Retinal biomarkers for Alzheimer's disease and vascular cognitive impairment and dementia (VCID): implication for early diagnosis and prognosis.

Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer's disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD-ß-amyloid peptide and hyperphosphorylated tau proteins-are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators-such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction-for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.

TGF-ß superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury.

Traumatic brain injury (TBI) increases neurogenesis in the forebrain subventricular zone (SVZ) and the hippocampal dentate gyrus (DG). Transforming growth factor-ß (TGF-ß) superfamily cytokines are important regulators of adult neurogenesis, but their involvement in the regulation of this process after brain injury is unclear. We subjected adult mice to controlled cortical impact (CCI) injury, and isolated RNA from the SVZ and DG at different post-injury time points. qPCR array analysis showed that cortical injury caused significant alterations in the mRNA expression of components and targets of the TGF-ß, BMP, and activin signaling pathways in the SVZ and DG after injury, suggesting that these pathways could regulate post-injury neurogenesis. In both neurogenic regions, the injury also induced expression of Runt-related transcription factor-1 (Runx1), which can interact with intracellular TGF-ß Smad signaling pathways. CCI injury strongly induced Runx1 expression in activated and proliferating microglial cells throughout the neurogenic regions. Runx1 protein was also expressed in a subset of Nestin- and GFAP-expressing putative neural stem or progenitor cells in the DG and SVZ after injury. In the DG only, these Runx1+ progenitors proliferated. Our data suggest potential roles for Runx1 in the processes of microglial cell activation and proliferation and in neural stem cell proliferation after TBI.

Candesartan, an angiotensin II AT1-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice.

Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT1R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFß1 while increasing expression of TGFß3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT1R-blocking and PPARγ activation properties may have therapeutic value in treating TBI.