Cortical microvascular raspberries and ageing: an independent but not exclusive relationship

Abstract

Introduction: Raspberries are cerebral microvascular formations of unknown origin, defined as three or more transversally sectioned vascular lumina surrounded by a common perivascular space. We have previously demonstrated an increased raspberry density in the cortex of patients with vascular dementia and cerebral atherosclerosis, while studies by other authors on overlapping and synonymously defined vascular entities mainly associate them with advancing age. The aim of the present study was to examine the relationship between raspberries and age in a large study sample while including multiple potential confounding factors in the analysis.

Materials and methods: Our study sample consisted of 263 individuals aged 20-97 years who had undergone a clinical autopsy including a neuropathological examination. The cortical raspberry density had either been quantified as part of a previous study or was examined de novo in a uniform manner on haematoxylin- and eosin-stained tissue sections from the frontal lobe. The medical records and autopsy reports were assessed regarding neurodegeneration, cerebral infarcts, cerebral atherosclerosis and small vessel disease, cardiac hypertrophy, nephrosclerosis, hypertension, and diabetes mellitus. With the patients grouped according to 10-year age interval, non-parametric tests (the Kruskal-Wallis test, followed by pairwise testing with Bonferroni-corrected P values) and multiple linear regression models (not corrected for multiple tests) were performed.

Results: The average raspberry density increased with advancing age. The non-parametric tests demonstrated statistically significant differences in raspberry density when comparing the groups aged 60-99 years and 70-99 years to those aged 20-29 years (P < 0.012) and 30-59 years (P < 0.011), respectively. The multiple linear regression models demonstrated positive associations with age interval (P < 0.001), cerebral atherosclerosis (P = 0.024), cardiac hypertrophy (P = 0.021), hypertension subgrouped for organ damage (P = 0.006), and female sex (P = 0.004), and a tendency towards a negative association with Alzheimer's disease neuropathologic change (P = 0.048).

Conclusion: The raspberry density of the frontal cortex increases with advancing age, but our results also indicate associations with acquired pathologies. Awareness of the biological and pathological context where raspberries occur can guide further research on their origin.

Keywords: Aging; Atherosclerosis; Brain ischemia; Cardiac hypertrophy; Cerebral angiogenesis; Cerebral neovascularization; Cerebrovascular disease; Hypertension; Small vessel disease.

Fig. 1

A–C Three microvascular raspberries in the frontal cortex. Stain: haematoxylin and eosin. Scalebar: 50 µm

Fig. 2

The frequency distribution of age within the study sample (n = 263)

Fig. 3

Overview of a tissue section from the frontal lobe. The cortical area has been delineated and the observed raspberries have been marked. Stain: haematoxylin and eosin. Scalebar: 2 mm

Fig. 4

Raspberry density (raspberries/cm²) of the frontal cortex in relation to 10-year age interval. With the sample grouped according to the graph, pairwise testing (Dunn’s post hoc test with Bonferroni-corrected P values; Table 5) indicated differences between the groups aged 20–59 years and those aged 70–99 years; the group aged 20–29 years also differed from the one aged 60–69 years

Fig. 5

Raspberry density (raspberries/cm²) of the frontal cortex in relation to A hypertension subgrouped for organ damage, B cardiac hypertrophy, C cerebral atherosclerosis, and D sex. Multiple linear regression models indicated independent associations between these variables and raspberry density (Table 6 and Table 7; for definitions of the variables, see Table 2)