A Stress Syndrome Prototype Reflects Type 3 Diabetes and Ischemic Stroke Risk: The SABPA Study.

Type 3 diabetes (T3D) accurately reflects that dementia, e.g., Alzheimer's disease, represents insulin resistance and neurodegeneration in the brain. Similar retinal microvascular changes were observed in Alzheimer's and chronic stressed individuals. Hence, we aimed to show that chronic stress relates to T3D dementia signs and retinopathy, ultimately comprising a Stress syndrome prototype reflecting risk for T3D and stroke. A chronic stress and stroke risk phenotype (Stressed) score, independent of age, race or gender, was applied to stratify participants (N = 264; aged 44 ± 9 years) into high stress risk (Stressed, N = 159) and low stress risk (non-Stressed, N = 105) groups. We determined insulin resistance using the homeostatic model assessment (HOMA-IR), which is interchangeable with T3D, and dementia risk markers (cognitive executive functioning (cognitiveexe-func); telomere length; waist circumference (WC), neuronal glia injury; neuron-specific enolase/NSE, S100B). Retinopathy was determined in the mydriatic eye. The Stressed group had greater incidence of HOMA-IR in the upper quartile (≥5), larger WC, poorer cognitiveexe-func control, shorter telomeres, consistently raised neuronal glia injury, fewer retinal arteries, narrower arteries, wider veins and a larger optic cup/disc ratio (C/D) compared to the non-Stressed group. Furthermore, of the stroke risk markers, arterial narrowing was related to glaucoma risk with a greater C/D, whilst retinal vein widening was related to HOMA-IR, poor cognitiveexe-func control and neuronal glia injury (Adjusted R2 0.30; p ≤ 0.05). These associations were not evident in the non-Stressed group. Logistic regression associations between the Stressed phenotype and four dementia risk markers (cognitiveexe-func, telomere length, NSE and WC) comprised a Stress syndrome prototype (area under the curve 0.80; sensitivity/specificity 85%/58%; p ≤ 0.001). The Stress syndrome prototype reflected risk for HOMA-IR (odds ratio (OR) 7.72) and retinal glia ischemia (OR 1.27) and vein widening (OR 1.03). The Stressed phenotype was associated with neuronal glia injury and retinal ischemia, potentiating glaucoma risk. The detrimental effect of chronic stress exemplified a Stress syndrome prototype reflecting risk for type 3 diabetes, neurodegeneration and ischemic stroke.

Delayed retinal vein recovery responses indicate both non-adaptation to stress as well as increased risk for stroke: the SABPA study.

OBJECTIVES: Low or high sympatho-adrenal-medullary axis (SAM) and hypothalamic-pituitary-adrenal axis (HPA) dysregulation reflect chronic stress. Retinal vessel dynamics may relate to SAM, HPA activity and stroke risk. Our objectives were therefore to assess the relationships between retinal vessel, SAM and HPA responses, and to determine stroke risk. METHODS: A prospective bi-ethnic gender cohort (n = 275, 45 ± 9 years) was included. Urine/serum/saliva samples for SAM [norepinephrine:creatinine ratio (u-NE)] and HPA [adrenocorticotrophic hormone (ACTH), cortisol] were obtained at baseline, three-year follow up and upon flicker light-induced provocation. Diastolic ocular perfusion pressure was measured as a marker of hypo-perfusion. Retinal arterial narrowing and venous widening calibres were quantified from digital images in the mydriatic eye. A validated stress and stroke risk score was applied. RESULTS: An interaction term was fitted for venous dilation in u-NE tertiles (p ≤ 0.05) and not in u-NE median/quartiles/quintiles. Independent of race or gender, tertile 1 (low u-NE) had a 112% increase in u-NE, decreases in cortisol, and no changes in ACTH over three years (positive feedback). Tertile 3 (high u-NE) contradictorily had decreases in u-NE and cortisol, and increases in ACTH (negative feedback). In tertile 1, reduced arterial dilation, and faster arterial vasoconstriction and narrowing were related to higher SAM activity and hypo-perfusion (p ≤ 0.05), whereas delayed venous dilation, recovery and widening were related to cortisol hypo-secretion (p ≤ 0.05). In tertile 1, delayed venous recovery responses predicted stress and stroke risk [odds ratio 4.8 (1.2-19.6); p = 0.03]. These associations were not found in u-NE tertiles 2 and 3. CONCLUSIONS: In response to low norepinephrine, a reflex increase in SAM activity occurred, enhancing arterial vasoconstriction and hypo-perfusion. Concomitant HPA dysregulation attenuated retinal vein vasoactivity and tone, reflecting delayed vein recovery responses and non-adaptation to stress. These constrained vein recovery responses are indicative of increased chronic stress and stroke risk.

Retinal-glia ischemia and inflammation induced by chronic stress: The SABPA study.

Background: Psychobiological processes linking stress and vascular diseases remain poorly understood. The retina and the brain share a common embryonic-diencephalon origin and blood-barrier physiology e.g. ongoing ischemia facilitates S100B release with astrocytic activity and glial-fibrillary-acidic-protein expression (GFAP). However, GFAP decreases revealed astrocyte pathology in the prefrontal cortex of depression/suicide cases; and might be a key mechanism in stress - disease pathways. Methods: A chronic emotional stress phenotype independent of age, ethnicity or sex was used to stratify the current prospective cohort (N â€‹= â€‹359; aged 46 â€‹± â€‹9 years) into Stress (N â€‹= â€‹236) and no-Stress groups (N â€‹= â€‹123). Prospective data for glia ischemia risk markers were obtained, including 24 â€‹h BP, fasting S100B, GFAP, HbA1C and tumor-necrosis-factor-α (TNF-α). At 3-yr follow-up: diastolic-ocular-perfusion-pressure (indicating hypo-perfusion risk) was measured and retinal vessel calibers were quantified from digital images in the mydriatic eye. Results: Higher hypertension (75% vs. 16%), diabetes (13% vs. 0%) and retinopathy (57% vs. 45%) prevalence was observed in Stress compared to no-Stress individuals. Stressed individuals had consistently raised S100B, TNF-α, HbA1C and higher diastolic-ocular-perfusion-pressure, but decreases in GFAP and GFAP:S100B. Furthermore stroke risk markers, arterial narrowing and venous widening were associated with consistently raised S100B, GFAP:S100B (p â€‹= â€‹0.060), TNF-α and higher diastolic-ocular-perfusion-pressure [Adj. R2 0.39-0.41, p â€‹≤ â€‹0.05]. No retinal-glia associations were evident in the no-Stress group. Conclusions: Retinal-glia ischemia and inflammation was induced by chronic stress. Persistent higher inflammation and S100B with GFAP decreases further reflected stress-induced astrocyte pathology in the human retina. It is recommended to increase awareness on chronic stress and susceptibility for brain ischemia.

Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials.

Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.