Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia

Abstract

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-β amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.

Fig 1. Analyzed regions of interest (ROIs) in the ¹⁸F-florbetepir PET scans.

Six individual cortical ROIs and a cerebellum ROI were analyzed for regional ¹⁸F-florbetapir binding and to calculate a composite ROI (see Methods). Representative trans-axial images from a Aβ negative (left) and positive (right) study demonstrate each ROI: (A) parietal cortex and precuneus; (B) frontal cortex; (C) anterior and posterior cingulate gyrus; (D) temporal cortex; and (E) cerebellum. Darker regions indicate higher ¹⁸F-florbetapir retention.

Fig 2. Cognitive and motor characteristics of the study population.

A. Total DRS-2 score was significantly lower in PD-MCI participants (134.3, 131.7 to 136.9) as compared to PD-NC (139.3, 138.1 to 140.6) (t(57) = 4.12, p < 0.001). B. Total DRS-2 score was not significantly different among H&Y stages (F(5,53) = 0.54, p = 0.75). C. UPDRS part 3 score was significantly higher in PD-MCI (24.5, 19.9 to 29.2) as compared to PD-NC (17.1, 14.5 to 19.7) (t(59) = 3.07, p = 0.003). D. UPDRS part 3 score was significantly higher with advanced H&Y stage (1.0: 13.5, 0.2 to 26.8; 1.5: 14.8, 12.4 to 17.1; 2.0: 18.2, 15.5 to 20.9; 2.5: 17.3, 11.8 to 22.9; 3.0: 28.1, 22.3 to 33.9; 4.0: 48) (F(5,55) = 6.57, p < 0.001). There was no association between motor phenotype (TD vs. PIGD) and H&Y stage (data not shown). Data depicted are mean ± 95% C.I. Significance identified by one-way ANOVA and Tukey post-hoc test. *** p < 0.005, **** p < 0.001.

Fig 3. No correlation between composite ¹⁸F-florbetapir ROI SUVr and global cognition or memory performance.

(A) Total DRS-2 score did not significantly correlate with composite ROI SUVr values, either analyzed in aggregate (F(1,57) = 2.39, p = 0.13) or by cognitive diagnosis (for PD-NC, F(1,39) = 0.02, p = 0.90; for PD-MCI, F(1,16) = 2.15, p = 0.16). (B) DRS-2 memory subscore did not significantly correlate with composite ROI SUVr values, either analyzed in aggregate (F(1,57) = 3.80, p = 0.06) or by cognitive diagnosis (for PD-NC, F(1,39) = 0.00, p = 0.97; for PD-MCI, F(1,16) = 3.03, p = 0.10).

Fig 4. Association between posterior cingulate gyrus ¹⁸F-florbetapir SUVr and memory performance.

Regional ¹⁸F-florbetapir SUVr in the posterior cingulate gyrus significantly correlated with memory performance on the DRS-2 (A, rho = -0.446, p < 0.0005), which remained significant after adjusting for age, sex, disease duration, education, and presence of an APOE ε4 allele (rho = -0.316, p = 0.02). SUVr in this region also significantly correlated with immediate free total recall on the Hopkins Verbal Learning Test (HVLT-R) on unadjusted analysis (B, rho = -0.263, p = 0.04) but not after adjustment (rho = -0.263, p = 0.054). Outlying participant indicated by closed diamond.