Dementia or progressive loss of memory and brain functions affects millions worldwide with an increase in the number of elderly people. In England there are 570,000 people living with some forms of dementia. This increase is expected to continue over the next three decades due to the increase in the elderly population and the increase in life expectancy. Usually dementia occurs in people aged 65 or over, very rarely after age 40. Dementia can be of different types depending on the characteristics, symptoms and severity. Alzheimer’s disease is where small groups of proteins, known as plaques, start to develop around the brain cells. This could cause serious memory loss over time. Vascular dementia (cerebrovasculopathy) occurs when there are problems with the supply of blood to the brain, which does not receive adequate oxygen. Frontotemporal dementia is said to occur when the frontal and temporal lobes (two parts of the brain) begin to contract. Dementia with Lewy bodies is another form of dementia in which small abnormal structures, known as Lewy bodies, develop within the brain. There is no cure for dementia. In most patients the symptoms get worse over time. Researchers at Johns Hopkins University examined brain scans of people with mild loss of thought and memory, and found that they have significantly lower levels of serotonin in their brains. Serotonin is a brain neurotransmitter responsible for various functions including mood, sleep and appetite and is also important for different mental health conditions. There have been previous studies that have shown that people with Alzheimer’s disease and those with severe cognitive decline tend to have lower levels of serotonin.
However, no study could quantify or explain the phenomenon and it is not clear whether low serotonin caused serotonin decline. This new study of people with early stages of memory decline showed conclusively that the loss of serotonin was causing memory loss rather than the other way around. The study was published together with a report that states that if you could determine ways to stop or slow down the loss of serotonin, or introduce a chemical substitute in the brain, the progression of Alzheimer’s and other dementias could be much slower. Gwenn Smith, professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of psychiatric geriatrics and neuropsychiatry, said this study provides us with evidence that we needed low levels of serotonin to be the reason for brain cognitive decline. The comprehensively enhanced serotonin function in the brain could be the key to preventing memory loss and also slowing the progression of these diseases. In a normal brain when a message arrives through a neuron, the neuron releases the serotonin at its extremity. This is detected by the next neuron receiving the message. Once the message has been propagated, there is a SERT (serotonin transporter) that collects the serotonin and returns it to the neuron that sends the message. This looks like the chemical flow of serotonin.
Neurons and serotonin transporters reduce with age in normal people. Because neurons die with age, SERTs also reduce their number. A group of drugs that improve brain serotonin levels are the drugs that block the cerebral reuptake of serotonin (known as SSRIs or selective serotonin reuptake inhibitors). These medications are useful in patients with depression and some forms of anxiety. They can significantly influence mood. According to Smith, with this idea in mind, researchers have already tried to treat Alzheimer’s disease and other diseases of cognitive decline with SSRIs, but they have had limited success. But these drugs require an adequate number of serotonin or SERT transporters in the brain to function, he noted, and this was lacking among those with cognitive decline. This is probably the reason why SSRIs do not show as much success as expected. For this study, the researchers looked at tomography scans (PET) of participants with mild cognitive problems. These mild cognitive problems usually lead to severe forms of dementia and Alzheimer’s disease. Participants were recruited using advertisements and flyers and also from the Johns Hopkins Memory and Alzheimer’s Treatment Center. There were 28 participants with mild cognitive impairment that were matched to 28 healthy participants for comparison. The participants were all aged about 66 years and 45% of the participant population was female.
Mild cognitive impairment was defined for the study as a slight decline in cognition, including memory loss, recalling sequences or organization, and those who scored low in the California Verbal Learning Test that asked participants to remember related words for example from a shopping list. The average scores of the learning and memory tests, in particular the California Verbal Learning Test, on a scale from 0 to 80, showed an average score of 55.8 healthy participants and an average of 40.5 among those with mild cognitive impairment. Another memory test was the Brief Visuospatial Memory Test in which the participants showed a series of shapes and had to redraw them from memory later. On a scale of 0 to 36, healthy participants achieved an average of 20.0 while those with mild cognitive problems averaged 12.6. Once diagnosed and grouped, these participants underwent magnetic resonance and PET to measure the brain structures and levels of serotonin transporters. To detect the serotonin transporters, patients took a drug that had a radioactive carbon label at a dose low enough to cause no effect. The chemical is bound to the serotonin transporter and the PET scanner has collected the branding. The researchers in this study found that people with mild cognitive impairment had up to 38% less SERT in their brains than the corresponding healthy controls that were of the same age.
This means that this loss of SERT has more to do with pathology than with age, the researchers explain. None of the people with mild cognitive impairment had higher levels of SERT than their healthy control. The scores of the two memory tests and the results of the PET scan were compared later. They noted that lower serotonin transporters were associated with lower test scores. Scientists are aware of 14 types of serotonin receptors that could become potential new targets for drug development in dementia. The study is published in the September issue of the journal Neurobiology of Disease.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Khoury R et al. Expert Opin Investig Drugs. 2018 Jun;27(6):523-533.
Joling M, Vriend C et al. Neuroimage Clin. 2018 Apr 6;19:130-136.
Kongpakwattana K et al. Br J Clin Pharmacol. 2018 Jul;84(7):1445.
Chen KH, Reese E et al. J Alzheimers Dis. 2011;26(4):755-66.