A Rare Case of Delayed‐Onset Post‐Stroke Dementia Associated with Cerebral Small Vessel and Alzheimer's Disease Pathologies

Abstract

Background For individuals surviving a stroke, the prevalence of delayed-onset post-stroke dementia (PSD) is 4-24% as compared to ~20% for early-onset PSD, which has a major contributing factor (30-50%) of pronounced Alzheimer's disease (AD) pathology. However, severe sporadic cerebral small vessel disease (cSVD) appears to play a dominant role (~60%) in the development and progression of delayed-onset PSD while the contribution from pronounced AD pathology diminishes to ~20%. The significance of severe sporadic cSVD is also underscored by the fact that it may trigger additional pathological processes, independent of recurrent strokes. The original view on the two major pathologies contribution to PSD was that they develop independently of one another, but researchers are now investigating the common etiology shared between the two, particularly through their underlining genetics. The latter, however, has been significantly complicated by their polygenic nature. Therefore, a combination of thorough postmortem histopathological examination and a genetic screen using the Next Generation Sequencing (NGS) platform could provide a powerful tool to address the above shortcomings. Results We report an 85-year-old, male cadaver who suffered a major stroke at age 59 which resulted in right-side paralysis and aphasia, followed by the onset of dementia 22 years later. Upon gross inspection of the brain, a large necrotic area was visible on the left hemisphere. Histological examination of the brain tissue stained with hematoxylin and eosin (H&E) revealed several important pathologies. These included the presence of neurofibrillary tangles and amyloid plaques in the hippocampus and frequent amyloid plaques in the cerebral cortex, indicating AD neuropathological changes. Upon further examination, thickened arterial walls, enlarge perivascular spaces, arteriolosclerosis, microbleeds, and white matter rarefactions were also noted and consistent with features of cSVD. Subsequent staining using the Bielschowsky method, on brain tissue procured from the same areas, confirmed the H&E staining results while showing some positive staining of vessel walls that might be consistent with amyloid angiopathy, further suggesting cSVD presence. In order to gain insights into the molecular mechanisms underlining the observed brain pathologies, the whole coding region (exome) sequencing of the DNA extracted from the cadaveric tissue was performed on the Ilumina NGS platform. This genetic screen identified ~ 200 rare, deleterious genetic variants with the minor allele frequency of ≤ 1%. Among those variants, the most intriguing was the presence of the mucin gene family members, MUC2, MUC4, MUC6, and MUC16; previously linked to AD (MUC6 & MUC16), cerebrovascular pathology (MUC16), and dementia (MUC2 & MUC4). Conclusion The current case highlights potentially additive, or synergistic, involvement of AD and cSVD pathologies into the development of delayed-onset PSD. As the mucin gene family is highly expressed in the gut, the observed genetic polymorphisms may underscore the importance of the gut-vagus nerve-brain axis in delayed-onset PSD.