Zachary Rickmeyer

Background : Vascular cognitive impairment (VCI) is a broad term which covers a number disorders ranging from mild neurocognitive disorder to vascular dementia.¹ As of 2018, VCI was the second-leading cause of dementia globally, accounting for as many as 20 million cases of dementia.¹ To date, there are no disease-modifying treatments for VCI patients with pre-existing cognitive impairment.¹ There are a multitude of pathophysiologic causes of VCI, however one of the most fundamental causes of VCI seems related to the production of nitric oxide (NO), prominently known for its vasodilatory function.² Given the scarcity of treatment options for VCI patients, this study investigated potential drug targets which may provide these patients relief.

Methods: A literature review of the PubMed database limited to publications within the past 5 years, utilized search terms including: “vascular cognitive impairment,” “vascular dementia,” “nootropics,” “nitric oxide,” “cerebral,” “eNOS,” and “ADMA.”

Results: This review focused on two aspects of VCI: first, the effects of altered NO metabolism on cognitive outcomes. Key to this report was a 2022 study by Bragin et al. which showed endothelial nitric oxide synthase (eNOS) knockout mice recovered less effectively from traumatic brain injury than wild type mice at 1 day and 3 days later.³ Work by Choi et al. compared the effect of the exogenous eNOS inhibitor asymmetric dimethyl arginine (ADMA) on transgenic mice expressing β-amyloid precursor proteins (Tg-SwDI) against WT counterparts. The authors found both groups experienced elevated mean arterial pressure, but only the Tg-SwDI mice performed significantly worse on Morris water maze tests of cognitive capacity.⁴ The second part of this study was an investigation of repurposing existing drugs which may be beneficial to patients with VCI. Ölmestig et al. showed that prostaglandin-5 inhibitors (which deactivate NO second messengers) significantly increased cerebral microperfusion in patients with cerebral small vessel disease.⁵ Tarantini et al. showed aged mice treated with nicotinamide mononucleotide showed improved performance during maze tests, improved cerebral blood flow, and better levels of cellular ATP.⁶

Conclusions: Based on the results of this investigation, it is reasonable to conclude the NO pathway has a significant, but not solitary, role in cognitive outcomes for VCI patients. NO deficiency exacerbates existing pathology. Further, there are NO-related drug targets which show promise and warrant further investigation.

Works cited:

1. Rundek T, Tolea M, Ariko T, Fagerli EA, Camargo CJ. Vascular Cognitive Impairment (VCI). Neurotherapeutics. 2022;19(1):68-88. doi:10.1007/s13311-021-01170-y
2. Hosoki S, Hansra GK, Jayasena T, et al. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol. 2023;19(12):737-753. doi:10.1038/s41582-023-00884-1
3. Bragin DE, Bragina OA, Trofimov AO, Huang PL, Atochin DN. Involvement of Endothelial Nitric Oxide Synthase in Cerebral Microcirculation and Oxygenation in Traumatic Brain Injury. Adv Exp Med Biol. 2022;1395:3-7. doi:10.1007/978-3-031-14190-4_1
4. Choi S, Singh I, Singh AK, Khan M, Won J. Asymmetric dimethylarginine exacerbates cognitive dysfunction associated with cerebrovascular pathology. FASEB J. 2020;34(5):6808-6823. doi:10.1096/fj.201901318R
5. Ölmestig J, Marlet IR, Hansen RH, et al. Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study. Brain Commun. 2020;2(1):fcaa020. doi:10.1093/braincomms/fcaa020
6. Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019;24:101192. doi:10.1016/j.redox.2019.101192