Serotonin loss may contribute to cognitive decline in the early stages of Alzheimer's disease

Comparing PET scans of more than 90 adults with and without mild cognitive impairment (MCI), Johns Hopkins Medicine researchers say relatively lower levels of the so-called "happiness" chemical, serotonin, in parts of the brain of those with MCI may play a role in memory problems including Alzheimer's disease.

The findings, first published online Sept. 13 in the Journal of Alzheimer's Disease, lend support to growing evidence that measurable changes in the brain happen in people with mild memory problems long before an Alzheimer's diagnosis, and may offer novel targets for treatments to slow or stop disease progression.

"The study shows that people with mild cognitive impairment already display loss of the serotonin transporter. This measure that reflects serotonin degeneration is associated with problems with memory, even when we take into account in our statistical model MRI measures of neurodegeneration and PET measures of the amyloid protein that are associated with Alzheimer's Disease," says Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

MCI describes the diagnostic stage between normal brain function in aging and Alzheimer's Disease (AD). Symptoms of MCI include frequent forgetfulness of recent events, word finding difficulty, and loss of the sense of smell.

Those with MCI may stay in this stage indefinitely, or progress to more severe forms of cognitive deficits, giving urgency to the search for predictive markers, and possible early prevention interventions, investigators say.

The investigators cautioned that their study showed a correlation between lower serotonin transporter levels and memory problems in MCI, and was not designed to show causation or the role of serotonin in the progression from MCI to AD. To answer these questions, further research is needed to study over time healthy controls and individuals with MCI to demonstrate the role of serotonin in disease progression.

For the study, the Hopkins scientists recruited 49 volunteers with MCI, and 45 healthy adults ages 55 and older who underwent an MRI to measure changes in brain structure and two positron emission tomography (PET) scans of their brains at Johns Hopkins between 2009 and 2022.

The research team used PET scans to look specifically at the serotonin transporter -- a neurotransmitter, or brain chemical long associated with positive mood, appetite and sleep -- and to look at the amyloid-beta protein (Aβ) distribution in the brain.

Aβ is thought to play a central role in the pathology of AD. Studies in mice done at Johns Hopkins have shown that serotonin degeneration occurs before the development of widespread beta-amyloid deposits in the brain.

Loss of serotonin is often associated with depression, anxiety, and psychological disorders.

Researchers found that MCI patients had lower levels of the serotonin transporter, and higher levels of Aβ than healthy controls.

The MCI patients had up to 25% lower serotonin transporter levels in cortical and limbic regions than healthy controls.

In particular, they report, lower serotonin transporter levels were found in cortical, limbic, and subcortical regions of the brains in those with MCI, areas specifically responsible for executive function, emotion, and memory.

"The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms," says Smith.

"If we can show that serotonin loss over time is directly involved in the transition from MCI to AD, recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and thus, may be a powerful way forward to slow disease progression."

Researchers say future studies include longitudinal follow up of individuals with MCI to compare serotonin degeneration to the increase in and Aβ levels, as well as the increase in levels of the Tau protein that is also associated with AD compared to healthy adults.

They are also studying multi-modal antidepressant drugs to treat depression and memory deficits in hopes of mitigating and halting symptoms.

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Musical tests can detect mental deterioration in old age

Researchers at Tel Aviv University have developed a method that employs musical tests and a portable instrument for measuring brain activity to detect cognitive decline in old age. According to the researchers, the method, which is based on the measurement of 15 minutes of electrical activity in the brain while performing simple musical tasks, can be easily implemented by any staff member in any clinic, without requiring special training.

The researchers: "Our method enables routine monitoring and early detection of cognitive decline in order to provide treatment and prevent rapid, severe deterioration. Prophylactic tests of this kind are commonly accepted for a variety of physiological problems such as diabetes, high blood pressure or breast cancer; however, to date no method has yet been developed to enable routine, accessible monitoring of the brain for cognitive issues." The researchers further note that tests of this kind are particularly important in light of increasing longevity and associated growth of the elderly population.

The study was led at Tel Aviv University by PhD student Neta Maimon from the School of Psychological Sciences and the Buchmann-Mehta School of Music, and Lior Molcho from Neurosteer Ltd, headed by Prof. Nathan Intrator from the Blavatnik School of Computer Science and the Sagol School of Neuroscience. Other participants included: Adi Sasson, Sarit Rabinowitz, and Noa Regev-Plotnick from the Dorot-Netanya Geriatric Medical Center. The article was published in the journal Frontiers in Aging Neuroscience.

As part of the study, the researchers developed a groundbreaking method combining a portable device for the measurement and innovative analysis of electroencephalography (EEG), developed by Neurosteer, and a short musical test of about 12-15 minutes, developed by Neta Maimon. During the test, the subject is connected to the portable EEG device by means of a adhesive band with only three electrodes attached to the forehead. The subject performs a series of musical-cognitive tasks according to audible instructions given automatically through earphones. The tasks include short melodies played by different instruments, with the subjects instructed to perform various tasks on them at varying levels of difficulty. For example, pressing a button each time any melody is played or pressing it only when the violin plays. In addition, the test includes several minutes of musically guided meditation designed to bring the brain to a resting state, as this state is known to indicate cerebral functioning in various situations.

Neta Maimon, who specializes in musical cognition, explains that music has great influence on different centers in the brain. On the one hand, music is known to be a quick mood stimulant, particularly of positive emotion. On the other hand, in different situations, music can be cognitively challenging, activating the frontal parts of the brain, especially if we try to concentrate on different aspects of the music, and at the same time perform a particular task.

According to Maimon, if we combine these two capabilities, we can create cognitive tests that are quite complex, yet also pleasant and easy to perform. Furthermore, music that is positive and reasonably rhythmic will enhance concentration and performance of the task. Thus, for example, the famous "Mozart effect," showing improved performance on intelligence tests after listening to Mozart's music, actually has nothing to do with Mozart's music, but rather the fact that music creates a positive mood and stimulates us to a state that is optimal for performing intelligence and creativity tests.

Accordingly, the researchers hypothesized that with musical tools, it would also be possible to challenge the subjects to an extent that would enable testing of the brain's frontal activity as well as raising their spirits, thus enhancing their performance on the test while the overall experience is pleasant.

The study included an experiment at the Dorot-Netanya Geriatric Medical Center. Neta Maimon: "Anyone hospitalized at Dorot, or any other geriatric rehabilitation institution, undergoes a standard test called "mini-mental," designed to evaluate their cognitive condition as a routine part of the intake process. The test is conducted by an occupational therapist specially trained for it, and includes a variety of tasks. For example, enumerating the days of the week or months of the year backwards. In this test, up to 30 points can be accrued. A high score indicates normal cognition.

The experiment included the testing of 50 elderly people hospitalized at Dorot who scored 18-30 on the mini-mental test, indicating various levels of cognitive functioning. The participants performed the musical-cognitive tasks, administered automatically. The EEG device registered the electrical activity in the brain during the activity, with the results analyzed using machine learning technology. This allowed mathematical indices to be identified that were precisely correlated with the mini-mental test scores; in other words, we obtained new neuro-markers (brain markers) that may stand alone as indices of the subject's cognitive status.

Maimon adds: "We have actually succeeded in illustrating that music is indeed an effective tool for measuring brain activity. The brain activity and response times to tasks correlated to the subjects' cerebral conditions (correlating to the mini-mental score assigned to them). More importantly, all those who underwent the experiment reported that, on the one hand, it challenged the brain, but on the other it was very pleasant to perform."

The researchers conclude: "Our method enables the monitoring of cognitive capability and detection of cognitive decline already in the early stages. all by simple and accessible means, with a quick and easy test that can be conducted in any clinic. This method is of special importance today due to the increase in longevity and accelerated population growth, particularly among the elderly. Today, millions of people around the world already suffer or are liable to suffer soon from cognitive decline and its dire consequences, and their number will only increase in the coming decades. Our method could pave the way towards efficient cognitive monitoring of the general population, and thus detect cognitive decline in its early stages, when treatment and prevention of severe decline are possible. It is therefore expected to improve the quality of life of millions around the world."

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Cases of cognitive decline in older people more than doubles in ten years

The researchers set out to see if there had been an increase in the numbers of older people who were reporting their first concerns about memory loss or cognitive decline to their doctor and what their chances of developing dementia were after consultation.

The study, published today in Clinical Epidemiology, looked at data from more than 1.3m adults aged between 65 and 99 years old, taken between 2009 and the end of 2018. The researchers identified 55,941 adults who had spoken to their GP about memory concerns and 14,869 people who had a record of cognitive decline.

For every 1,000 people that were observed for one year in 2009, there was one new case of cognitive decline being recorded. By 2018, for every 1,000 people that were observed for one year, there were three new cases of cognitive decline being recorded.

Lead author and PhD candidate Brendan Hallam (UCL Epidemiology & Health Care) said: "This is an important study which sheds new light on how prevalent memory concerns and cognitive decline are among the older generation in the UK and how likely these symptoms might progress to a dementia diagnosis.

"The study showed that while memory concern rates had remained stable, incidence of cognitive decline, a step beyond memory concern, had more than doubled between 2009 and 2018.

"There has been a drive in the past decade to encourage people to seek help earlier from their doctors if they are worried about their memory and we found that among those over 80, women and people living in more deprived areas were more likely to have a record of memory concern or cognitive decline, and their symptoms were more likely to progress to dementia diagnosis."

The study also showed that within three years of following up a person from the date when the doctor reported a memory concern, 46% of people would go on to develop dementia. For people with cognitive decline, 52% would go on to develop dementia.

Co-author, Professor Kate Walters (UCL Epidemiology & Health Care) explained: "People who have been noted in their health records as having concerns about their memory are at just under 50% chance of developing dementia within the next three years."

Brendan Hallam also outlined "Memory concerns and cognitive decline are not only hallmark symptoms of dementia, but they also predict a high risk of developing dementia. It is important for GPs to identify people with memory concerns as soon as possible to deliver recommendations to improve memory and allow timely diagnosis of dementia."

The authors note one potential limitation of the present study is the potential variations in which GPs record memory concerns and memory decline. They also say more research is needed to better understand the discrepancy between rates of memory symptoms and cognitive decline in the general population and those recorded in primary care.

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