Abstract
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.
There are no treatments available for vascular dementia, the second-most common dementia syndrome, and patients decline rapidly after diagnosis. This syndrome is primarily due to hypertension and is ...associated with reduced cerebral blood flow (CBF). To explore this, we studied mechanisms of vascular dysfunction in pial arteries from hypertensive mice. These mice exhibit reduced CBF, hyperconstricted pial arteries, and behavior approximating human vascular dementia. Using myography, electrophysiology, and Ca
2+
imaging, we found that the increased constriction was due to separation of the sarcoplasmic reticulum from the plasma membrane in vascular smooth muscle cells, which prevented vasodilatory Ca
2+
signals from activating large-conductance K
+
channels. We propose that restoring this coupling could improve CBF and slow disease progression.
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 Ca
2+
-activated K
+
(BK) channels—key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca
2+
signals from the sarcoplasmic reticulum (SR), termed Ca
2+
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 Ca
2+
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.
Abstract
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.
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 Ca
-activated K
(BK) channels-key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca
signals from the sarcoplasmic reticulum (SR), termed Ca
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 Ca
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.
We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been ...undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation.
Seventeen consecutive PAH patients (mean age 56 ± 15) who underwent right heart catheterization mean pulmonary arterial pressure (mPAP) 43 ± 12 mmHg had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging. RV and left ventricular (LV) FDG and FTHA uptake standard uptake values (SUVs) were measured. The SUV was corrected for the partial volume effect (SUV
) based on cardiac magnetic resonance imaging (CMR). Right ventricular ejection fraction (RVEF) was determined by CMR. There was a significant positive correlation between mPAP and RV/LV FDG SUV
(r = 0.68, P = 0.003), and the ratio of RV/LV FDG SUV : RV/LV FTHA SUV (r = 0.60, P = 0.02). RVEF was negatively correlated with RV/LV FDG SUV
uptake (r = -0.56, P = 0.02) and RV/LV FTHA SUV
(r = -0.62, P = 0.019).
Increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV. Inverse correlation between the uptake of the metabolic tracers and RV function may reflect a shift towards increased fatty acid oxidation and glycolysis associated with RV failure in maladaptive remodelling.
This study was designed to investigate the factors associated with the high rate of false-positive test results observed with the 4th-generation Murex HIV Ag/Ab Combination EIA (enzyme immunoassay) ...within an adolescent and young-adult cohort in northwest Tanzania. (4th-generation assays by definition detect both HIV antigen and antibody.) The clinical and sociodemographic factors associated with false-positive HIV results were analyzed for 6,940 Tanzanian adolescents and young adults. A subsample of 284 Murex assay-negative and 240 false-positive serum samples were analyzed for immunological factors, including IgG antibodies to malaria and schistosoma parasites, heterophile antibodies, and rheumatoid factor (RF) titers. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). False-positive HIV test results were associated with evidence of other infections. False positivity was strongly associated with increasing levels of Schistosoma haematobium worm IgG1, with adolescents with optical densities in the top quartile being at the highest risk (adjusted OR = 40.7, 95% CI = 8.5 to 194.2 compared with the risk for those in the bottom quartile). False positivity was also significantly associated with increasing S. mansoni egg IgG1 titers and RF titers of ≥80 (adjusted OR = 8.2, 95% CI = 2.8 to 24.3). There was a significant negative association between Murex assay false positivity and the levels of S. mansoni worm IgG1 and IgG2 and Plasmodium falciparum IgG1 and IgG4. In Africa, endemic infections may affect the specificities of immunoassays for HIV infection. Caution should be used when the results of 4th-generation HIV test results are interpreted for African adolescent populations.
The effects of riociguat treatment on right ventricular (RV) metabolism, perfusion, and output in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are unknown. In this study, RV ...changes associated with riociguat therapy were investigated.
Six patients with CTEPH received riociguat for 6 months. Right heart catheterization (only baseline), cardiac magnetic resonance imaging, and positron emission tomography using tracers for myocardial glucose uptake (18F-fluorodeoxyglucose 18F-FDG) and perfusion (13N-ammonia) were performed at baseline and follow-up time points.
At baseline, median RV ejection fraction (RVEF) was 47% (22%-53%) with a mean pulmonary artery pressure (PAP) of 42 mm Hg (27-57 mmHg). Two patients were New York Heart Association functional class III and the rest were class II. Baseline RV 18F-FDG uptake was inversely correlated with RVEF (rs = −0.82; P = 0.04) and positively correlated with mean PAP (rs = 0.94; P = 0.004). Riociguat treatment was associated with a significant increase in RV stroke volume index by 13.5 mL/m2 (6.8-17.5 mL/m2; P = 0.03) and a trend of improved RVEF by 5% (1%-9%; P = 0.09). Myocardial fibrosis indicated by the volume of myocardium exhibiting late gadolinium enhancement was reduced by 4.4 mL (0.2-5.2 mL; P = 0.09). 18F-FDG (metabolism) and 13N-ammonia (perfusion) positron emission tomography did not show a significant difference over the follow-up period. The studied patients (except for 1) had a reduction in the ratio of RV 18F-FDG uptake to RV perfusion, suggesting improved RV metabolism-flow relationships.
Riociguat treatment was associated with increased RV stroke volume index and trends for improvement in myocardial remodelling in patients with CTEPH. A larger clinical study is warranted to observe the therapeutic benefits of riociguat on RV remodelling.
Les effets du traitement par le riociguat sur le métabolisme, la perfusion et le débit du ventricule droit (VD) chez les patients atteints d’hypertension pulmonaire thromboembolique chronique (HPTC) sont inconnus. Dans la présente étude, nous analysons les changements aux ventriculaires droits associés au traitement par le riociguat.
Six patients atteints d’HPTC ont reçu du riociguat pendant 6 mois. Au début de l’étude et aux points de mesure de suivi, les examens suivants ont été effectués: cathétérisme cardiaque droit (au début de l’étude seulement), imagerie par résonance magnétique cardiaque, et tomographie par émission de positrons à l’aide de traceurs pour évaluer l’absorption de glucose par le myocarde (18F-fluorodéoxyglucose 18F-FDG) et la perfusion (13N-ammoniaque).
Au début de l’étude, la fraction d’éjection du VD (FEVD) médiane était de 47 % (22 %-53 %), et la pression artérielle pulmonaire (PAP) moyenne de 42 mmHg (27-57 mmHg). Deux patients étaient dans la classe fonctionnelle III de la New York Heart Association, tandis que les autres se situaient dans la classe II. L’absorption de 18F-FDG par le VD au début de l’étude était inversement corrélée à la FEVD (rs = −0,82; p = 0,04) et positivement corrélée à la PAP moyenne (rs = 0,94; p = 0,004). Le traitement par le riociguat était associé à une augmentation importante de l’indice de volume systolique du VD de 13,5 ml/m2 (6,8-17,5 ml/m2; p = 0,03) et à une tendance à une amélioration de la FEVD de 5 % (1 %-9 %; p = 0,09). La fibrose myocardique, indiquée par le volume de myocarde présentant un rehaussement tardif par le gadolinium, a été réduite de 4,4 ml (0,2-5,2 ml; p = 0,09). La tomographie par émission de positrons à l’aide de 18F-FDG (métabolisme) et de 13N-ammoniaque (perfusion) n’a pas mis en évidence de différence significative durant la période de suivi. Chez les patients étudiés (sauf un), une réduction du rapport entre l’absorption de FDG et la perfusion dans le VD a été observée, ce qui laisse croire à une amélioration de la relation métabolisme-flux dans le VD.
Le traitement par le riociguat a été associé à une augmentation de l’indice de volume systolique du VD et à une tendance à l’amélioration du remodelage myocardique chez les patients atteints d’HPTC. Une étude clinique plus importante s’impose pour observer les bienfaits thérapeutiques du riociguat sur le remodelage du VD.
Physical treatments Dunne, Ross A; McLoughlin, Declan M
Medicine (Abingdon. 1995, UK ed.),
12/2012, Letnik:
40, Številka:
12
Journal Article
Recenzirano
Abstract Electroconvulsive therapy (ECT) is the most effective treatment available for severe depression, with a remission rate of 60%. It is a safe procedure and the major medical risks are related ...to anaesthesia (mortality 1:80,000). Early use of ECT is associated with shorter and less costly hospital stays and it is reported to enhance health-related quality of life and activities of daily living. Bilateral ECT is more powerful than low-dose unilateral ECT but is associated with more effects on cognitive function. The precise mechanism of action of ECT is not yet known, but in animal models it up-regulates neurotrophic factors and induces hippocampal neurogenesis and synaptogenesis. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for moderate depression when compared to placebo treatment alone. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) remain experimental treatments. Stereotactic neurosurgery for mental illness is practised only in specialized centres for intractable illness, but has a good outcome in selected patients.
Interferon (IFN) therapy has an important role in the treatment of multiple sclerosis and chronic hepatitis C infection. A few case reports have described an association between IFN therapy and the ...development of irreversible pulmonary arterial hypertension (PAH), and it is currently listed as a possible drug-induced cause of PAH in the most recent classification of pulmonary hypertension. A causal link between IFN use and PAH remains to be elucidated; many reports of PAH resulting from IFN occur in individuals with some other risk factor for PAH. The authors present a case involving a patient with multiple sclerosis with no known risk factors for PAH, who developed severe PAH after exposure to IFN therapy. The patient experienced significant clinical and hemodynamic improvement, with normalization of her pulmonary pressures after the initiation of combination therapy for PAH. At 28 months after diagnosis, she remains asymptomatic with no hemodynamic evidence of PAH and has been off all PAH therapy for 10 months.
Aim: Previous studies have demonstrated increased glucose uptake by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in lung parenchyma in animal models or small pulmonary arterial ...hypertension (PAH) cohorts. However, it is not well known whether increased FDG uptake in the lung is a unique phenomenon in PAH or whether elevated pulmonary artery pressure (PAP) induces FDG uptake. Methods and results: Nineteen patients with PAH, 8 patients with pulmonary hypertension due to left heart disease (PH-LHD), and 14 age matched control subjects were included. All PH patients underwent right heart catheterization and FDG-PET. The mean standard uptake value (SUV g/mL) of FDG in each lung was obtained and average values of both lungs were calculated as mean lung FDG SUV. The correlation between hemodynamics and mean lung FDG SUV was also analyzed in PH patients. Mean PAP (mPAP) was not significantly different between PAH and PH-LHD (45 ± 11 vs 43 ± 5 mmHg, p=0.51). PAH patients demonstrated significantly increased mean lung FDG SUV compared with PH-LHD and controls (PAH: 0.76 ± 0.26 vs PH-LHD: 0.51 ± 0.12 vs controls: 0.53 ± 0.16, p=0.0025). The mean lung FDG SUV did not correlate with mPAP either in PAH or PH-LHD. Conclusion: PAH is associated with increased lung FDG uptake indicating increased glucose utilization in the lung. This may represent metabolic shift to glycolysis and/or active inflammation in the remodeled pulmonary vasculature, and is observed to a greater extent in PAH than in patients with PH secondary to LHD and control subjects without PH.
PDF
