Stroke is a leading cause of disability in the United States [1] [2] . Approximately 610,000 Americans suffer from an incident stroke each year, with the probability of death in the following 5 years ranging from 19% to 67%, depending on demographics [2] [3] . Along with focal neurological deficits, dementia is another common result of stroke found among survivors with up to one third estimated to have post-stroke cognitive impairment [4] . The latter along with dementia represents a major underlining cause for morbidity and mortality in patients after stroke [1] . As stroke mortality rates have been slowly decreasing and life expectancy increasing, possibly due to advances in patient care, delayed-onset post-stroke dementia (PSD) has begun to receive increased attention primarily because of its high disability and mortality risks [2] [5] . In contrast to early-onset PSD, which defines the development of dementia within 3 - 6 months after stroke onset, delayed-onset PSD describes dementia development any time thereafter and has a prevalence of 4.4% - 23.9% [5] . Early-onset dementia is mostly associated with dementia-prone stroke lesions, i.e. cerebral infarcts affecting large brain areas or infarcts targeting brain cognition centers, whereas delayed-onset dementia is mostly driven by severe cerebral small vessel disease (cSVD) (60% of delayed-onset PSD cases) and Alzheimer’s disease (AD) related pathologies (less than 20% of delayed-onset PSD cases) [5] .

Given the complex etiology of post-stroke dementia, particularly of its delayed-onset form, there is a paucity of information regarding the molecular mechanism (s) governing those processes which resulted in disappointing outcomes of clinical trials aimed at development of an efficient treatment for post-stroke cognitive impairment and dementia [5] . With that in mind, we took advantage of a unique opportunity to study post-mortem a case of an 85-year-old male with a history of stroke and PSD onset delayed by 22 years. The results of this study where we used a combination of neuropathological examination and genetic screening by WES on the NGS Illumina platform are presented in this report. It was concluded that such a long delay in LOPSD observed in the current case could be explained, at least in part, by an aberrant activation of the gut-brain and bladder-gut-brain axes with a potential contribution from cancer-dementia crosstalk.

The current case of remarkably delayed, by more than two decades, dementia in an elderly individual after a massive stroke and who eventually succumbed to bladder cancer could provide important insights into the etiology of stroke and post-stroke dementia. First, the results of neuropathological examination revealed this case as a massive stroke affecting predominantly the left hemisphere of the donor’s brain being consistent with the right-side paralysis and aphasia noted in the donor’s medical history. The detection of pronounced neuropathologies related to AD (amyloid plaques and NFTs), and vascular dementia (arteriosclerosis and microbleeds) point toward a possible development of mixed dementia at the terminal stage of the donor. Second, the presence of multiple mutated genes linked to stroke, including those involved in post-stroke recovery, MUC2 [9] , MUC4 [9] , and SLIT1 [10] , was consistent with stroke having a polygenic underlining. Third, very interesting was an association of three affected mucin gene family members with dementia and AD—MUC2 [11] , MUC4 [11] , and MUC6 [12] —which point toward a potential role of the gut-brain axis in the development of post-stroke dementia in the present case [13] [14] . Intriguingly, the same genes were also linked to bladder cancer: MUC2 [15] [16] , MUC4 [16] , and MUC6 [15] . Therefore, given an intricate inverse relationship between cancer and dementia in general [17] and between cancer and AD in particular [18] - [22] we may conclude that remarkably delayed (by 22 years) post-stroke dementia in the current case could be explained, at least in part, by mutually opposing effects of co-developing mixed dementia and bladder cancer in the donor. An adversely activated bladder-gut-brain axis [23] [24] may also serve as a contributing factor in the above process. It is worth noting that mutated genes associated with dementia were detected earlier in cancer patients [25] and affected cancer related pleiotropic genes have been recently found in an individual with amyotrophic lateral sclerosis [26] .

The results of the current study highlight potential involvement of the gut-brain and bladder-gut-brain axes as well as cancer comorbidity in the development of a remarkably delayed post-stroke dementia in the elderly individual.

The presence of a plethora of mutated pleiotropic genes involved in both cancer and stroke, cognitive impairment/dementia, AD, PD, and vascular dementia warrants a closer look at a putative link between cancer and neurological disorders.

Given that the current case describes a post-mortem, single-patient study, the respective results and conclusions should be viewed as an important lead for follow-up ante-mortem studies using a large cohort of patients diagnosed with post-stroke dementia and comorbid cancer.

We are grateful to all individuals and their families for their invaluable contribution to SLU Gift Body Program. We also like to thank Dr. Paul Cliften (Genome Technology Access Center, Washington University in St. Louis, St. Louis, MO, USA) for his expert assistance with the bioinformatics analysis as well as Caroline Murphy (Advanced Spatial Biology and Research Histology Core, SLU SOM) for her skillful help with the histology slides preparation.

The study was performed with a small number of cases.

All authors have read and approved the final version of the manuscript.

These data were presented in part as an abstract at the Experimental Biology Meeting on April 27-30, 2021.

This study was supported by the Center for Anatomical Science and Education, SLU School of Medicine.