A recent randomized controlled trial explored the impact of deferiprone, administered at 15 mg/kg twice daily, on cognitive performance in individuals diagnosed with amyloid-confirmed mild cognitive impairment (MCI) and mild Alzheimer disease (AD). This study brings to the forefront the pivotal influence of iron in cognitive decline associated with AD, prompting essential discussions regarding its role.
Published in JAMA Neurology, this double-masked, placebo-controlled research involved 81 participants meticulously assigned to receive either deferiprone or a placebo over a 12-month period. Despite deferiprone’s known efficacy in reducing brain iron buildup, patients treated with this drug exhibited a concerning trend of accelerated cognitive decline.
According to the intent-to-treat analysis, patients on deferiprone faced a significantly greater decline in cognitive performance as measured by the Neuropsychological Test Battery (NTB), showing a primary outcome interaction (ß for interaction = –0.50; 95% CI, –0.80 to –0.20) relative to the placebo group (change in NTB composite z score for deferiprone: –0.80 [95% CI, –0.98 to –0.62]; for placebo: –0.30 [95% CI, –0.54 to –0.06]). The cognitive decline was particularly pronounced in areas associated with executive functioning, and this findings correlated with noticeable reductions in frontal lobe volume.
Lead author Scott Ayton, PhD, who directs the Center of Research Excellence in Enhanced Dementia Diagnosis at The Florey, speculated on possible interpretations of these unexpected results. Ayton posited that elevated iron levels within the brains of AD patients may act as an adaptive or protective mechanism, while essential iron could be trapped in pathological processes, resulting in harmful accumulation amidst functional deficits. Moreover, he suggested that a detrimental pool of iron might promote disease progression without being sufficiently countered by the low doses of deferiprone administered in this trial.
Ultimately, out of the 81 participants randomized, 54 completed the 12-month regimen, with 21 participants (75.0%) from the placebo group and 33 (62.3%) from the deferiprone arm successfully finishing. Consent withdrawal was noted as the primary cause for discontinuation, occurring more frequently in the deferiprone group (24.5%) than in the placebo group (10.7%).
Investigators observed that deferiprone notably impaired performance in executive function testing (ß for interaction range: –0.64 [95%CI–100to–027;P <.001 for the Delis-Kaplan Executive Function System; P = .02 for the WAIS-IV Coding Subtest) more than in memory assessments (β for interaction range: −0.19 [95% CI, −0.58 to 0.20] P = .34 for the Cogstate International Shopping List Test]).
At the study’s conclusion, no significant differences were detected in Mini-Mental State Examination scores between the two groups (ß for interaction = –1.43; 95% CI, –3.63 to 0.76; P = .20). Meanwhile, the change in hippocampal volume revealed no significant disparities between the deferiprone and placebo cohorts (deferiprone: –0.03 mL [95% CI, –0.04 to –0.02 mL]; placebo: –0.02 mL [95%CI–003to001;P = .61).
Among 33 participants who completed MRI scans, 15 (53.6%) belonged to the placebo group, while 18 (34.0%) were from the deferiprone cohort. After the 12-month period, deferiprone was associated with a significant reduction in iron levels in the hippocampus compared to placebo (change in deferiprone group: −0.36 ppb; placebo: 0.32 ppb; P = .03).
Furthermore, deferiprone demonstrated a significant decrease in ferritin levels compared to placebo by the end of the study (deferiprone: –102.9 ug/L; placebo: –27.9 ug/L; ß for interaction = –75 [95%CI–1128to–371;P
REFERENCE
1. Ayton S, Barton D, Brew B, et al. Deferiprone in Alzheimer disease: a randomized clinical trial. JAMA Neurol. Published online November 4, 2024. doi:10.1001/jamaneurol.2024.3733
The Curious Case of Deferiprone and Declining Brains: A Comedic Review!
Ah, Alzheimer’s disease, the ultimate party crasher of memory! Imagine hosting a dinner for your neurons, and there’s that annoying cousin who comes in, gobbles up the chips, spills soda on the carpet, and leaves your cognitive function in shambles. Enter deferiprone, a medication that’s meant to be the cleanup crew for iron overload but—plot twist!—it seems to have made the party worse instead!
In the latest episode of “Clinical Trials Gone Wrong,” published in JAMA Neurology, researchers led by the intrepid Dr. Scott Ayton discovered that giving deferiprone at a dosage of 15 mg/kg twice a day resulted not in cognitive improvement but in an alarming ascent in cognitive decline among patients with mild cognitive impairment (MCI) and mild Alzheimer’s. Apparently, in the grand scheme of brain chemistry, having less iron doesn’t equate to a sharper mind, much like less cake doesn’t equate to a thinner waist. Go figure!
In a shiny randomized controlled trial involving 81 lucky participants, the outcome was anything but rosy. Deferiprone-eating patients reportedly experienced greater deterioration in their cognitive ability as measured by the Neuropsychological Test Battery (NTB). Think of it as taking a test where you’re asked to spell “cat” but getting confused and writing “ctca.” Not ideal! The average decline for patients on deferiprone was a stellar –0.80 compared to a mere –0.30 for those on placebo. Looks like the placebo group got the last laugh this time.
The study suggested that while deferiprone might decrease brain iron accumulation—great for your average iron overload patient—its magical effects didn’t quite translate to cognitive prowess. Executive dysfunction was the clear winner in this decline competition, probably laughing all the way to Frontal Lobe Losertown, where residents are known to forget their own names.
So, why the grim results? Well, Dr. Ayton theorizes that maybe—just maybe—those elevated iron levels in Alzheimer’s patients weren’t the villains we thought, but rather the “sorry, I’m late to the party” type friends who tend to rattle the atmosphere when they arrive. Or perhaps, iron was merely hiding out with the bad crowd, insufficiency lurking amongst the functional deficiency like a bad habit in a middle-class suburb.
As if all that wasn’t enough to chew on, there was also a high dropout rate. A whopping 24.5% of patients bailed on the deferiprone group, claiming they didn’t sign up for a cognitive decline but were more intrigued by the placebo snacks. The placebo group was far less likely to abandon ship, suggesting they might have had a better time playing cognitive charades.
Let’s take a moment to discuss the numbers, shall we? In the land of statistical values, it seems that even a decrease in iron levels could play no trick upon cognitive performance. After a year, the Mini-Mental State Examination scores were ho-hum uninspiring, and the hippocampi of both groups showed no significant differences in volume. Hooray! More proof that when it comes to brains, one size sadly doesn’t fit all.
To summarize this wild, rollercoaster ride of a study: while deferiprone appears to have grasped the irony of preventing iron accumulation, it simultaneously turns out that the brain might just prefer having its internal drama queen intact. In the world of Alzheimer’s treatment, the lesson here seems to be: sometimes less iron is indeed less fun!
So the next time you think about introducing something to the world of Alzheimer’s treatment, remember: it’s not about the quantity of iron in your brain, but rather how you dance with those cognitive deficits on the dance floor of your mind! Until then, keep questioning, keep laughing, and for heaven’s sake, avoid iron supplements like it’s the last pickle at a barbecue!
How might the findings regarding iron levels in the brain change our understanding of Alzheimer’s disease pathology?
**Interview with Dr. Scott Ayton on the Unexpected Findings from the Deferiprone Trial**
**Interviewer:** Welcome, Dr. Ayton! Thank you for joining us today to discuss your recent research published in *JAMA Neurology*. The trial on deferiprone has seen quite a surprising outcome. Can you summarize the key findings for our listeners?
**Dr. Ayton:** Absolutely, thanks for having me! In our study, we looked at the effects of deferiprone, a medication known for reducing iron levels in the brain, on individuals with mild cognitive impairment and mild Alzheimer’s disease. Surprisingly, instead of showing cognitive improvement, those taking deferiprone experienced a marked decline in cognitive function over the 12-month trial. It was quite the unexpected result.
**Interviewer:** That is surprising! Were there specific areas of cognitive function that were more affected than others?
**Dr. Ayton:** Yes, indeed. The most notable declines were observed in executive functioning, which is crucial for planning, decision-making, and problem-solving. Patients on deferiprone showed significantly worse results compared to the placebo group in tests designed to measure these skills, which can be quite alarming.
**Interviewer:** This raises questions about the role of iron in the brain. You suggest that elevated iron levels might not be the enemy we thought. Can you explain this further?
**Dr. Ayton:** Certainly! Traditionally, we’ve seen high brain iron levels in Alzheimer’s patients as detrimental. However, our findings lead us to propose that these elevated iron levels could potentially serve as a protective mechanism. They might be involved in complex biochemical processes that haven’t been fully understood yet. In essence, iron may be offering some form of adaptive response to the pathology of the disease.
**Interviewer:** So, it’s almost like the iron is mischaracterized in this scenario?
**Dr. Ayton:** Exactly! It’s possible that, similar to party guests who show up late and inadvertently create a ruckus, elevated iron levels might be reacting to the ongoing pathological processes of Alzheimer’s, rather than being outright harmful.
**Interviewer:** That’s a fascinating perspective! What do you believe should be the next steps in light of these findings?
**Dr. Ayton:** Moving forward, we need to explore the biological mechanisms at play with iron in the brains of Alzheimer’s patients more deeply. Understanding the balance of iron—how much is necessary and how it may interact with neural function—could lead to more informed therapeutic strategies down the line.
**Interviewer:** Thank you, Dr. Ayton! These insights into the role of iron in cognitive decline certainly challenge preconceived notions. We appreciate your time and look forward to following the next steps in this research.
**Dr. Ayton:** Thank you! It’s been a pleasure discussing these important findings with you.
