A cortical microvascular structure in vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls: a sign of angiogenesis due to brain ischaemia?

Abstract

AimsWe observed a microvascular structure in the cerebral cortex that has not, to our knowledge, been previously described. We have termed the structure a ‘raspberry’, referring to its appearance under a bright‐field microscope. We hypothesized that raspberries form through angiogenesis due to some form of brain ischaemia or hypoperfusion. The aims of this study were to quantify raspberry frequency within the cerebral cortex according to diagnosis (vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls) and brain regions (frontal, temporal, parietal and occipital cortices, regardless of diagnosis).Materials and methodsIn each of 10 age‐matched subjects per group, a 20‐mm section of the cerebral cortex was examined in haematoxylin‐and‐eosin‐stained sections of the frontal, temporal and parietal, and/or occipital lobes. Tests were performed to validate the haematoxylin‐and‐eosin‐based identification of relative differences between the groups, and to investigate inter‐rater variability.ResultsRaspberry frequency was highest in subjects with vascular dementia, followed by those with frontotemporal lobar degeneration, Alzheimer's disease and last, nondemented controls. The frequency of raspberries in subjects with vascular dementia differed from that of all other groups at a statistically significant level. In the cerebral lobes, there was a statistically significant difference between the frontal and occipital cortices.ConclusionsWe believe the results support the hypothesis that raspberries are a sign of angiogenesis in the adult brain. It is pertinent to discuss possible proangiogenic stimuli, including brain ischaemia (such as mild hypoperfusion due to a combination of small vessel disease and transient hypotension), neuroinflammation and protein pathology.

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

“…The number of capillaries in the frontal cortex, as revealed with GLUC-t immunohistochemistry, is significantly increased in all GGT cases when compared with controls in the present series. Our hypothesis is that this effect is due to the neuronal loss and cortical atrophy of frontal degeneration in GGT cases, together with angiogenesis (capillary sprouting) induced by protein pathology and neuroinflammation, as proposed in ageing and other brain diseases [93].…”

A multi-omics dataset for the analysis of Frontotemporal Dementia genetic subtypes

“…Our pathway enrichment and deconvolution analyses pointed toward increased blood vessel abundance and growth in FTD brains compared to controls, which is consistent with the results from the RiMod-FTD proteomics data (Mediema et al, manuscript in preparation). It is generally not known how and if the vasculature system is involved in FTD pathogenesis, although recent studies have observed abnormalities in a mouse model of tau pathology and post-mortem human brains 22,23 . To our knowledge, angiogenesis as a pathological feature in several genetic FTD subtypes has not been reported before and therefore depicts an important subject to study for future FTD research.…”

“…3A). Another recent study observed a particular microvascular structure with increased frequency in brains of patients with frontotemporal lobar degeneration (FTLD) 23 and Park et al have shown that soluble tau can interfere with nitric oxide production and thus lead to reduced vasodilation of blood vessels, ultimately leading to insufficient blood supply 24 . To better understand transcriptional changes and regulatory mechanisms, it is often helpful to cluster genes into modules with similar expression or function.…”

Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

“…3a). Another recent study observed a particular microvascular structure with increased frequency in brains of patients with frontotemporal lobar degeneration (FTLD)23 and Park et al have shown that soluble tau can interfere with nitric oxide production and thus lead to reduced vasodilation of blood vessels, ultimately leading to insufficient blood supply24 .…”

“…In a recent review, Molnár and colleagues have discussed several available drugs that could potentially regulate necroptosis39 , highlighting the potential of this pathway as a drug target for developing therapies for FTD.Our pathway enrichment and deconvolution analyses pointed toward increased blood vessel abundance and growth in FTD brains compared to controls, which is consistent with the results from the RiMod-FTD proteomics data (Mediema et al, manuscript in preparation). It is generally not known how and if the vasculature system is involved in FTD pathogenesis, although recent studies have observed abnormalities in a mouse model of tau pathology and post-mortem human brains22,23 . To our knowledge, angiogenesis as a pathological feature in several genetic FTD subtypes has not been reported before and therefore depicts an important subject for FTD research.…”