synuclein, called Lewy bodies.
- Vascular dementia, a form of dementia caused by conditions that damage blood vessels in the brain or interrupt the flow of blood and oxygen to the brain.
- Mixed dementia, a combination of two or more types of dementia.
How is dementia diagnosed?
To diagnose dementia, doctors first assess whether a person has an underlying, potentially treatable, condition that may relate to cognitive difficulties. A physical exam to measure blood pressure and other vital signs, as well as laboratory tests of blood and other fluids to check levels of various chemicals, hormones, and vitamins, can help uncover or rule out possible causes of symptoms.
The following procedures also may be used to diagnose dementia:
- Cognitive and neurological tests. These tests are used to assess thinking and physical functioning. These include assessments of memory, problem solving, language skills, and math skills.
- Brain scans. These tests can identify Strokes , tumors, and other problems that can cause dementia. Scans also identify changes in the brain’s structure and function. The most common scans are:
- Computed tomography (CT), which uses X-rays to produce images of the brain and other organs
- Magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to produce detailed images of body structures, including tissues, organs, bones, and nerves
- Positron emission tomography (PET), which uses radiation to provide pictures of brain activity
- Psychiatric evaluation. This evaluation will help determine if depression or another mental health condition is causing or contributing to a person’s symptoms.
- Blood tests. It is now possible for doctors to order a blood test to measure levels of beta-amyloid, a protein that accumulates abnormally in people with Alzheimer’s. Several other blood tests are in development. However, the availability of these diagnostic tests for Alzheimer’s and related dementias is still limited.
Early detection of symptoms is important, as some causes can be treated. However, in many cases, the cause of dementia is unknown and cannot be treated. Still, obtaining an early diagnosis can help with managing the condition and planning ahead.
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