Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy

Abstract

Lewy bodies (LBs) are alpha-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. In this study, the presence of LBs was assessed in 347 cases of Alzheimer disease (AD). In 87 cases, LB pathology was diagnostic of brainstem (n=3), transitional (n=32), or diffuse (n=52) Lewy body disease (LBD). The remaining 260 cases of AD were screened for amygdala LBs (AD/ALB) and 62 (24%) cases were found. If AD/LBD cases are included, LBs were detected in 149 (43%) cases of AD. The presence alpha-synuclein pathology was assessed in multiple brain regions of the 62 cases of AD/ALB and 57 randomly selected cases of AD, and only sparse alpha-synuclein pathology was detected in both. The burden of alpha-synuclein pathology in brainstem nuclei, amygdala, and neocortex was significant lower in AD/ALB than in AD/LBD. In comparison to AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density, or apolipoprotein E epsilon4 allele frequency. The results suggest that AD/ALB is pathologically different from AD/LBD, suggesting that it is a neuropathologically distinct and isolated alpha-synucleinopathy.

FIGURE 1

A flow chart of the study design and classification of cases stemming from standardized neuropathologic evaluation to diagnose Alzheimer disease (AD) or AD with concurrent Lewy body disease, followed by screening of the amygdala section for α-synuclein pathology in all AD cases. For those cases with any amygdala α-synuclein pathology, brainstem sections and limbic areas (entorhinal and cingulate gyrus) are screened for additional α-synuclein pathology. A randomly selected series of AD cases without amygdala α-synuclein pathology are processed in the same manner.

FIGURE 2

(A–C) Range of morphologies of amygdala Lewy bodies (LBs) with hematoxylin and eosin. Only exceptionally do amygdala LBs have dense hyaline appearance (C); more often, they are pleomorphic lesions indistinguishable from neurofibrillary tangles (NFTs) (A, B). Double immunostaining with α-synuclein (brown) and phospho-tau (blue) shows a range of morphologies as well. The α-synuclein-positive lesions may be separate from tau-positive NFTs (D) or variably intermingled within the same neuron (E, F). Double immunofluorescence for α-synuclein (red) and tau (green). In the merged images (I, L), colocalization appears yellow. The neuron in (G–I) shows intermingling of 2 distinct types of filaments within the same neuron, whereas the neuron in (J–L) shows an α-synuclein-immunoreactive, Lewy-like inclusion surrounded by a tau-immunoreactive NFT. Scale bars = (A–F) 25 μm; (D–I) 10 μm.

FIGURE 3

Immunoelectron microscopy with double labeling for phospho-tau (18-nm gold particles) and α-synuclein (5-nm gold particles) in a case of Alzheimer disease with amygdala Lewy bodies. (A) At low magnification, a neuron with separate filamentous aggregates (right) is distinguished from the neuron with intermingled filaments (left). L, lipofuscin. Boxed areas are enlarged at the same magnification in (B) and (C). (B) In the intermingled area, tau filaments (arrowheads) have the morphology of paired helical filaments (P) or straight filaments (S). α-synuclein is localized to granulofilamentous aggregates, arrows). (C) Tightly packed tau filaments (arrowheads) are separate from α-synuclein-positive granulofilamentous aggregates (arrows). The α-synuclein filaments are thinner than tau filaments. Scale bars = (A) 1 μm; (B, C) 300 nm.

FIGURE 4

Comparison of α-synuclein score in subcortical regions vulnerable to α-synuclein pathology (DMN, LC, SN, and nbM) for AD/ALB, AD/TLBD, and AD/DLBD. The boxes show median and 25th and 75th percentiles with whisker plots showing 10th and 90th percentiles. The outliers are shown as filled circles. (Median scores for DMN, LC, SN, and nbM are, respectively: AD/ALB 0, 0, 0, 0; AD/TLBD 2.4, 1.7, 2.3, 1.4; and AD/DLBD 2.9, 2.9, 2.8, 2.1.) The α-synuclein scores in DMN, LC, SN and nbM are significantly less in AD/ALB than in AD/TLBD and AD/DLBD (*, p < 0.05). The α-synuclein scores in DMN, LC, SN, and nbM are significantly less in AD/TLBD than in AD/DLBD (#, p < 0.05). DMN, dorsal motor nucleus; nbM, nucleus of Meynert; AD/ALB, Alzheimer disease with amygdala Lewy bodies; AD/TLBD, Alzheimer disease with transitional Lewy body disease; AD/DLBD, Alzheimer disease with diffuse Lewy body disease.

FIGURE 5

Comparison of Lewy body (LB) density in amygdala and cortical regions for AD/ALB, AD/TLBD and AD/DLBD. Bar charts show mean and error bars show standard errors of the mean. The LB density in the amygdala was significantly less (*) in AD/ALB than in AD/TLBD and AD/DLBD. The LB density in the limbic cortices (ERC and Cing) and ST was significantly less (*) in AD/ALB than in AD/TLBD and AD/DLBD. The LB density in the limbic cortices and neocortical regions (ST, MF, and IP) was significantly less (#) in AD/TLBD than AD/DLBD. AD/ALB, Alzheimer disease with amygdala Lewy bodies; AD/TLBD, Alzheimer disease with transitional Lewy body disease; AD/DLBD, Alzheimer disease with diffuse Lewy body disease; ERC, entorhinal cortex; Cing, anterior cingulate gyrus; ST, superior temporal gyrus; MF, middle frontal gyrus; IP, inferior parietal gyrus.

FIGURE 6

(A) Neuronal population is well preserved in the substantia nigra with hematoxylin and eosin stain. (B) A few Lewy neurites (arrows) are found in the substantia nigra with α-synuclein immunostaining. (C) Neuronal loss with Lewy bodies (LBs) is found in the substantia nigra. Higher magnification (upper left corner, arrows) shows brainstem type LBs clearly. (D) Large amounts of LBs and Lewy neurites are found in the substantia nigra with α-synuclein immunostaining. (A, B) Alzheimer disease with amygdala Lewy bodies case, (C, D) Alzheimer disease with diffuse Lewy body disease case. Scale bars = (A–D) 50 μm.

FIGURE 7

Average amygdala Lewy body counts in 4 subtypes of Alzheimer disease with amygdala Lewy bodies. The boxes show median and 25th and 75th percentiles with whisker plots showing 10th and 90th percentiles. The outliers are shown as filled circles. Type 1 cases have no α-synuclein pathology in the brainstem and limbic cortex. Type 2 cases have α-synuclein pathology only in the brainstem. Type 3 cases have α-synuclein pathology only in the limbic cortex. Type 4 cases have α-synuclein pathology in the brainstem and limbic cortex. #, Type 4 significantly different from type 1. LB, Lewy body.