The research, led by Gerda Thomsen and Kristoffer Brendstrup-Brix of the Neurobiology Research Unit at Copenhagen University Hospital Rigshospitalet, together with colleagues including senior author Gitte M. Knudsen, enrolled 35 patients who had been referred for diagnostic dopamine transporter imaging between October 2021 and January 2024. Fifteen healthy controls were recruited for comparison. Every patient underwent two nuclear medicine scans and a magnetic resonance imaging session: single-photon emission computed tomography with the radiotracer [123I]FP-CIT, the long-standing gold standard known commercially as DaTscan, performed on a modern three-headed SPECT-CT camera equipped with high-resolution multi-pinhole collimators; positron emission tomography with the newer radioligand [18F]FE-PE2I; and a dedicated midbrain MRI protocol combining neuromelanin-sensitive gradient echo magnetization-transfer imaging with iron-sensitive STAGE sequences on a 3T Siemens Prisma scanner.

The biological logic behind all three approaches rests on the same target: the nigrostriatal pathway. Parkinson’s disease is characterized by widespread accumulation of intracellular alpha-synuclein aggregates and the progressive death of dopaminergic neurons in the substantia nigra, which denervates the caudate nucleus and putamen, the striatal structures that regulate movement. Dopamine transporter imaging measures the presynaptic dopaminergic terminals still surviving in the striatum, and reduced binding signals neurodegenerative parkinsonism. Neuromelanin MRI exploits the fact that the pigment neuromelanin, an iron chelator that accumulates in nigral dopaminergic neurons over a lifetime, brightens the substantia nigra on specially weighted sequences; as neurons die, that signal fades. Iron-sensitive techniques, including quantitative susceptibility mapping, attempt to capture the corresponding rise in paramagnetic iron deposition.

The head-to-head results were striking. Eighteen of the 35 patients were ultimately diagnosed with neurodegenerative parkinsonism after a median follow-up of 2.6 years, including 13 with Parkinson’s disease, three with Parkinson’s disease dementia or Lewy body dementia, and one each with progressive supranuclear palsy and a non-specific neurodegenerative basal ganglia disease. Dopamine transporter availability measured with SPECT and PET showed complete concordance across cases, with quantitative measures correlating strongly, Pearson coefficients ranging from 0.7 to 0.9 and reaching an almost perfect 0.9 for the ratio of putamen to caudate nucleus binding. Receiver operating characteristic analysis confirmed equally excellent diagnostic performance for both modalities, with areas under the curve between 0.84 and 0.92 for SPECT and 0.80 to 0.93 for PET across most regional measures.

Why does this equivalence matter? Conventional wisdom has held that PET, with its superior spatial resolution and shorter waiting times between tracer injection and scanning, would outperform SPECT for dopamine transporter imaging. But the Copenhagen team used the AnyScan Trio SC, a three-headed brain SPECT-CT camera whose multi-pinhole collimators deliver roughly 2.4 times the sensitivity of conventional systems at the edges of the field of view, with reconstructed voxel sizes of 1.8 cubic millimeters. The study suggests that this hardware leap has closed the gap, meaning that centers without on-site cyclotrons or radiochemistry facilities can achieve state-of-the-art diagnostic accuracy with SPECT, which is generally less costly and more widely accessible. PET retains an advantage where tracer logistics allow, and some prior literature hints at higher specificity, but the choice between modalities may now legitimately rest on local availability and cost.

Patients themselves offered a surprising verdict on the scanning experience. Twenty-seven participants completed satisfaction questionnaires covering waiting time from injection to scan, tracer injection, comfort during the procedure, and overall experience, each rated on a five-point Likert scale. SPECT requires a three-hour wait after injection and a 30-minute acquisition, whereas PET scanning begins just 30 minutes after a 200 MBq [18F]FE-PE2I injection and lasts 10 minutes. Yet no statistically significant differences emerged for waiting time, injection, or the scanning procedure itself, and overall satisfaction was actually higher for SPECT, with a moderate effect size of Cohen’s d of 0.59, likely reflecting the extra clinical attention patients received during the add-on examination performed on the same day as their MRI.

The MRI results told a more sobering story. Substantia nigra neuromelanin content, quantified by summing z-scores within semi-automatically delineated hyperintense regions and normalized to reference areas in the cerebral crus, was significantly reduced in patients with neurodegenerative parkinsonism compared with individuals who had no neurological disease, with a large effect size of Cohen’s d of -1.03. A trend toward lower neuromelanin with longer symptom duration hinted at progressive nigral loss. But at the level of the individual patient, neuromelanin MRI achieved only an intermediate area under the curve of 0.7, well short of the nuclear medicine measures. Midbrain iron content fared worse still: it did not differ between any diagnostic groups and performed essentially at chance, with an area under the curve of 0.55, offering no diagnostic information in this early-stage cohort.

The authors interpret these MRI findings through the lens of disease timing. Their patients had a median symptom duration of just 29 months at the time of imaging, and accumulating evidence indicates that striatal dopaminergic dysfunction precedes measurable nigral neuromelanin loss and iron accumulation in the spatiotemporal evolution of Parkinson’s disease. Meta-analyses of neuromelanin and iron MRI similarly report lower diagnostic accuracy in patients within the first five years of symptoms. The reproducibility of the MRI quantification itself was excellent, with repeated region-of-interest delineations correlating at 0.95 for neuromelanin and 0.97 for iron, suggesting the method is technically sound and that its modest performance reflects biology rather than measurement noise. Standardized acquisition protocols, automated segmentation, and refined quantification strategies, the authors argue, will be needed before nigral MRI can serve as a reliable standalone clinical biomarker.

The study has limitations typical of real-world imaging research. Final diagnoses rested on best clinical practice, with movement disorder specialists integrating examinations, dopamine transporter imaging, and structural scans over follow-up periods of 20 to 48 months, rather than on neurohistological confirmation, which remains the definitive gold standard for synucleinopathies. Consecutive, unselected recruitment produced a realistic but heterogeneous cohort, and the small number of patients with atypical parkinsonism limits specific conclusions for that subgroup. Nevertheless, the practical takeaway is clear and consequential: in early, clinically uncertain parkinsonism, dopamine transporter imaging with modern multi-pinhole SPECT and with PET are equivalent, radiation-free MRI biomarkers of neuromelanin and iron are not yet ready to replace them, and hospitals can confidently choose the nuclear medicine pathway that best fits their infrastructure without compromising diagnostic accuracy for their patients.

Subject of Research: Comparative diagnostic performance of dopamine transporter SPECT, PET, and neuromelanin and iron-sensitive MRI in clinically uncertain parkinsonian syndromes.

Article Title: Nigrostriatal imaging in patients with clinically uncertain Parkinsonian syndromes: a head-to-head comparison between SPECT, PET, and MRI

Article References: Thomsen, G., Brendstrup-Brix, K., Svarer, C., Lindberg, U., Pinborg, L. H., Kettless, K., Law, I., Hasselbalch, S. G., Biering-Sørensen, B., & Knudsen, G. M. (2026). Nigrostriatal imaging in patients with clinically uncertain Parkinsonian syndromes: a head-to-head comparison between SPECT, PET, and MRI. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08184-8

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08184-8

Keywords: Parkinson's disease, dopamine transporter imaging, SPECT, PET, MRI, neuromelanin, iron deposition, substantia nigra, [123I]FP-CIT, [18F]FE-PE2I, parkinsonism diagnosis, multi-pinhole collimators

The research, led by Bernard Mulvey, Heena R. Divecha, and colleagues at the Lieber Institute for Brain Development working with collaborators at Johns Hopkins and the University of Cambridge, applied spatially resolved transcriptomics, a technique that maps gene expression across intact tissue sections while preserving information about where each gene is active, to postmortem locus coeruleus tissue from 33 neurotypical middle-aged human brain donors. Crucially, the donors were stratified by major Alzheimer’s disease risk factors, including biological sex, African or European genetic ancestry, and apolipoprotein E haplotype, specifically carriers of the APOE E4 allele, which raises disease risk, versus carriers of the APOE E2 allele, which appears protective. This design allowed the investigators to ask a subtle but important question: do the genes expressed in and around the locus coeruleus already differ, in healthy middle age, depending on which Alzheimer’s risk variants a person carries?

The answer, in several respects, is yes, and the details are illuminating. When the researchers compared gene expression patterns across APOE haplotypes, they found reduced expression of astrocytic genes, meaning genes characteristically active in star-shaped support cells called astrocytes, in the tissue immediately surrounding locus coeruleus neurons in E4 carriers. Astrocytes are far more than passive glue; they regulate synapse formation, supply neurons with cholesterol and metabolic support, control local blood flow, buffer neurotransmitters, and respond to norepinephrine signaling from the locus coeruleus itself. A diminishment of astrocytic gene expression near these noradrenergic neurons suggests that E4 carriers may have subtly weakened local support infrastructure around one of the brain’s most Alzheimer’s-vulnerable cell populations, potentially lowering the threshold at which tau pathology or other stresses become damaging.

The study also uncovered ancestry-specific differences in locus coeruleus gene expression, a finding with real public health significance given well-documented disparities in dementia incidence and outcomes across populations. Follow-up analyses using in situ sequencing at single-cell resolution demonstrated that the APOE-related differences in regional gene expression were partly attributable to astrocytes themselves, and that the haplotype effects were more pronounced in donors of European ancestry. This interaction between genetic ancestry and APOE haplotype echoes earlier work showing that the relationship between APOE E4 and Alzheimer’s pathology differs across admixed populations, and it underscores the importance of including ancestrally diverse cohorts in neuroscience research rather than extrapolating from studies of predominantly European-ancestry subjects.

Perhaps the most visually and conceptually striking component of the study concerns neuromelanin, the dark pigment that gives the locus coeruleus its name, which means “blue spot” in Latin. Neuromelanin accumulates in certain catecholaminergic neurons, including the noradrenergic neurons of the locus coeruleus and the dopaminergic neurons of the substantia nigra, as a byproduct of oxidative metabolism of neurotransmitters. It is sequestered within specialized autolysosomal organelles that bind potentially toxic metals such as iron, and its loss from these neurons is a hallmark of both Alzheimer’s and Parkinson’s disease. Neuromelanin-sensitive magnetic resonance imaging has emerged as a promising biomarker, with reduced pigment signal in the locus coeruleus predicting clinical severity and future progression in Alzheimer’s patients. What has remained unclear is the precise molecular relationship between a neuron’s pigment content and its gene expression program.

To address this, the team quantified neuromelanin content directly in the tissue and related it to spatial gene expression. They found that higher APOE gene expression correlated with reduced neuromelanin, and that genes whose expression tracked with local pigment levels were enriched for aging-related biological pathways. Taking the analysis to its finest resolution, the investigators used in situ sequencing data to examine individual locus coeruleus neurons, measuring neuromelanin in each cell and validating its associations with the expression of APOE itself, genes involved in norepinephrine metabolism, and components of the autophagy machinery, the cellular recycling system that clears damaged proteins and organelles. This constellation of pigment-linked genes paints a coherent picture: neuromelanin content reflects, at the single-cell level, the interplay of neurotransmitter handling, lipid biology, and protein quality control, all processes implicated in neurodegeneration.

The significance of these findings is best appreciated against the backdrop of what is already known about the locus coeruleus in Alzheimer’s disease. Postmortem studies stretching back decades, including the classic staging work of Heiko Braak and colleagues, established that phosphorylated tau appears in locus coeruleus neurons exceptionally early, often in individuals who died with no cognitive impairment. Autopsy studies have documented substantial neuronal loss in this nucleus in mild cognitive impairment and early Alzheimer’s disease, and neuroimaging research has repeatedly linked reduced locus coeruleus integrity to tau burden, memory decline, neuropsychiatric symptoms, and sleep disruption. Animal work has shown, conversely, that noradrenergic depletion exaggerates the inflammatory response to amyloid-beta pathology, while pharmacological enhancement of norepinephrine signaling can suppress neuroinflammation. The locus coeruleus, in other words, is not merely a passive victim of Alzheimer’s pathology; its noradrenergic output actively modulates the brain’s response to it.

The new study adds two crucial molecular threads to this narrative. First, it demonstrates that Alzheimer’s genetic risk acts on the locus coeruleus ecosystem, not just on its neurons in isolation. The astrocytic deficit observed near E4-carrier neurons is particularly intriguing in light of recent evidence that norepinephrine signals through astrocytes to modulate synaptic function, and that astrocytes undergo stereotyped transcriptomic changes across the spatiotemporal progression of Alzheimer’s disease. If E4 carriers begin adulthood with less robust astrocytic support around their noradrenergic neurons, this could help explain why these neurons succumb early, and why E4 homozygosity has recently been characterized as a distinct, nearly deterministic genetic form of Alzheimer’s disease. Second, by tying neuromelanin, a biomarker measurable in living patients with specialized MRI, to concrete gene expression programs involving autophagy and catecholamine metabolism, the study strengthens the mechanistic bridge between what clinicians can image and what is happening molecularly inside vulnerable neurons.

Technically, the study represents a tour de force of modern spatial genomics applied to a notoriously difficult brain region. The locus coeruleus is small, deeply located in the dorsal pons, and densely pigmented, making it easy to miss in standard postmortem dissection and challenging to analyze with conventional bulk methods that average away spatial relationships. The team’s spatially resolved transcriptomics data captured tissue architecture at spot-level resolution, while their in situ sequencing pushed the analysis to individual cells, using the pigment itself as an additional segmentation cue to define neuromelanin-rich cellular compartments. The authors have deposited all data in public repositories and built interactive web portals, using visualization tools such as Samui and spatialLIBD, allowing any researcher to explore the spatial domain assignments, gene expression maps, and stained tissue sections, an unusually transparent approach that should accelerate follow-up work across the field.

The implications reach toward prevention and early detection. Because the donors in this study were neurotypical and middle-aged, the observed molecular differences, diminished astrocytic gene expression in E4 carriers, ancestry-dependent expression patterns, pigment-linked autophagy and norepinephrine genes, represent the brain’s baseline state before overt pathology, a snapshot of vulnerability rather than of damage. Interventions aimed at supporting astrocytic function, enhancing autophagic clearance of tau, or modulating noradrenergic tone might therefore be most effective when targeted at these early molecular states rather than at established dementia. Meanwhile, the confirmation that APOE expression itself inversely tracks neuromelanin suggests that pigment imaging could serve not only as a marker of neuronal loss but as a window into the lipid-handling pathways that connect APOE biology to neurodegeneration. As the authors conclude, Alzheimer’s risk factors appear to modulate locus coeruleus vulnerability through molecular processes intrinsic to both the noradrenergic neurons and their astrocytic partners, a reminder that the neurons that wake us, focus us, and help us remember may hold some of the earliest clues to when and how Alzheimer’s disease takes hold.