- This study explored how Parkinson's disease (PD) alters functional brain network organization and how pathologic α-synuclein protein spreads across such networks
- A novel graph theory metric called stepwise functional connectivity was used to characterize which brain regions were connected to the medulla oblongata—the putative "epicenter" of PD—at various distances
- PD-related connectivity did originate from the brainstem and there were distinct patterns of functional network reorganization for early- and late-stage PD patients
- The level of expression of SNCA, the gene encoding α-synuclein protein, in various brain regions of healthy individuals was associated with the brain connectivity pattern from the epicenter of PD in the brainstem
- α-synuclein pathology along a brain disease trajectory might lead to early diagnosis of PD and could inspire novel therapeutic strategies
The Lewy bodies that accumulate to cause Parkinson's disease (PD) include aggregates of a neuronal protein called α-synuclein. In a seminal paper published in Neurobiology of Aging in 2003, Braak and colleagues proposed based on postmortem findings that pathologic α-synuclein spreads throughout the nervous system in patients with PD in a definable pattern, from one susceptible brain region to the next.
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Recent evidence supports this hypothesis, but there's a gap in knowledge: how does the spread of α-synuclein relate to disruptions of large-scale neuronal circuits across the brain? Silvia Basaia, of the Gordon Center for Medical Imaging at Massachusetts General Hospital, Jorge Sepulcre, MD, PhD, DMSc, director of the Sepulcre Lab at the center, and colleagues shed light on this question in NeuroImage: Clinical.
Graph theory–based research into PD pathophysiology uses resting-state functional MRI (RS-fMRI) to investigate the propagation of neuronal damage through brain networks. This study relied on a new graph theory metric called stepwise functional connectivity (SFC). It characterizes which brain regions are connected to specific "seed" brain areas at different "link-step" distances (the number of links in the path that connect a node to the target region).
154 patients with PD underwent clinical, cognitive/behavioral, and RS-fMRI assessments. Two main subgroups were identified: 86 patients with mild disease and 60 with moderate to severe disease. 60 age- and sex-matched healthy controls were also assessed.
The researchers produced SFC maps across different link-step distances from the medulla oblongata, which was used as the seed because it's the first stage of PD in the staging system by Braak and colleagues. Maps of healthy controls were used to confirm connectivity alterations in PD patients.
Connectivity Reorganization in PD Patients
The findings were strongly consistent with the ascending staging system of brain pathology in PD as proposed by Braak and colleagues:
In healthy controls, there were direct functional connections from the medulla seed (one step-link distance) to the insular cortex and the pericalcarine, lingual and parahippocampal gyri. With subsequent steps in the connectivity network, the seed region was connected to parietal, occipital, and temporal lobes, and the isthmus cingulate gyrus.
In patients with PD, maps displayed similar pathways at all link-step distances, but patterns of disruption were different in the two PD subgroups:
- Patients with mild PD showed direct and indirect connections from the medulla to the sensorimotor network, cuneus, lateral and medial parietal regions, and lateral temporal gyri. These results are congruent with the mild motor and cognitive symptoms of early PD
- Patients with moderate to severe PD showed decreased connectivity in the cuneus and the lateral occipital and inferior parietal gyri at one link-step distance. Across two to four link steps, there were extended reductions in functional connectivity within the parietal, temporal, frontal, and limbic lobes. These findings jibe with the non–motor manifestations of moderate to severe PD, including more severe cognitive impairment
Thus, functional connections form "highways" through which α-synuclein could spread.
The researchers also determined that the level of expression of SNCA (the gene encoding α-synuclein protein) in various brain regions in healthy individuals was associated with the region's proximity to the "epicenter" of PD pathology.
Thus, brain regions close to the epicenter that have greater SNCA expression may accumulate pathological proteins before other regions do, conferring greater vulnerability to disease spread.
In fact, in an exploratory analysis, genes displaying high spatial overlap with the PD-related spreading pattern were predominantly implicated in microtubule function, which is impaired in neurons overexpressing α-synuclein.
These results lay a foundation for studying functional network reorganization at different stages of PD. A better understanding of the mechanisms underlying distinct spatial vulnerability to PD pathology could inform early diagnosis and novel therapeutic strategies.
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