Neuroimaging Advances in Parkinson's Disease and Atypical Parkinsonian Syndromes

Abstract

Parkinson's disease (PD) and atypical Parkinsonian syndromes are progressive heterogeneous neurodegenerative diseases that share clinical characteristic of parkinsonism as a common feature, but are considered distinct clinicopathological disorders. Based on the predominant protein aggregates observed within the brain, these disorders are categorized as, (1) α-synucleinopathies, which include PD and other Lewy body spectrum disorders as well as multiple system atrophy, and (2) tauopathies, which comprise progressive supranuclear palsy and corticobasal degeneration. Although, great strides have been made in neurodegenerative disease research since the first medical description of PD in 1817 by James Parkinson, these disorders remain a major diagnostic and treatment challenge. A valid diagnosis at early disease stages is of paramount importance, as it can help accommodate differential prognostic and disease management approaches, enable the elucidation of reliable clinicopathological relationships ideally at prodromal stages, as well as facilitate the evaluation of novel therapeutics in clinical trials. However, the pursuit for early diagnosis in PD and atypical Parkinsonian syndromes is hindered by substantial clinical and pathological heterogeneity, which can influence disease presentation and progression. Therefore, reliable neuroimaging biomarkers are required in order to enhance diagnostic certainty and ensure more informed diagnostic decisions. In this article, an updated presentation of well-established and emerging neuroimaging biomarkers are reviewed from the following modalities: (1) structural magnetic resonance imaging (MRI), (2) diffusion-weighted and diffusion tensor MRI, (3) resting-state and task-based functional MRI, (4) proton magnetic resonance spectroscopy, (5) transcranial B-mode sonography for measuring substantia nigra and lentiform nucleus echogenicity, (6) single photon emission computed tomography for assessing the dopaminergic system and cerebral perfusion, and (7) positron emission tomography for quantifying nigrostriatal functions, glucose metabolism, amyloid, tau and α-synuclein molecular imaging, as well as neuroinflammation. Multiple biomarkers obtained from different neuroimaging modalities can provide distinct yet corroborative information on the underlying neurodegenerative processes. This integrative "multimodal approach" may prove superior to single modality-based methods. Indeed, owing to the international, multi-centered, collaborative research initiatives as well as refinements in neuroimaging technology that are currently underway, the upcoming decades will mark a pivotal and exciting era of further advancements in this field of neuroscience.

Keywords: Parkinson's disease (PD); atypical Parkinsonian syndromes; biomarkers; diffusion-weighted imaging (DWI); magnetic resonance imaging (MRI); positron emission tomography (PET); single photon emission computed tomography (SPECT); transcranial sonography (TCS).

Figure 1

Schematic diagram illustrating the progression of α-synuclein pathology (Lewy bodies and Lewy neurites) in Parkinson's disease (PD), as proposed by Braak et al. (7). According to the Braak model, α-synuclein pathology in the brain spreads caudo-rostrally in a characteristic pattern starting in stage I and II in the lower brainstem regions of medulla oblongata and pons (dorsal motor nucleus of the cranial nerve IX/X, raphe nuclei, gigantocellular reticular nucleus, and coeruleus-subcoeruleus complex). In stages III and IV, α-synucleinopathy spreads further to the susceptible regions of the midbrain (e.g., dopaminergic neurons in the substantia nigra pars compacta), forebrain (e.g., hypothalamus, thalamus, and limbic system), as well as involving some of the cortical regions in the temporal mesocortex (transentorhinal region) and allocortex. In the last two stages (V and VI), α-synuclein pathology reaches the neocortex contributing to cognitive dysfunction (as seen in dementia with Lewy bodies and PD dementia). It is hypothesized that the initiation site of α-synuclein pathology may be outside the central nervous system (CNS), probably beginning in the peripheral (enteric) nervous system and gaining access to the CNS through retrograde transport mechanisms in a prion-like fashion. Whether this sequential spread of α-synuclein pathology as proposed by the Braak model is followed in all cases in Lewy body spectrum disorders is less clear. Figure adapted from Visanji et al. (32), under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0/).

Figure 2

Anatomical locations of some of the structures and regions important in Parkinson's disease and atypical Parkinsonian syndromes, highlighted on a standard averaged T1-weighted MNI template for normal population. Labeling: a = cerebral gray matter (frontal lobe), b = cerebral white matter (frontal lobe), c = head of caudate nucleus, d = midbrain, e1 = genu of corpus callosum, e2 = body of corpus callosum, e3 = splenium of corpus callosum, f = anterior limb of internal capsule, g = globus pallidus, h = hippocampus, i = insular cortex, j = claustrum, k = posterior limb of internal capsule, m = medulla oblongata, n = tail of caudate nucleus, o = optic radiation, p = putamen, q = crus cerebri (anterior portion of cerebral peduncle), r = red nucleus, s = substantia nigra, t = thalamus, u = pons, v = anterior horn of lateral ventricle, w = posterior horn of lateral ventricle, x = cerebellum, y = superior cerebellar peduncle, z = cingulate gyrus, * = fourth ventricle. Note: p and g together constitute the lentiform nucleus; c and p together constitute the dorsal striatum. The template was obtained from McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University Copyright 1993–2004 Fonov et al. (33).

Figure 3

The “swallow tail” sign. All MRI presented above are taken at the level of substantia nigra in the midbrain. (A) Susceptibility-weighted MRI depicting dorsolateral nigral hyperintensity (the “swallow tail” sign, red arrows) in a healthy control. Loss of dorsolateral nigral hyperintensity can be seen in PD and may even be seen in some PSP and MSA cases on susceptibility-weighted MRI. (B) High resolution susceptibility-weighted MRI (gradient echo-echo planar imaging sequence, magnitude image) is shown for a PD patient and a control. (C) High resolution T2*/susceptibility-weighted MRI (multi-shot fast field echo-echo planar imaging sequence) is shown for a PD patient and a non-PD case who was diagnosed with aneurysmal subarachnoid hemorrhage. In both (B,C), loss of dorsolateral nigral hyperintensity (white arrows) corresponding to nigrosome-1 can be seen in PD as compared to control and a non-PD subject. (A) was adapted from Chougar et al. (40), and (B,C) were adapted from Schwarz et al. (39), under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). HC, healthy control; MSA, multiple system atrophy; PD, Parkinson's disease; PSP, progressive supranuclear palsy.

Figure 4

Magnetic resonance imaging of a patient clinically-diagnosed with multiple system atrophy (cerebellar type). (a) Axial proton density weighted sequence is presented at the level of pons, which shows cruciform pontine T2 hyperintensity as consistent with the “hot cross bun” sign, resulting from selective susceptibility of the pontocerebellar tract in multiple system atrophy (cerebellar type). In addition, disproportionate atrophy of the pons and partially visible cerebellar hemispheres are also apparent. (b) Axial fluid-attenuated inversion recovery (FLAIR) sequence is presented with cruciform T2 hyperintensity within the pons and middle cerebellar peduncles (i.e., “middle cerebellar peduncle” sign) along with marked atrophy. In addition, cerebellar hemispheric and vermian atrophy is evident with ex vacuo dilatation of the fourth ventricle. (c) Sagittal T1-weighted sequence is presented showing disproportionate atrophy of the brainstem and cerebellar vermis. Figure reproduced from Saeed et al. (10), under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/).

Figure 5

Magnetic resonance imaging of a patient clinically-diagnosed with progressive supranuclear palsy. The left image is a sagittal T1-weighted sequence showing the “hummingbird” sign (smaller box), while the right image is an axial T1-weighted sequence showing the “morning glory” sign (arrows); both features are seen in progressive supranuclear palsy. The pons (p) and midbrain (m) areas are also shown (larger box), and their ratios have been used to calculate an index to assist in the diagnosis (128). Figure adapted from Saeed et al. (10), under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/).

Figure 6

Magnetic resonance imaging of a patient with a pathology-proven diagnosis of corticobasal degeneration. Serial axial T1-weighted sequences are presented showing right greater than left parietofrontal atrophy commonly seen in corticobasal syndrome. Figure reproduced from Saeed et al. (10), under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/).

Figure 7

Transcranial sonographic image outlining the butterfly-shaped midbrain at the mesencephalic plane. In (A), enlarged area of echogenicity at the anatomical site of substantia nigra (long arrows) is depicted, as may be seen in Parkinson's disease patients. In addition, interrupted echogenic line of the raphe can be observed (short arrows). In (B), normal midbrain echogenicity is shown. The aqueduct is indicated by an asterisk. Figure adapted from Richter et al. (182), under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).