Unique Case of Remarkably Delayed Dementia in an Elderly Individual after a Massive Stroke: Neuropathological and Genetic Insights

Stroke is a neurological disorder defined as an interruption of blood delivery to the brain resulting in impairment of brain function often leading to patient’s death or major disability. Stroke survivors face a high risk of developing dementia which is a major cause of post-stroke morbidity and mortality. Dementia occurring 3 - 6 months after stroke is termed late-onset post-stroke dementia (LOPSD) and has gained a significant interest from researchers because such delay, which could last for several years, offers a reasonable time window for early dementia diagnosis and preventive treatment. However, little is known about biological process (es) underlining LOSPD. To address this issue, we studied a case of an 85-year-old individual who had stroke with right-side paralysis and aphasia with dementia onset 22 years later. The cause of death for this individual was bladder cancer. By using a combination of post-mortem neuropathological examination and genetic screening by whole exome sequencing (WES) on the Illumina next generation sequencing (NGS) platform we identified the respective pathological and genetic underlining. The former was characterized by pronounced cerebral small vessel disease (cSVD) and Alzheimer’s disease (AD) related pathologies that were known to be associated with LOSPD. The latter revealed a presence of multiple pleiotropic genes with rare (minor allele frequency, MAF ≤ 0.01) pathological/deleterious variants that were grouped into the following categories: Cardiovascular Disease, Stroke, Vascular Pathology, Cognitive Impairment/Dementia, Alzheimer’s Disease, Vascular Dementia, and Parkinson’s Disease. Surprisingly, the genetic pleiotropy was observed not only across those categories but also across an additional category “Cancer” including bladder cancer. The mucin gene family members MUC2, MUC4, and MUC6 were the ones of such pleiotropic genes. The results obtained pointed toward a potential involvement of the gut-brain and bladder-gut-brain axes as well as a putative cross-talk between cancer and dementia in the development of LOPSD in an elderly individual.