Imaging biomarkers in Parkinson's disease and Parkinsonian syndromes: current and emerging concepts

Abstract

Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson's disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson's disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson's disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a 'window' into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson's disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well-established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors), and cerebral perfusion, 5) positron emission tomography for gauging nigrostriatal functions, glucose metabolism, amyloid and tau molecular imaging, as well as neuroinflammation, 6) myocardial scintigraphy for dysautonomia, and 7) transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity. Imaging biomarkers, using the 'multimodal approach', may aid in making early, accurate and objective diagnostic decisions, highlight neuroanatomical and pathophysiological mechanisms, as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials.

Keywords: Atypical parkinsonian syndrome; Biomarkers; Diffusion tensor imaging; MRI; Molecular imaging; Myocardial scintigraphy; PET; Parkinson’s disease; SPECT; Transcranial sonography.

Fig. 1

MRI of a patient with a clinical diagnosis of Multiple System Atrophy-C. a Axial proton density sequence at the level of the pons demonstrates cruciform pontine T2 hyperintensity consistent with the ‘hot cross bun’ sign secondary to selective vulnerability of the pontocerebellar tract in Multiple System Atrophy-C. Disproportionate atrophy of the pons and partially visualized cerebellar hemispheres is also evident. b Axial FLAIR sequence with cruciform T2 hyperintensity within the pons and middle cerebellar peduncles (i.e., ‘Middle Cerebellar Peduncle sign’) with marked atrophy. Cerebellar hemispheric and vermian atrophy is also seen with ex vacuo dilatation of the fourth ventricle. c Sagittal T1 sequence showing marked atrophy of the brainstem and cerebellar vermis

Fig. 2

MRI of a patient with a clinical diagnosis of Progressive Supranuclear Palsy. The image on the left is a sagittal T1 sequence showing the ‘Hummingbird’ sign (box), while the axial T1 sequence on the right shows the ‘Morning Glory’ sign (arrows) both features seen in Progressive Supranuclear Palsy

Fig. 3

MRI of a patient with a pathological diagnosis of Corticobasal Degeneration. Serial axial T1 sequences showing right greater than left parietofrontal atrophy typical of that seen in Corticobasal Syndrome. In this case, the patient had a confirmed pathological diagnosis of Corticobasal Degeneration