Retinal inner nuclear layer thickness in the diagnosis of cognitive impairment explored using a C57BL/6J mouse model.

Major neurocognitive disorder (NCD) affects over 55 million people worldwide and is characterized by cognitive impairment (CI). This study aimed to develop a non-invasive diagnostic test for CI based upon retinal thickness measurements explored in a mouse model. Discrimination indices and retinal layer thickness of healthy C57BL/6J mice were quantified through a novel object recognition test (NORT) and ocular coherence tomography (OCT), respectively. Based on criteria from the Diagnostic and statistical manual of mental disorders 5th ed. (DSM-V), a diagnostic test was generated by transforming data into rolling monthly averages and categorizing mice into those with and without CI and those with a high or low decline in retinal layer thickness. Only inner nuclear layer thickness had a statistically significant relationship with discrimination indices. Furthermore, our diagnostic test was 85.71% sensitive and 100% specific for diagnosing CI, with a positive predictive value of 100%. These findings have potential clinical implications for the early diagnosis of CI in NCD. However, further investigation in comorbid mice and humans is warranted.

The central role of the NLRP3 inflammasome pathway in the pathogenesis of age-related diseases in the eye and the brain.

With increasing age, structural changes occur in the eye and brain. Neuronal death, inflammation, vascular disruption, and microglial activation are among many of the pathological changes that can occur during ageing. Furthermore, ageing individuals are at increased risk of developing neurodegenerative diseases in these organs, including Alzheimer's disease (AD), Parkinson's disease (PD), glaucoma and age-related macular degeneration (AMD). Although these diseases pose a significant global public health burden, current treatment options focus on slowing disease progression and symptomatic control rather than targeting underlying causes. Interestingly, recent investigations have proposed an analogous aetiology between age-related diseases in the eye and brain, where a process of chronic low-grade inflammation is implicated. Studies have suggested that patients with AD or PD are also associated with an increased risk of AMD, glaucoma, and cataracts. Moreover, pathognomonic amyloid-ß and α-synuclein aggregates, which accumulate in AD and PD, respectively, can be found in ocular parenchyma. In terms of a common molecular pathway that underpins these diseases, the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome is thought to play a vital role in the manifestation of all these diseases. This review summarises the current evidence regarding cellular and molecular changes in the brain and eye with age, similarities between ocular and cerebral age-related diseases, and the role of the NLRP3 inflammasome as a critical mediator of disease propagation in the eye and the brain during ageing.

Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy.

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1ß and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1+ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset.