The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson’s disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson’s disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson’s disease. Forty-two patients with mild-to-moderate stage Parkinson’s disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson’s disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson’s disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson’s disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson’s disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

A BS TRACT: Background: Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective: This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods: GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[ 18 F]fluoro-L-Dopa positron emission tomography (PET), [ 18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results: Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [ 18 F] fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers.

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting-state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) is largely unknown. We applied multimodal resting-state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG-PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the

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.

Graphical abstract