Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia.

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 mechanisms 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 sarcoplasmic reticulum (SR), termed Ca2+ sparks, leads to hyperpolarization and vasodilation. 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.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Systematic review and meta-analysis of bifrontal electroconvulsive therapy versus bilateral and unilateral electroconvulsive therapy in depression.

OBJECTIVES: Our aim was to perform a meta-analysis of randomized controlled trials comparing efficacy and side effects of bifrontal (BF) ECT to bitemporal (BT) or unilateral (RUL) ECT in depression. METHODS: We performed a systematic review of randomized controlled trials comparing BF ECT with RUL or BT ECT in depression. Eight trials (n=617) reported some cognitive outcome. Efficacy was measured by reduction in Hamilton Depression Rating Scale score. Cognitive outcomes were limited to Mini-Mental State Examination (MMSE) in seven studies, with two studies measuring each of: Complex-figure delayed recall, Trail-making tests and verbal learning. RESULTS: Efficacy was equal between BF and BT ECT (Hedges's g=0.102, P=0.345, confidence interval (CI): -0.110, 0.313) and BF and RUL ECT (standardized mean difference=-0.12, P=0.365, CI: -0.378, 0.139). Post-treatment MMSE score decline was less for BF than BT ECT (g=0.89, CI: 0.054, 1.724) but not RUL ECT. RUL ECT impaired Complex figure recall more than BF ECT (g=0.76, CI :0.487, 1.035), but BF ECT impaired word recall more than RUL ECT (g=-1.45, CI: -2.75, -0.15). CONCLUSIONS: Bifrontal ECT is not more effective than BT or RUL ECT but may have modest short-term benefits for specific memory domains. BF ECT has potential advantages, but given longer experience with BT and RUL, bifrontal ECT requires better characterization.