Acetylcholinesterase (AchE) PET imaging

Methyl-4-piperidyl acetate (MP4A) and related tracers have been used to study PD and PD-D, demonstrating cholinergic dysfunction comparable to or greater than that found in AD [64]. Poor performance on tests of attention and working memory, followed by executive function, correlated with loss of cortical cholinesterase activity in PD-D [65]. A study that measured both striatal fluorodopa (F-DOPA) uptake and MP4A found that PD patients without dementia had moderate cholinergic dysfunction, but those with PD-D had a severe cholinergic deficit affecting the entire cortex, presumably reflecting loss of ascending projections from the nucleus basalis of Meynert. Frontal and temporo-parietal F-DOPA and MP4A binding covaried in PD-D, suggesting a role for both cholinergic denervation and dopaminergic deficits in PD-D [66].

Amyloid imaging

Amyloid imaging has been used to distinguish AD and DLB from PD-D, with a higher amyloid burden being associated with AD and DLB [67]. In a longitudinal study of 46 PD cases without dementia followed for up to 5 years [68], amyloid burden, measured by retention of Pittsburgh compound B (PiB), did not differ between PD cases who were cognitively normal and those with PD-MCI at baseline. However, higher amyloid burden did predict cognitive decline and transition to MCI and dementia, independent of APOE e4. Amyloid burden was correlated with executive impairment but did not correlate with motor decline. The authors suggested that amyloid burden may contribute to cognitive impairment both independently and by enhancing the toxicity of a-synuclein.

Cerebrospinal fluid (CSF) biomarkers

CSF biomarkers that are classically associated with AD including amyloid-beta peptide 1-42 (Api-42), total tau, and p-tau have been studied in DLB and PD-D compared with AD and controls. There are only a few longitudinal studies of CSF biomarkers in PD-MCI patients, and change in the level of these proteins over time and the combination of biomarkers as they relate to cognitive impairment has not been systematically examined in large samples. A comprehensive review of CSF biomarkers was published by Parnetti et al. in 2013 [69]. There have been no studies of biomarkers associated with cognitive impairment in pre-manifest PD in carriers of dominantly inherited mutations such as LRRK2, or in carriers of GBA mutations who are at high risk of DLB and PD-D [54]. The strongest evidence was found for a relationship between low CSF A^1-42 and cognitive decline, suggesting an association between amyloid and cognitive decline in PD. Mean CSF Api-42 in PD has been reported to be lower than in healthy controls, but higher than in AD [70]. In a cross-sectional study, A^1-42 levels decreased systematically from cognitively normal PD to PD- MCI to PD-D to AD [71]. A 19% reduction of CSF A^1-42 was seen in newly diagnosed PD patients compared with controls in the Norwegian ParkWest study, and it correlated with memory performance [72]. A longitudinal study of 45 PD patients found that low CSF A^1-42 was an independent predictor of cognitive decline, a level of <192 being associated with a 5.85 points/year decline on the MDRS; CSF total tau or p-tau were not associated with cognitive decline [73]. It is unclear to what extent changes in CSF DJ-1 or a-synuclein levels correlate with cognitive impairment, since these measures have not been assessed longitudinally in parallel with changes in cognitive function.

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