The deficit in cerebral blood flow (CBF) seen in patients with hypertension- induced vascular dementia is increasingly viewed as a therapeutic target for disease- modifying therapy. Progress is limited, however, due to uncertainty surrounding the mech-anisms through which elevated blood pressure reduces CBF. To investigate this, we used the BPH/2 mouse, a polygenic model of hypertension. At 8 mo of age, hypertensive mice exhibited reduced CBF and cognitive impairment, mimicking the human presentation of vascular dementia. Small cerebral resistance arteries that run across the surface of the brain (pial arteries) showed enhanced pressure- induced constriction due to diminished activity of large- conductance Ca2+- activated K+ (BK) channels—key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca2+ signals from the sarco-plasmic reticulum (SR), termed Ca2+ sparks, leads to hyperpolarization and vaso-dilation. Combining patch- clamp electrophysiology, high- speed confocal imaging, and proximity ligation assays, we demonstrated that this vasodilatory mechanism is uncoupled in hypertensive mice, an effect attributable to physical separation of the plasma membrane from the SR rather than altered properties of BK channels or Ca2+ sparks, which remained intact. This pathogenic mechanism is responsible for the observed increase in constriction and can now be targeted as a possible avenue for restoring healthy CBF in vascular dementia.

    Taylor JL, Walsh KR, Mosneag IE, Danby TGE, Luka N, Chanda B, Schiessl I, Dunne RA, Hill-Eubanks D, Hennig GW, Allan SM, Nelson MT, Greenstein AS, Pritchard HAT. Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia. Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2307513120. doi: 10.1073/pnas.2307513120. Epub 2023 Aug 7. PMID: 37549299.

   Personalised Alzheimer’s disease prevention and treatment will rely on APOE genotyping but this well-validated predictor is rarely used in routine care

Preventing or delaying dementia due to Alzheimer’s disease (AD) requires personalised risk reduction plans.1 Obesity is a risk factor for dementia, but the ‘obesity paradox’ suggests that higher mid-life Body Mass Index (BMI) is a risk factor for later dementia, whereas higher BMI seems protective in later life. This is partially explained by the long AD prodrome itself causing weight loss,2 but heterogeneity between studies perhaps implies additional mechanisms.

Dunne R, Coulthard E. Tipping the scales towards routine APOE genotyping. Journal of Neurology, Neurosurgery & Psychiatry 2023;94:669.

   Compassionate Healthcare for Excellence in Nursing: Experiences of Nurses and Healthcare Staff Participating in a Reflective Course on Compassion-Based Care; British Journal of Nursing 2019. Donald G, Wilson I, McCarthy J, Hall I, Crossley B, Adshead P, Shaw V, Dunne R, Dwyer T. Br J Nurs. 2019 Aug 8;28(15):1020-1025. doi: 10.12968/bjon.2019.28.15.1020

     Husain MO, Zehra SS, Umer M, Kiran T, Husain M, Soomro M, Dunne R, Sultan S, Chaudhry IB, Naeem F, Chaudhry N, Husain N. Stigma toward mental and physical illness: attitudes of healthcare professionals, healthcare students and the general public in Pakistan. BJPsych Open. 2020 Aug 3;6(5):e81. doi: 10.1192/bjo.2020.66. PMID: 32741419; PMCID: PMC7453804.

     Iracema Leroi, Charlotte Peel, Rebecca Davenport, Ross Dunne, Louise Ebenezer, Mahesh Gopakumar, Vachagan Krishnaswami, Jane Lumsden, Helen Martin, Jane Price and Wilby Williamson (2020) Blueprint for a Brain Health Clinic to Detect and Manage Early-Stage Cognitive Decline: A Consensus Exercise. J Neurodegener Disord 3(1):54-64.