Study: Iron Deposits in Brain Not Tied to Parkinson’s Development

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by Steve Bryson, PhD |

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Iron buildup in the region of the brain largely affected in Parkinson’s disease did not contribute to disease development or progression, an MRI study has found.

In contrast, iron accumulation was related to disease duration and the use of levodopa, a standard Parkinson’s therapy, a finding that needs further investigation, researchers noted.

The MRI study, “Dynamics of Nigral Iron Accumulation in Parkinson’s Disease: From Diagnosis to Late Stage,” was published in the journal Movement Disorders.

In Parkinson’s disease, cells that produce the nerve-signaling molecule dopamine are lost in certain parts of the brain stem, particularly the crescent-shaped cell group called the substantia nigra. Because these cells are needed to control body movement and coordination, their loss triggers the onset of Parkinson’s symptoms.

Several studies examining postmortem brain tissue from Parkinson’s patients have found higher iron levels in the substantia nigra (nigral iron). Moreover, animal studies suggest that excess iron in the brain is associated with neuronal death.

Based on these findings, there are ongoing clinical trials evaluating iron chelators (binders) as a treatment for Parkinson’s. But these studies, which enroll newly diagnosed, untreated patients, assume that iron buildup is related to disease development and progression. Data from one small Phase 2 study suggested that the iron chelator deferiprone did not affect motor function or quality of life.

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A more recent analysis that the standard Parkinson’s therapy levodopa, designed to increase dopamine levels in the brain, forms a stable complex with iron and siderocalin, a protein that plays a role in iron uptake by cells is elevated in the substantia nigra of patients.

However, it remains unclear whether iron buildup in the substantia nigra occurs before Parkinson’s diagnosis, during disease progression, is a consequence of the disease itself, or is influenced by Parkinson’s therapies.

Using noninvasive, iron-detecting MRI, researchers at Penn State Milton S. Hershey Medical Center in Pennsylvania examined brain iron deposits in 18 newly diagnosed, untreated Parkinson’s patients and 87 with more advanced disease who had received regular Parkinson’s therapies. A group of 78 age- and sex-matched healthy individuals were recruited as controls.

Although newly diagnosed participants had shorter disease duration, they did not differ in tests related to motor- and non-motor functions, except for cognitive impairment, which was worse in treated patients with established disease. All patients reported more depression than controls.

Compared to controls, the newly diagnosed, untreated patients had lower iron levels in the substantia nigra, but not in other areas of the brain, suggesting that “in some way lower iron may be a risk factor in [Parkinson’s development],” the team wrote.

“The finding of lower nigral iron in [treatment-naïve] patients in the current study makes the results from the deferiprone trial unsurprising,” they added.

In contrast, treated patients with longer disease duration had significantly higher iron content only in the substantia nigra, compared to both controls and new Parkinson’s patients.

To determine whether iron content increased with disease course, the team divided patients into three groups based on disease duration: early-stage was defined as less than two years, middle-stage from two to six years, and later-stage was more than six years.

Iron content in the substantia nigra was significantly higher in early-stage patients than in treatment-naïve individuals, but was not different than controls.

Nigral iron was elevated significantly in middle-stage patients compared to early-stage and treatment-naïve participants, whereas middle- and late-stage treated patients showed no significant difference.

Statistical analysis demonstrated that disease duration was significantly associated with iron accumulation in the substantia nigra.

Furthermore, patients taking levodopa had significantly higher iron content than those not taking this medication. There was a similar difference in iron buildup between treated patients and controls after adjusting for disease duration.

In comparison, nigral iron was lower in those who received Zelapar (selegiline), an adjunct therapy that prevents the metabolic breakdown of dopamine in the brain, than those not taking this medicine.

“These new findings are inconsistent with the current hypothesis that higher nigral iron leads to the initiation of [Parkinson’s disease development] and the notion that increased iron causes disease progression,” the researchers wrote.

“The resulting data, however, are tantalizing and hint that antiparkinson treatments may interact with disease and nigral iron progression in a complex fashion that may have clinical relevance,” the researchers added. “Validation of these findings with longitudinal [over time] follow-up and using independent cohorts is warranted.”