Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Abstract

The prevailing network perspective of Parkinson’s disease (PD) emerges not least from the ascending neuropathology traceable in histological studies. However, whether longitudinal in vivo correlates of network degeneration in PD can be observed remains unresolved. Here, we applied a trimodal imaging protocol combining 18F-fluorodeoxyglucose (FDG)- and 18F-fluoro-L-Dopa- (FDOPA)-PET with resting-state functional MRI to assess longitudinal changes in midbrain metabolism, striatal dopamine depletion and striatocortical dysconnectivity in 17 well-characterized PD patients. Whole-brain (un)paired-t-tests with focus on midbrain or striatum were performed between visits and in relation to 14 healthy controls (HC) in PET modalities. Resulting clusters of FDOPA-PET comparisons provided volumes for seed-based functional connectivity (FC) analyses between visits and in relation to HC. FDG metabolism in the left midbrain decreased compared to baseline along with caudatal FDOPA-uptake. This caudate cluster exhibited a longitudinal FC decrease to sensorimotor and frontal areas. Compared to healthy subjects, dopamine-depleted putamina indicated stronger decline in striatocortical FC at follow-up with respect to baseline. Increasing nigrostriatal deficits and striatocortical decoupling were associated with deterioration in motor scores between visits in repeated-measures correlations. In summary, our results demonstrate the feasibility of in-vivo tracking of progressive network degeneration using a multimodal imaging approach. Specifically, our data suggest advancing striatal and widespread striatocortical dysfunction via an anterior-posterior gradient originating from a hypometabolic midbrain cluster within a well-characterized and only mild to moderately affected PD cohort during a relatively short period.

Progressive Cerebrovascular Reactivity Reduction Occurs in Parkinson's Disease: A Longitudinal Study

“…A recent study further reported reduced FC of the posterior putamen with widespread cortical areas at follow-up visits. 47 In agreement with the abovementioned studies, serial spatial FC varied over time in PD patients. Furthermore, our findings implicated that brain FC dysfunction was secondary to or synchronized cerebral perfusion as disease progressing.…”

“…Li et al 46 found progressive weakening FC of the posterior putamen, the thalamus, midbrain, supplementary motor area, and sensorimotor cortex over time. A recent study further reported reduced FC of the posterior putamen with widespread cortical areas at follow‐up visits 47 . In agreement with the above‐mentioned studies, serial spatial FC varied over time in PD patients.…”

Simulated brain networks reflecting progression of Parkinson’s disease

“…Julian Caspers 3 , Christian Mathys 3,4,5 , Martin Südmeyer 6,7 , Felix Hoffstaedter 1,2 , Christian J. Hartmann 6 , Christian Rubbert 3 , Alfons Schnitzler 6 , Bernd Turowski 3…”

“…Medication with levodopa or dopaminergic therapy is an effective treatment of PD without diminished effects in a long disease duration of decades 4,5 . However, with such a long-time neurologic state before and after the diagnosis, it may cause corresponding irreversible brain network alteration 6,7 as well as drug-induced dyskinesia 8 or cognitive deficits 9 . These degenerative alterations are important for understanding the progression of the disease in pre-motor or prodromal periods (before the disease onset), which is one of clinical challenges.…”

“…For the severity, we utilize the unified Parkinson’s disease rating scale (UPDRS) 25 in the modeling approach. It is also used to infer the effect of medication (dopaminergic therapy) on motor impairment with the extent of striatal dopamine depletion 7 . Accordingly, we demonstrate an important and intriguing dependence of the modeling results on clinical variables by applying the behavioral network-based model fitting.…”