A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease

Abstract

The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein.

Fig 1

Typical examples of α-synuclein-immunoreactive pathology in dementia associated with Parkinson’s disease (DPD): Lewy bodies (LB*), Lewy neurites (LN, arrow heads), and Lewy grains (LG, arrows) (α-synuclein immunohistochemistry, haematoxylin, bar = 50µm)

Fig 2

Densities of α-synuclein-immunoreactive lesions (LB, LN, and LG) in various brain regions (MF = middle frontal cortex, CG = cingulate gyrus, EC = entorhinal cortex, CA1/4 = sectors of the hippocampus, DG = dentate gyrus, ML = molecular layer, GCL = granule cell layer, AM = basolateral amygdala, U = Upper cortex, L = Lower cortex) in fifteen cases of dementia associated with Parkinson’s disease (DPD). Analysis of variance (ANOVA): One-way, (Upper cortical laminae, CA1-2, DG, AM): Between brain regions LB F = 8.71 (P < 0.01); LN F = 8.44 (P < 0.001), LG F = 8.31 (P < 0.001); One-way, (Upper cortical laminae, CA1-4, DG, AM): Between brain regions LB F = 8.49 (P < 0.01); LN F = 9.44 (P < 0.001), LG F = 8.82 (P < 0.001)

Fig 3

Densities of vacuoles, abnormally enlarged neurons (EN), neurons, and glial cell nuclei in the upper and lower laminae in in various brain regions (MF = middle frontal cortex, CG = cingulate gyrus, EC = entorhinal cortex, CA1/4 = sectors of the hippocampus, DG = dentate gyrus, ML = molecular layer, GCL = granule cell layer, AM = basolateral amygdala, U = Upper cortex, L = Lower cortex) in fifteen cases of dementia associated with Parkinson’s disease (DPD). Analysis of variance (ANOVA): (Upper cortical laminae, CA1-4, AM): Between brain regions EN F = 1.81 (P < 0.05); neurons F = 3.74 (P < 0.01), Vacuoles F = 0.73 (P > 0.05), GL F = 8.66 (P < 0.001); (Lower cortical laminae, CA1-4, AM): Between brain regions EN F = 1.06 (P < 0.05); neurons F = 2.16 (P < 0.05), Vacuoles F = 0.72 (P > 0.05), GL F = 9.15 (P < 0.001)

Fig 4

Examples of the distribution of LC, LN, and LG across the cortex from pia mater to white mater in the entorhinal cortex (EC) of a case of dementia associated with Parkinson’s disease (DPD)

Fig 5

Principal components analysis (PCA) of fifteen cases of dementia associated with Parkinson’s disease (DPD) based on all histological variables. A plot of cases in relation to PC1 and PC2