Serotonin Levels Linked to Iron Buildup in Dopamine Brain Region

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by Steve Bryson, PhD |

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Low levels of the hormone serotonin in the bloodstream of people with Parkinson’s disease were associated with a buildup of iron in the substantia nigra — the brain region most damaged in this disorder, a study reveals for possibly the first time.

Researchers found this serotonin-iron relationship was primarily seen in early disease stages, was linked to a common set of clinical assessments, and was strongly associated with the use of medications to treat anxiety and depression.

“We propose that these findings lend further support for a serotonin-iron relationship in the [Parkinson’s disease] process and indicate a potential biochemical basis for the link between depression and nigral iron accumulation in … patients,” the scientists wrote.

The study, “Low plasma serotonin linked to higher nigral iron in Parkinson’s disease,” was published in the journal Nature Scientific Reports.

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Parkinson’s is caused by the loss of neurons (nerve cells) in the substantia nigra, a region of the midbrain. Neurons in this region that release the signaling molecule dopamine are primarily affected, leading to the disease’s characteristic symptoms.

Iron buildup in the brain is common with aging but can be greater in Parkinson’s patients — particularly in the substantia nigra — suggesting that excess iron may play a role in the loss of dopamine-producing neurons.

Serotonin, a key hormone that stabilizes mood, feelings of well-being, and happiness, is also often lower in the blood of Parkinson’s patients and thought to contribute to the high rate of clinical depression among them.

Although iron accumulation and low serotonin levels have been studied independently in people with Parkinson’s, recent reports suggest they may be closely related.

To investigate further, researchers based at Penn State University designed a study to examine a potential connection between iron and serotonin in patients.

“In the present study, we tested the hypothesis that lower serotonin would be associated with higher nigral iron in [Parkinson’s disease] patients, even in early-stage disease,” the team wrote. (Nigral iron refers to this mineral’s presence specifically in the substantia nigra, Latin for “black substance” due to its darker color — relative to other brain regions — reflecting the melanin pigment of its dopaminergic neurons.

Scientists collected blood samples and clinical data from 97 Parkinson’s patients (53% female) and 89 healthy age- and sex-matched people serving as controls. MRI scans were obtained from 62 patients and 70 controls who completed a scan with good imaging quality.

Patients were prescribed medications for depression and anxiety at a rate four times higher than control participants (32% vs. 8%).

Blood tests showed that Parkinson’s patients had significantly lower serotonin levels in their bloodstream than controls overall, with about one-third of patients having extremely low concentrations. The serotonin levels ranged widely in the remaining patients, some within the normal range.

Although blood-clotting platelets transport and store serotonin at high levels, no difference was found in the mean platelet counts between the two groups, suggesting that platelet serotonin did not affect bloodstream levels of the hormone.

MRI imaging data showed patients had higher mean iron levels than controls in both subregions of the substantia nigra: the pars reticulata (SNr) and the pars compacta (SNc). There were no significant differences in iron levels between patients and controls in other brain areas of interest or in bloodstream iron markers.

Notably, low serotonin in the bloodstream of Parkinson’s patients significantly correlated with higher iron levels in the brain, but not among controls.

After adjusting for age and sex, this relationship was strengthened and remained after controlling for disease duration and measures of motor symptom severity, “suggesting low serotonin and higher nigral iron are not simply clustering together in males or females or worsening in parallel as patients get older or the disease progresses,” the researchers wrote.

The significant connection between low serotonin and high iron levels in the SNc was seen in the early disease stage (less than one year since diagnosis) and in middle-stage patients (one to five years), while only a higher trend was evident in later disease stages (more than five years).

“The correlation appeared strongest in patients during the first year of diagnosis but waned in later stage disease, when an increasing number of influences on these features presumably come into play,” the researchers added.

While the strongest correlation between serotonin and iron was found in patients’ SNc, lower serotonin was also significantly associated with higher iron in the SNr and brain regions called the putamen, globus pallidus, subthalamic nucleus, and dentate nucleus.

In comparison, no correlations were observed in any brain region of healthy controls. There was also no connection between serotonin and iron in the bloodstream in either group.

An analysis of clinical outcomes found a weak association between lower serotonin and worse scores for the disease’s non-motor impacts on daily life (UPDRS-I), the Parkinson’s disease questionnaire 39 (PDQ-39), and the freezing of gait questionnaire (FOG-Q) on movement difficulties. A higher levodopa equivalent daily dose — the contribution made by each Parkinson’s therapy — was also related to low serotonin.

In contrast, researchers saw no links between serotonin concentrations and motor severity or complications, loss of smell, cognitive abilities, or sleepiness. Low serotonin also did not associate with age, sex, or disease duration.

In both patients and controls, low blood levels of serotonin were strongly related to the use of medicines to treat anxiety or depression — selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) — designed to increase serotonin or related norepinephrine in the brain.

However, no relationship was evident between serotonin levels and scores for anxiety or depression (Hamilton anxiety/depression rating scales) in either group, even after adjusting for the use of SSRIs or SNRIs.

While a strong relationship was evident between SSRI/SNRI use for anxiety or depression and low serotonin, it “did not explain the correlation between these two features,” the scientists noted.

“Taken together, our findings reveal an early, robust association between low serotonin and higher iron in the SNc in [Parkinson’s disease],” the researchers wrote. “This correlation was present even in patients within one year of diagnosis, suggesting it might also be present in the prodromal [pre-symptomatic] phase, and was stronger in the SNc than any other brain region examined.”

Given these findings, further “studies in both patients and carefully selected and rigorously used animal models” are needed to “determine direct mechanistic links if they exist,” the team added.

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