Over the last two decades, researchers have built a growing foundation of evidence on the value of neuromelanin as a biomarker for neurological and psychiatric disorders, particularly Parkinson’s disease.
Sam Clark, MD., Ph.D., CEO of Terran Biosciences, discusses the growing interest in leveraging neuromelanin to diagnose and track disease, the challenges that have held back its clinical application, and the innovations helping to bring neuromelanin-based diagnostic tools to fruition.
First identified in the 19th century, neuromelanin is a pigment produced during catecholamine synthesis in the brain.
It is highly concentrated in functional dopaminergic and noradrenergic neurons, particularly areas of the brain like the substantia nigra and locus coeruleus.
This has led to significant interest in the compound’s utility as a biomarker for neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease.
Specifically, Parkinson’s disease is characterised by a loss of neuromelanin-containing dopaminergic neurons in the substantia nigra and noradrenergic neurons of the locus coeruleus.
For most patients, a Parkinson’s diagnosis is spurred by the onset of motor symptoms, such as a tremor, instability, or rigidity.
Unfortunately, an estimated 30 per cent of neuromelanin-containing neurons of the substantia nigra are already lost by the time motor symptoms appear, leaving patients unaware of their illness before significant progression has already occurred.
Currently, there is no lab or imaging test available to provide a definitive diagnosis of Parkinson’s disease.
In 2011, the U.S. FDA approved DaTscan (dopamine transporter scan) as an adjunctive imaging test to aid in diagnosis.
DaTscan testing uses an intravenous infusion of ioflupane (123I), a radioactive tracer that crosses the blood-brain barrier and binds to dopamine transporter proteins on nigrostriatal neurons.
Patients then undergo imaging in a SPECT scanner to visualise the distribution of healthy dopaminergic neurons labeled with the tracer.
DaTscan is currently indicated for the distinction of Parkinson’s disease from essential tremor, particularly when neurologic exam results are unclear.
However, the invasive nature, long scan time, and high cost of DaTscan testing are key limiting factors in its widespread use.
Leveraging neuromelanin as a biomarker for Parkinson’s disease
Neuromelanin-sensitive MRI (NM-MRI) has emerged as a promising alternative approach to visualising changes in catecholaminergic neuron populations in Parkinson’s disease and other conditions.
In postmortem histological assessments of brain tissue, Parkinson’s disease is characterized by a loss of neuromelanin-containing neurons in midbrain regions.
Numerous studies have confirmed the correlation of NM-MRI signal intensity and volume of neuromelanin in the substantia nigra and locus coeruleus with both histological findings of neurodegeneration and severity of motor symptoms.
In addition, a 2020 meta-analysis of 12 clinical studies of NM-MRI comprising 403 patients with Parkinson’s and 298 healthy control participants concluded that the method yielded a “favourable diagnostic performance in discriminating patients with Parkinson’s disease from healthy controls.”
According to ClinicalTrials.gov, more than 15 trials are currently underway to explore the use of NM-MRI in Parkinson’s disease, schizophrenia, Lewy body disease, and more.
With this breadth of promising evidence, why has NM-MRI not become a widespread part of the diagnostic workflow for Parkinson’s disease?
The challenging nature of consistent and efficient quantitative analysis of NM-MRI data is one key reason.
Historically, researchers and clinicians have struggled to standardise neuromelanin measurement due to variability in results among scanners, even from those of the same model.
This issue was addressed with a breakthrough enabling the cross scanner harmonisation of NM-MRI data. (Wengler, Kenneth, et al. “Cross‐scanner harmonization of neuromelanin‐sensitive MRI for multisite studies.” Journal of Magnetic Resonance Imaging 54.4 (2021): 1189-1199).
How could simplified NM-MRI transform the diagnosis of Parkinson’s disease?
The 2023 FDA clearance of Terran Biosciences’ NM-101, a cloud-based software platform for the fully automated analysis of NM-MRI data, has blazed a new trail in bringing the utility of neuromelanin to the clinic.
NM-101 is the first FDA-cleared medical device that gives neurologists access to harmonised NM-MRI data from the locus coeruleus and substantia nigra while integrating seamlessly into existing clinical workflows.
The software produces a comprehensive report of imaging data that can be interpreted by a neuroradiologist and used to provide adjunctive information to aid in diagnostic decisions.
NM-101 opens the door to improved patient care by providing physicians with previously unobtainable NM-MRI data.
This is particularly notable when compared to the existing clinical workflow which may include a DaTscan.
Patients already undergo an MRI as part of a standard initial workup for Parkinson’s disease, whereas a DaTscan is an entirely separate procedure with its own inconveniences.
DaTscan is expensive, takes a total of five hours, and requires IV placement and exposure to radiation, while NM-MRI is noninvasive and can be added to the patient’s standard MRI scan in under ten minutes.
With analysis by NM-101, clinicians are able to efficiently and easily access potentially useful adjunctive data without an additional procedure.
Realising the full potential of neuromelanin as a biomarker
By providing a standardised, validated, and accessible approach to quantifying neuromelanin in key brain regions, the FDA clearance of NM-101 represents a key step towards realising the full potential of NM-MRI as a valuable tool.
Research studies have shown that in addition to providing adjunctive diagnostic information, NM-MRI may be used to monitor disease progression in Parkinson’s disease and potentially enable presymptomatic detection.
Researchers have suggested that individuals at risk for Parkinson’s disease could undergo NM-MRI at routine intervals to track changes in the substantia nigra and locus coeruleus and that as disease-modifying treatments are developed in the future, early detection could have a massive impact on our clinical capacity to intervene prior to substantial degenerative changes.
But the value of neuromelanin imaging is certainly not limited to Parkinson’s disease.
Clear data regarding changes in neuromelanin concentration may help predict the severity of psychosis in individuals with and at risk for schizophrenia.
Additionally, neuromelanin imaging could provide a noninvasive and accessible approach to tracking pathological degeneration in Alzheimer’s disease to enable early diagnosis and intervention.
While NM-MRI is not yet a commonplace clinical approach, innovative research continues to highlight its value in the diagnosis of numerous neurological and psychiatric conditions, and the FDA clearance of NM-101 analysis software has finally brought this tool into the clinic.
Together, these milestones signal a future where we can leverage the full potential of neuromelanin as an essential brain biomarker to gain deeper insights into neurological and psychiatric health and disease.
Sam Clark, MD, PhD, founder and CEO of Terran Biosciences, is a multi-published neuroscientist and innovator with over 200 patent applications.
With MD and PhD degrees from Columbia University and a BS in neuroscience from MIT, he founded Terran Biosciences to create a platform biotech company to transform the approach to therapeutics in neuropsychiatry.
Terran has one of the largest psychedelic development programs in the industry and is a leader in the manufacturing and supply of GMP psychedelic compounds to researchers globally.
You can connect with Sam on LinkedIn.
