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). [...]

Background and Purpose- Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods- We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1-38, Aβ1-40, and Aβ1-42 were assessed using ELISA. Results- Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1-42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, <0.001). Similarly, among persons in higher tertile of Aβ1-38, a strong association was observed between CRP and microbleed counts ( P interaction, 0.004). Conclusions- Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.