Abstract
According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer’s disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.
Highlights
Dementia with Lewy bodies (DLB) is considered the second most common primary neurodegenerative disease after Alzheimer’s disease (AD) [44, 45]
It has been proposed that AD-associated Lewy-related pathology (LRP) forms a distinct type of α-synucleinopathy, in which LRP arises de novo in the amygdala and progresses to entorhinal cortex, brainstem or both [11, 43]
Based on LRP scores and LRP classification types, we studied if individuals could fit consistently to the previously hypothesized caudo-rostral and amygdala-based progression patterns by systematic anatomical scoring
Summary
Dementia with Lewy bodies (DLB) is considered the second most common primary neurodegenerative disease after Alzheimer’s disease (AD) [44, 45]. The widely used DLB Consortium guidelines [28] classify LRP into three types based on the extent of LRP in the brain—brainstem, limbic or neocortex—following a generally accepted concept, suggesting that LRP evolves hierarchically, starting in the dorsal medulla oblongata and progressing through brainstem to supratentorial structures (caudo-rostral progression) [1, 6, 23, 28, 29]. Recent studies, based on a datadriven cluster analysis, supported this hypothesis [34, 41] and an idea of distinct types of LRP progression has been raised by some other studies [3, 13] It is noteworthy, that the hypothesis of LRP based in the amygdala is grounded on studies on patients from referral-based institutions, and these studies may involve selection bias. Population- or community-based studies that could ascertain the prevalence of the amygdala-based progression pattern in the general population do not exist
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