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Realizing the Promise of Neuromelanin-Sensitive MRI (NM-MRI)

Routine NM-MRI for individuals at risk of Parkinson’s could provide a means of identifying the disease before symptoms emerge.

Parkinson’s disease (PD) is a nervous system disorder that reduces voluntary motor control, causing muscle tremors, loss of mobility, and difficulties with balance and coordination. These symptoms are the result of neuronal damage and death, especially within the substantia nigra (SN) and locus coeruleus (LC) regions of the brain. However, loss of coordination and motor control is also associated with a range of other neurodegenerative diseases, which may require significantly different treatments than PD. It is, therefore, crucial that PD can be accurately diagnosed and differentiated from similar disorders so that patients can receive the appropriate care. 

Today, the promise of technology powered by AI offers enormous potential for advancing our understanding of this debilitating illness. Recent advances in neuromelanin-sensitive MRI (NM-MRI) can provide valuable adjunctive data to help detect, diagnose, and monitor neurodegenerative diseases such as PD. 

Parkinson’s Disease (PD) and related disorders

Parkinson’s disease is one diagnosis among a category of neurodegenerative diseases known as Parkinson’s spectrum disorders. This category also includes diseases such as Lewy body disease and multiple system atrophy (Shy-Drager), which are sometimes referred to as PD subtypes due to similarities in the underlying causes and symptoms of these disorders. Further complicating the picture are other neurological disorders, such as essential tremors, which are frequently confused with PD. In fact, some estimates place the overdiagnosis rate for essential tremors as high as 50%, and similar research suggests that PD is underdiagnosed in patients with tremors. The overlap between these two diagnoses is concerning, as treatment for these conditions can vary significantly.

DaTscan: A first step towards accurate diagnosis of PD

To address this complexity and aid in conclusive diagnoses, healthcare providers use brain scans to identify key markers of PD. PD is characterized by a loss of neurons (specifically dopaminergic and noradrenergic neurons) from the SN and LC brain regions. In 2011, the FDA approved an adjunctive imaging procedure known as DaTscan which reveals whether crucial dopaminergic axons originating from the SN are present in the striatum region. A DaTscan works by administering a radioactive agent (ioflupane I123) through an IV infusion. Ioflupane I123 is visible on a specialized machine called a SPECT scanner. Because ioflupane I123 binds to dopamine transporters (DATs) found on dopaminergic axons, it can be used as a proxy measurement for this neuronal population.

The DaTscan was an important initial advancement that provided adjunctive information to aid providers in differentiating tremor due to Parkinsonian syndromes from essential tremor. However, there are inherent limitations to this technology. Due to the need for an injected radiotracer (ioflupane I123) and specialized machinery (SPECT scanner), this test is both expensive and time-consuming. Furthermore, the SPECT scanner exposes patients to radiation, which, in addition to the use of the radiotracer, can cause unwanted side effects. Finally, DaTscans are specifically labeled as an adjunct to aid the diagnosis of Parkinsonian syndromes and dementia with Lewy bodies and do not help physicians and healthcare teams gain insights into other neuropsychiatric conditions.

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NM-MRI: An evolution in neurodegenerative diagnostics

The limitations of DaTscan have created a demand for alternative methodologies to aid in diagnosing PD. One particularly promising approach is the use of neuromelanin-sensitive MRI or NM-MRI. Neuromelanin is a metabolic byproduct of dopamine metabolism that accumulates in healthy neurons within the SN as people age. Neuromelanin is thought to help protect SN neurons and, crucially, neuromelanin levels within the SN have been shown to significantly decrease in patients with PD and Parkinsonian syndromes. Studies have demonstrated that NM-MRI has “favorable diagnostic performance” for PD and is currently being explored for its ability to assist in the diagnosis and assessment of schizophrenia, Lewy body disease, and more.

Because neuromelanin contains iron, it can be detected using a standard neuromelanin-sensitive scan on an MRI machine without the use of contrast. This prevents patients from being exposed to radiation or radioactive pharmaceuticals while still providing essential insights into the health of dopaminergic neurons in the SN. Furthermore, the ability to perform this test in a standard MRI machine eliminates the need for a specialized SPECT scanner, reducing costs and increasing the feasibility of incorporating this test into a patient’s care plan. An MRI scan is typically already part of a standard initial workup for patients suspected of having Parkinson’s disease, making it easy and efficient for providers to gather useful NM-MRI data without additional procedures. 

Historically, the use of NM-MRI data has been restrained by difficulties in processing and standardization. Raw NM-MRI data can be inconsistent between locations due to differences in MRI hardware or software, preventing healthcare providers from interpreting results with confidence. In 2021, an international group of researchers published a methodology for successfully harmonizing NM-MRI scan data across multiple locations. This was recently followed by the 2023 FDA clearance of a cloud-based software program, NM-101, which automates the processing and analysis of NM-MRI data. These advancements have improved the utility of NM-MRI scans and their ability, when interpreted by a trained physician, to provide valuable information in determining neuromelanin association as an adjunct to diagnosis.

Looking towards the future

These improvements in access to NM-MRI data represent a momentous step forward in bringing this promising approach to the clinic. One of the most exciting aspects of NM-MRI scans is that their non-invasive nature allows providers to easily incorporate them into routine screenings in aging populations, which may be crucial for early detection and regular monitoring. The treatments being explored for PD primarily focus on preventing further neurodegeneration due to the extreme difficulty of reversing neuronal damage. However, by the time PD patients develop symptoms, it is estimated that up to 30% of critical neurons have already been lost. Early diagnosis of PD is thus crucial for improving the prognosis of people with this disease, and the literature has suggested that routine NM-MRI scans could provide valuable supportive data for identifying and monitoring PD cases. Leaders in the field propose that routine NM-MRI for individuals at risk of PD could provide a means of identifying the disease before symptoms emerge, enabling intervention before substantial neurodegeneration has occurred. 

The ability to study neuromelanin is likely to have benefits well beyond PD as well. In addition to studies suggesting that NM-MRI provides valuable adjunctive information useful for differentiating between Parkinsonian syndromes, there are promising data suggesting NM-MRI can aid in the differential diagnosis of Alzheimer’s disease, schizophrenia, and even depression. As our understanding of neuromelanin’s role in healthy brain aging continues to grow, it is clear that imaging of this crucial biomarker will deepen the field’s comprehension of neurodegenerative diseases. We still have much to learn, but harnessing the power of NM-MRI may be a key step in reducing the burden of Parkinson’s disease and other neurological and psychiatric conditions. 

Image by Dr_Microbe, Getty Images

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 medicinal and synthetic chemistry and novel approaches to the improvement and optimization of psychedelic compounds for patient use.

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