Brain scan study adds to evidence that lower brain serotonin levels are linked to dementia

In a study looking at brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter—a natural brain chemical that regulates mood, sleep, and appetite. Their results, the researchers say, suggest that lower serotonin transporters may be drivers of the disease rather than a byproduct.

A report on the study, published in Neurobiology of Disease, also suggests that finding ways to prevent the loss of serotonin or introducing a substitute neurotransmitter could slow or stop the progression of Alzheimer's disease and perhaps other dementias.

"Now that we have more evidence that serotonin is a chemical that appears affected early in cognitive decline, we suspect that increasing serotonin function in the brain could prevent memory loss from getting worse and slow disease progression," says Gwenn Smith, professor of psychiatry and behavioral sciences and director of geriatric psychiatry and neuropsychiatry at the School of Medicine.

Smith notes that researchers have tried with limited success to treat Alzheimer's disease and cognitive impairment with antidepressants such as SSRIs, which bind to the serotonin transporters and block the brain's "reuptake" of the chemical. But because these transporters are at much lower levels in people with Alzheimer's, she speculates that the drugs can't serve their purpose without their target.

The Johns Hopkins research team paired 28 participants with mild cognitive impairment, which may be an early harbinger of Alzheimer's disease or other forms of dementia, with 28 healthy matched controls. People with mild cognitive impairment were defined as those who have a slight decline in cognition, mainly in memory in terms of remembering sequences or organization, and who score lower on tests such as the California Verbal Learning Test, which requires participants to recall a list of related words, such as a shopping list. According to Smith, the inability to do this test accurately reflects changes in memory and cognitive impairment indicative of Alzheimer's disease.

Participants were an average age of 66 and about 45 percent were women.

Each participant underwent an MRI and PET scan to measure brain structures and levels of the serotonin transporter. During the PET scans, participants were given a chemical—similar in structure to an antidepressant but not a high enough dose to have a pharmacological effect—labeled with a radioactive carbon. The chemical binds to the serotonin transporter and the PET scanner detects the radioactivity.

The researchers found that people with mild cognitive impairment had up to 38 percent less of the serotonin transporter detected in their brains compared to each of their age-matched healthy controls. And not a single person with mild cognitive impairment had higher levels of the serotonin transporter compared to their healthy control.

Each participant also underwent learning and memory tests. In the California Verbal Learning Test, on a scale of 0 to 80, with 80 reflecting the best memory, the healthy participants had an average score of 55.8, whereas those with mild cognitive impairment scored an average of 40.5. During a Brief Visuospatial Memory Test, participants were shown a series of shapes to remember and draw later. From a scale of 0 to 36, with 36 being the top score, healthy people scored an average of 20.0 and those with mild cognitive problems scored an average of 12.6.

The idea for Smith's study was inspired by the work of co-author Alena Savonenko, an associate professor of pathology who showed that loss of serotonin neurons was associated with more protein clumps, or amyloid, in mouse brains. Savonenko and Smith say their group will investigate whether PET imaging of serotonin could be a marker to detect progression of disease, whether alone or in conjunction with scans that detect amyloid, which has also been shown to accumulate in the brains of those with Alzheimer's disease.