Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes

Abstract

Background: Parkinsonisms are neurodegenerative disorders characterized pathologically by α-synuclein-positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau-positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown.

Objective: The current study investigated the pathological correlates of these susceptibility MRI measures.

Methods: In vivo MRIs (T1- and T2-weighted, and T2*) and pathology were obtained from 14 subjects enrolled in an NINDS PD Biomarker Program (PDBP). We assessed R2* and quantitative susceptibility mapping values in the SN, semiquantitative α-synuclein, tau, and iron values, as well as neuronal and glial counts. Data were analyzed using age-adjusted Spearman correlations.

Results: R2* was associated significantly with nigral α-synuclein (r = 0.746; P = 0.003). Quantitative susceptibility mapping correlated significantly with Perls' (r = 0.758; P = 0.003), but not with other pathological measurements. Neither measurement correlated with tau or glial cell counts (r ≤ 0.11; P ≥ 0.129).

Conclusions: Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as α-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. © 2018 International Parkinson and Movement Disorder Society.

Keywords: iron; substantia nigra; susceptibility MRI; tau; α-synuclein.

Figure 1

A and B Schematic of substantia nigra segmentation (pars compacta and pars reticulata are lumped together). Illustration of the region of interest (ROI) definition of the substantia nigra in the axial (A) and coronal (B) planes. The yellow arrows indicate the substantia nigra (SN) and red nucleus (RN). C-E: Representative immunostaining images from the substantia nigra pars compacta. α-Synuclein (panel C) immunostaining is a light brown color (denoted by arrow), whereas neuromelanin is a darker shade of brown. Note that α-synuclein immunostaining is not visible in all neuromelanin-containing neurons. Panel D demonstrates tau distribution (light brown) and the presence of helical paired filaments. An arrow denotes a neuron filled with tau and the star indicates a glial cell with tau and filaments. In Panels C and D, hematoxylin is used as a counterstain (blue/purple cells). Perls’ stain for iron is depicted in Panel E. The reaction product is bright blue, with the arrow denoting neuromelanin-positive cells with iron inclusions. F-O: Spearman correlation analysis of raw pathology (α-synuclein, tau, neuronal and glial cell counts, and Perls’ staining) and MRI (R2* and QSM) data. α-Synuclein was either present (1) or absent (0) in the SN. Level of tau staining in the SN was rated semi-quantitatively by our neuropathologist (JWB) such that 0=absence of tau, 1=low levels, 2=moderate levels, 3=ubiquitous levels. Significant findings are in bold-italics, and trends in italics. The diagnosis for each subject is noted above the correlation graphs.