Parkinsonism is a clinical syndrome defined as bradykinesia, combined with rest tremor, rigidity, or both (Postuma et al., 2015). Parkinson's disease (PD) is the most common cause of parkinsonism and the fastest-growing neurodegenerative disorder worldwide with currently almost 12 million affected people worldwide (Bloem et al., 2021; Murray, 2024). Atypical parkinsonisms, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB), are collectively less prevalent than idiopathic PD. These disorders are classified as rare, with estimated prevalence rates ranging from 5 to 22 cases per 100,000 population depending on the specific subtype and diagnostic criteria used (Lo, 2022). MSA and PSP are the most frequently encountered atypical forms. For example, MSA has a reported prevalence of about 3–5 per 100,000, while PSP may reach up to 6 per 100,000 in some studies. DLB, often overlapping with both PD and Alzheimer's disease, appears to be more common, with estimates around 0.4 %–5 % of the elderly population, depending on whether clinical or neuropathological criteria are used (Nysetvold et al., 2024; Sekiya et al., 2024; Delpirou et al., 2024). Diagnosis is typically made based on clinical grounds, and several exclusion criteria as well as red flags have been defined that should urge the clinician to consider an atypical parkinsonian syndrome (Postuma et al., 2015). For instance, in case of early severe autonomic failure or frequent falls, the diagnosis of MSA or PSP should be considered respectively (Wenning et al., 2022; Höglinger et al., 2017). Atypical parkinsonism (AP) has a more aggressive disease course than PD, leading to earlier loss of independent functioning and shorter life spans. Moreover, dopamirgenic treatments are less effective when applied in persons with AP. Therefore, for appropriate guidance and treatment, a timely accurate diagnosis is crucial. However, AP diagnoses are frequently missed in the early stages with reported sensitivities for MSA and PSP below 65 % (Hughes et al., 2002; Joutsa et al., 2014). [...]

Differentiating among early-stage parkinsonisms is a challenge in clinical practice. Quantitative MRI can aid the diagnostic process, but studies with singular MRI techniques have had limited success thus far. Our objective is to develop a multi-modal MRI method for this purpose. In this review we describe existing methods and present a dedicated quantitative MRI protocol, a decision model and a study design to validate our approach ahead of a pilot study. We present example imaging data from patients and a healthy control, which resemble related literature.

Aims: Aceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron deposits, of which the molecular composition is unknown. We aimed to quantitatively determine the molecular iron forms in the aceruloplasminemia brain, and to illustrate their influence on iron-sensitive MRI metrics. Methods: The inhomogeneous transverse relaxation rate (R₂*) and magnetic susceptibility obtained from 7 T MRI were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry. The basal ganglia, thalamus, red nucleus, dentate nucleus, superior- and middle temporal gyrus and white matter of a post-mortem aceruloplasminemia brain were studied. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison. Results: The brain iron pool in aceruloplasminemia detected in this study consisted of EPR-detectable Fe³⁺ ions, magnetic Fe³⁺ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe³⁺ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Ferrihydrite-iron represented above 90% of all iron and was the main driver of iron-sensitive MRI contrast. Although deep gray matter structures were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron was already six times more abundant in the temporal cortex of the patient with aceruloplasminemia compared to the healthy situation (162 µg/g vs. 27 µg/g), on average. The concentrations of Fe³⁺ ions and maghemite-iron in the temporal cortex in aceruloplasminemia were within the range of those in the control subjects. Conclusions: Iron-related neurodegeneration in aceruloplasminemia is primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.