Abstract
Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. In-vivo human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients (N = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients (N = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects (N = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are “higher” in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.
Highlights
Parkinson’s disease, a progressive neurodegenerative disorder, is characterized by cell death within the substantia nigra and presence of misfolded α-synuclein aggregates known as Lewy Bodies throughout the brain parenchyma [1,2,3]
With respect to sex distribution, males represented the majority of the subjects of each group. 61.8% of the early PD were male, 74.3% of the advanced PD were male, and 65.0% of the healthy controls were male, with males more highly represented in the advanced PD group than in the early PD group (p = 0.016)
This study found pathological gray matter degeneration in subcortical regions of the cholinergic basal forebrain and amygdala, but found general sparing of hippocampal and neo-cortical regions in a population of advanced Parkinson’s disease patients
Summary
Parkinson’s disease, a progressive neurodegenerative disorder, is characterized by cell death within the substantia nigra and presence of misfolded α-synuclein aggregates known as Lewy Bodies throughout the brain parenchyma [1,2,3]. Braak’s model and others which propose ascending spread are underpinned by the “prion hypothesis,” which posits that α-synuclein aggregates are taken up by neurons, undergo axonal transport, and are transferred to other neurons as part of a prion-like process [5]. This model has been challenged [6], and other theories have emerged which attempt to explain why large subsets of PD patients do not follow proposed ascending patterns [7]. Though it is important to note that evidence connecting Lewy pathology and neuronal death is limited and neurodegeneration is an imperfect proxy for Lewy pathology [16, 17], neurodegeneration may follow an ascending pattern in PD that is measurable via MRI techniques
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