Cerebral Vascular Density and Its Possible Correlation with Alzheimer Disease Progression in Elderly Individuals with Rheumatoid Arthritis
Authors: Maglasang Maurice Nigel A. , Frolov Andrey , Guzman Miguel , Echols Scott , Daly Daniel 
Published: May 2022

Background

Rheumatoid Arthritis (RA) is characterized by chronic systemic inflammation, primarily affecting the joints. In RA patients, high concentrations of inflammatory cytokines are found within the synovial fluid and serum (PMID: 1700672). These cytokines reduce the blood brain barrier (BBB) integrity by decreasing the expression of tight junction proteins (PMID: 29910805). In a RA animal model such decreased BBB integrity has been shown to affect the transport of amyloid beta peptide (Aβ) between the peripheral circulation and the brain, thereby promoting accumulation of Aβ within the cerebral vasculature followed by the endothelial cell degeneration (PMID: 22029666). In humans, a similar pathologic process is a major risk factor for Alzheimer’s Disease (AD) which accelerates neuronal loss and cognitive impairment associated with AD (PMID: 29377008). Assessment of cerebral vascular density is an emerging modality for detection and monitoring the progression of cerebrovascular disease (CVD) (PMID: 15564412). Advancements in computed tomography (CT) imaging technology and the development of novel contrast agents should provide more accurate assessment for CVD in humans.

The main objective of this study was to test high‐resolution CT imaging using a recently developed BriteVu contrast agent in conjunction with conventional histological techniques for postmortem assessment of CVD and pathology in the cerebral cortex and hippocampus of two male cadavers. The first, 74‐year‐old (D1) was diagnosed with RA and AD, while the second, 90‐year‐old (D2) had RA.

Results

The D1 and D2 cadavers were fixed and perfused with BriteVu contrast agent. Heads were removed and scanned with a VimagoGT30 CT scanner at 300 µm. The images were subjected to volumetric analysis using Radiant software. The results showed that scans of the cerebral cortex from D2, specifically the middle frontal, inferior parietal, and superior temporal gyri, had significantly lower mean Hounsfield unit densities (MHUD) than those from the same regions of D1. The MHUD from the hippocampal scans revealed no significant difference. The lower MHUD count in the D2 cortex in comparison to D1 most likely reflects a lower vascular density in the respective brain region. The AD related pathology in both donors was assessed by histochemical and immunohistochemical techniques. To that end, the brains were extracted and fixed in formalin solution for 12‐16 weeks. The brain hippocampal and cortical sections were paraffin processed followed by H&E and immunohistochemical staining for Aβ 1‐42, phospho‐tau, and phospho‐TDP‐43. Analysis of the data confirmed the AD diagnosis in D1 and demonstrated distinct AD pathology in D2. The AD staging could be characterized as mild in D1 and intermediate in D2.

Conclusions

i) The vascular density within the cerebral cortex of elderly individuals with RA could correlate with the AD progression. ii) The adaptation of the reported CT imaging technique for its use in live individuals could provide more sensitive and accurate method for assessing AD in RA patients at the early AD stage(s).