Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85

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.

Keywords: Aged, 80 and over; Alzheimer’s disease; Lewy body diseases; Lewy-related pathology; Population-based; α-Synuclein.

Fig. 1

Distribution and density of Lewy-related pathology in the investigated brain regions. a, b Caudo-rostral n = 83 and c, d amygdala-based n = 40 progression patterns visualized (y-axis) by quantity (n) and percentage (%). Mean values (SD) of the investigated brain regions are shown in Supplemental Table 4. Spinal S = sacral spinal cord, spinal Th = thoracic spinal cord, sn = substantia nigra, amy = amygdala, ca2 = ca2 of hippocampus, tox = transentorhinal cortex of hippocampus, cing = cingulate cortex, temp = temporal cortex, front = frontal cortex, pariet = parietal cortex, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Lewy-related pathology

Fig. 2

Classification of individuals by the progression pattern of LRP by K-means cluster analysis. On the y-axis is the semiquantitative LRP score (0–4). On the x-axis are the different CNS regions from spinal cord to neocortex: 1 = sacral spinal cord, 2 = thoracic spinal cord, 3 = medulla, 4 = pons, 5 = substantia nigra, 6 = amygdala, 7 = ca2 of hippocampus, 8 = transentorhinal cortex of hippocampus, 9 = cingulate cortex, 10 = temporal cortex, 11 = frontal cortex, 12 = parietal cortex. Clusters 1, 2, 3, 5 and 6 include individuals with caudo-rostral LRP progression pattern. Clusters 7, 8 and 9 include individuals with amygdala-based progression pattern Cluster 4 includes most severe LRP progression pattern from both caudo-rostral and amygdala-based patterns