From synaptic pathology to connectome dysfunction in Parkinson's disease
Authors:   , Frigerio Irene 
Published: August 2024

Defining the regional patterns of synaptic and neuro-axonal degeneration in Parkinson’s disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB) phenotypes is crucial to understand disease progression and severity. The development of pathology-sensitive MRI biomarkers, able to detect such neurodegenerative patterns, is also important for monitoring disease status and the effectiveness of disease-modifying therapies. The aim of this thesis was to disentangle the differential patterns of synaptic and neuro-axonal degeneration in PD, PDD, and DLB, and the pathological sensitivity of structural, diffusion, and network MRI changes in PD and Alzheimer’s disease (AD).
This thesis shows that synaptic pathology is an early event in PD, occurring before dopaminergic denervation and possibly before occurrence of motor symptoms (Chapter II). Our results bring evidence to the hypothesis that α-synuclein pathological aggregation at dopaminergic terminals in the striatum might start in prodromal phases of disease and lead to dopaminergic terminal loss. These results suggest that attention should be shifted to early processes occurring at dopaminergic terminals to identify early disease mechanisms and drug targets in PD. In line with the theory of selective vulnerability in PD, results of this thesis also indicate that dopaminergic synapses are more vulnerable than cortical glutamatergic synapses to α-synuclein pathology. Moreover, we bring forward novel regional patterns of cortical synaptic and neuro-axonal degeneration, which differentiate PD from PDD and DLB (Chapter III and IV), indicating that clinical phenotyping has a neurobiological basis. Our results support the hypothesis that there might be a cortical dopaminergic dysfunction driven by α-synuclein pathology in PD, involving the anterior insular and anterior cingulate cortices in PD, and additionally the parahippocampal cortex in PDD and DLB (Chapter III). This thesis also highlights the contributing role of parahippocampal synaptic and neuro-axonal degeneration to cognitive impairment in PD and DLB (Chapter III and IV). Parahippocampal connections are specifically important since they converge information coming from the cortex to the hippocampus. The disruption of these connections leads to decreased cross-talk between cortex and hippocampus, and eventually might cause dementia in PD and DLB. The involvement of anterior insular and parahippocampal cortices was also captured at the connectome level by structural network resilience and topology changes in PD(D) compared to controls (Chapter VI). Finally, this thesis demonstrates that MRI cortical atrophy strongly reflects regional p-tau burden in AD (Chapter V), suggesting that cortical atrophy can be regarded as a pathology sensitive MRI biomarker in the context of AD. The picture is different in PD(D) and DLB, where MRI cortical atrophy only weakly reflects neuro-axonal degeneration, while it does not capture pathological accumulations (Chapter IV). Instead, intracortical mean diffusivity (MD) moderately captures not only neuro-axonal degeneration, but also severe α-synuclein and p-tau pathological burden and in PDD/DLB (Chapter IV). Unfortunately, lower pathological α-synuclein burden in the cortex such as can be found in the non-demented PD cortex, still remain undetected by intracortical MD. In Chapter VI, we show that structural network topology does not reflect regional pathology load, neuro-axonal, or synaptic degeneration in PD(D), but instead it seems to be able to capture connectome dysfunction and disease progression in PD(D). Therefore, in the context of pathological sensitivity of MRI, among the MRI biomarkers investigated in this thesis, intracortical MD seems to be the most promising pathology-sensitive MRI biomarker in PDD/DLB.