The development of
dementia is a devastating aspect of
Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective
therapies to prevent and slow progression to PD
dementia (PDD), the key mechanisms that determine why some people with PD develop early
dementia, while others remain cognitively unaffected, need to be understood.
Neuroinflammation and
tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other
neurodegenerative disorders leading to
dementia. However, whether these processes mediate
dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index
neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to
dementia risk in our '
Neuroinflammation and Tau Accumulation in
Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high
dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher
dementia risk have greater
inflammation and/or tau accumulation in advance of significant
cognitive decline. We found significantly elevated
neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high
dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high
dementia risk group also showed significantly greater
neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions.
Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall
neuroinflammation burden also correlated with serum levels of pro-inflammatory
cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional
neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high
dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional
neuroinflammation in early PD might underpin higher risk for PDD development, indicating
neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow
dementia development using immunomodulatory strategies.