Cardiovascular and lifestyle risk factors of mild cognitive impairment in UK veterans and non-veterans.

BACKGROUND: The link between poor cardiovascular health (CVH), lifestyle and mild cognitive impairment (MCI) has been well established in the general population. However, there is limited research exploring these associations in ageing UK veterans. AIMS: This study explored the risk of MCI and its association with nine CVH and lifestyle risk factors (including diabetes, heart disease, high cholesterol, high blood pressure, obesity, stroke, physical inactivity, the frequency of alcohol consumption and smoking) in UK veterans and non-veterans. METHODS: This prospective cohort study comprised data from the PROTECT study between 2014 and 2022. Participants comprised of UK military veterans and non-veterans aged ≥50 years at baseline. Veteran status was defined using the Military Service History Questionnaire. CVH and lifestyle risk factors were defined using a combination of self-report measures, medication history or physical measurements. MCI was defined as the presence of subjective and objective cognitive impairment. RESULTS: Based on a sample of 9378 veterans (n = 488) and non-veterans (n = 8890), the findings showed the risk of MCI significantly reduced in veterans with obesity, those who frequently consumed alcohol and were physically inactive compared to non-veterans. The risk of MCI significantly increased in veterans with diabetes (hazards ratio [HR] = 2.22, 95% confidence interval [CI] 1.04-4.75, P ≤ 0.05) or high cholesterol (HR = 3.11, 95% CI 1.64-5.87, P ≤ 0.05) compared to veterans without. CONCLUSIONS: This study identified CVH and lifestyle factors of MCI in UK veterans and non-veterans. Further work is needed to understand these associations and the underpinning mechanisms which could determine intervention strategies to reduce the risk of MCI.

Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer's Disease.

BACKGROUND: There is a clear need for simple and effective tests to identify individuals who are most likely to develop Alzheimer's Disease (AD) both for the purposes of clinical trial recruitment but also for improved management of patients who may be experiencing early pre-clinical symptoms or who have clinical concerns. OBJECTIVES: To predict individuals at greatest risk of progression of cognitive impairment due to Alzheimer's Disease in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using a polygenic risk scoring algorithm. To compare the performance of a PRS algorithm in predicting cognitive decline against that of using the pTau/Aß1-42 ratio CSF biomarker profile. DESIGN: A longitudinal analysis of data from the Alzheimer's Disease Neuroimaging Initiative study conducted across over 50 sites in the US and Canada. SETTING: Multi-center genetics study. PARTICPANTS: 515 subjects who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. MEASUREMENTS: Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess ability to predict subsequent cognitive decline as measured by CDR-SB and ADAS-Cog13 over 4 years. RESULTS: The overall performance for predicting those individuals who would decline by at least 15 ADAS-Cog13 points from a baseline mild cognitive impairment in 4 years was 72.8% (CI:67.9-77.7) AUC increasing to 79.1% (CI: 75.6-82.6) when also including cognitively normal participants. Assessing mild cognitive impaired subjects only and using a threshold of greater than 0.6, the high genetic risk participant group declined, on average, by 1.4 points (CDR-SB) more than the low risk group over 4 years. The performance of the PRS algorithm tested was similar to that of the pTau/Aß1-42 ratio CSF biomarker profile in predicting cognitive decline. CONCLUSION: Calculating polygenic risk scores offers a simple and effective way, using DNA extracted from a simple mouth swab, to select mild cognitively impaired patients who are most likely to decline cognitively over the next four years.

Anaphylactic responses of guinea-pig lung parenchymal strips: antigen concentration dependence and pharmacological modification.

The effects of mediator antagonists and synthesis inhibitors on anaphylactic responses of lung parenchymal strips from ovalbumin-sensitized guinea-pigs have been investigated. The dependence of the responses on the concentration of the antigen has been studied using a cumulative concentration-response technique. Anaphylactic contraction and histamine release were similar in response to cumulative and single additions of ovalbumin. Contractile responses to high doses of antigen (1 and 10 micrograms/ml) were slightly inhibited by mepyramine, whereas those to low doses (0.01 microgram/ml) were inhibited by leukotriene antagonist FPL 55712 and the lipoxygenase inhibitors nordihydroguaiaretic acid and BW 755C. Indomethacin potentiated both histamine release and contraction induced by ovalbumin. It is concluded that leukotrienes play a major role in anaphylactic responses to low antigen concentrations. Such responses may more closely resemble allergic bronchoconstriction in man. Histamine has a minor role in responses to higher antigen concentrations, where the major mediator of the responses may also be leukotrienes. This possibility cannot be proved with currently available leukotriene antagonists and synthesis inhibitors.

The effect of indomethacin on anaphylactic contraction and histamine release in guinea-pig lung parenchymal strips.

Indomethacin potentiates antigen-induced contraction and histamine release in lung parenchymal strips from ovalbumin-sensitized guinea-pigs. Mepyramine and the leukotriene antagonist FPL 55712 did not affect the potentiating effect of indomethacin on anaphylactic contraction, but two lipoxygenase inhibitors, BW 755C and nordihydroguaiaretic acid, abolished it. FPL 55712 inhibited contractile responses to leukotriene D4, but not those to leukotriene C4. The potentiation of histamine release by indomethacin was unaffected by the lipoxygenase inhibitors. It is concluded that a lipoxygenase product, possibly leukotriene C4, mediates the potentiation of contraction by indomethacin; the enhancement of histamine release, however, involves a different mechanism, possibly inhibition of the production of inhibitory prostaglandins.

The mediators of allergic contraction of human airway smooth muscle: a comparison of bronchial and lung parenchymal strip preparations.

Antigen-induced contractions of passively sensitized preparations of human bronchi and lung parenchymal strips were studied. Mepyramine did not affect the magnitude or time course of the contractile responses of either preparation. Indomethacin potentiated the responses of lung parenchymal strips, but inhibited those of bronchial preparations. Responses of both tissues were inhibited by the leukotriene antagonist FPL 55712, by the lipoxygenase inhibitor BW 755C, and by the anti-allergic compound disodium cromoglycate Disodium cromoglycate and BW 755C inhibited histamine release from lung parenchymal strips. The results indicate an important role for leukotrienes in allergic contraction of both large and small human airways, while histamine is of little importance. Bronchoconstrictor prostaglandins may also contribute to the response of large airways.

Leukotriene-induced contraction and thromboxane production in guinea-pig lung parenchymal strips.

Addition of leukotrienes (LTs)C4 and D4 to guinea-pig isolated lung parenchymal strips stimulated the production of thromboxane A2(TxA2) and prostacyclin (PGI2) as determined by radioimmunoassay of their respective degradation products, thromboxane B2(TxB2) and 6-keto-prostaglandin F1 alpha (6-keto PGF1 alpha) in the bathing medium. However, contraction of the lung strips in response to LTD4 preceded the increases in the levels of these products in the organ bath. Pretreatment of the lung strips with aspirin, indomethacin or BW 755C abolished the formation of TxA2 and PGI2 but had no significant effect (10-25% inhibition) on LT-induced contraction. By contrast, a similar concentration of indomethacin significantly inhibited LTD4-induced contractions when the agonist was administered as a bolus to superfused lung strips. It is concluded that the production of metabolites of arachidonic acid in response to the leukotrienes is not a major mechanism mediating their contractile action in peripheral lung tissues at equilibrium, but its contribution to the contractile response may vary with experimental technique.

Hyperreactivity of airways smooth muscle produced in vitro by leukotrienes.

The interactions of leukotriene C4 (LTC4) and D4 (LTD4) with histamine and acetylcholine in contracting guinea pig isolated tracheal smooth muscle have been investigated. In a bathing solution containing 2.5 mM Ca2+, threshold concentrations of the leukotrienes did not affect contractile responses of the smooth muscle to other agonists. However, at a low extracellular Ca2+ concentration (0.1 mM), LTD4 (10(-8) M and 10(-7) M) significantly enhanced contractions induced by histamine or acetylcholine. LTD4 (10(-7) M) shifted the concentration-response curves of these agents leftward by 0.27 and 0.46 log units respectively. The potentiating action of LTD4 was inhibited by the leukotriene antagonist FPL 55712 (3 X 10(-6) M), and was only partially reversible by washing. A subthreshold concentration of potassium chloride (1.5 X 10(-2) M) also increased the sensitivity of the tracheal muscle to acetylcholine in low Ca2+ medium, and this effect was not additive to that of LTD4. These results demonstrate that leukotrienes can alter the in vitro reactivity of airways smooth muscle to other bronchoconstrictor agents. The mechanism of this action may involve altered membrane binding or fluxes of Ca2+, associated with decreased resting potential of the plasma membrane of smooth muscle cells.

The effects of imidazole on contractility and cyclic AMP levels of guinea-pig tracheal smooth muscle.

1. Imidazole contracted guinea-pig isolated tracheal smooth muscle, and at low concentrations (50 mumol/l to 2 mmol/l) also enhanced contractions induced by histamine. 2. Imidazole had no effect on contractile responses to potassium chloride, acetylcholine, prostaglandin F2 alpha, or the ionophore A23187; nor did it affect anaphylactic contractions in tracheal strips from guniea-pigs sensitized to ovalbumin. 3. Imidazole had no effect on the content on cyclic AMP in guinea-pig tracheal smooth muscle, nor did it affect the accumulation of cyclic AMP induced by histamine, isoprenaline, theophylline plus isoprenaline, or prostaglandin E1. 4. Imidazole-induced contractions were partially antagonized by atropine, mepyramine maleate and the omission of extracellular calcium ions. 5. Imidazole-induced hyperreactivity to histamine was not affected by atropine or indomethacin, and was more pronounced in the absence of extracellular calcium ions. 6. It is concluded that imidazole does not affect cyclic nucleotide phosphodiesterase activity in guinea-pig trachea, and its effects on contractile responses of the smooth muscle are unrelated to any action of cyclic AMP metabolism. The potentiating effect of imidazole may involve inhibition of histaminase, or the facilitation of calcium ion release from intracellular storage sites.

Sources of calcium for contraction of guinea-pig isolated tracheal smooth muscle.

1. Contractile responses of guinea-pig tracheal smooth muscle to KCl, histamine, acetylcholine and prostaglandins were reduced after the removal of extracellular Ca2+ from the bathing medium. 2. KCl-induced contractures were more dependent on extracellular Ca2+ than acetylcholine-induced responses, but less so than histamine-induced contractures. 3. Responses to high concentrations of contractile agents were less dependent on extracellular Ca2+ than those to low concentrations. 4. Repeated additions of histamine or acetylcholine in the absence of extracellular Ca2+ resulted in progressively smaller contractile responses. 5. Treatment of tracheal muscle with EGTA considerably inhibited drug-induced contractures and abolished the response to KCl. 6. It is concluded that contractile responses of guinea-pig tracheal smooth muscle involve both the influx Ca2+ from the extracellular space and release of Ca2+ from intracellular sites. The relative contributions of these two Ca2+ sources depend on both the contractile agent and its concentration. Intracellular Ca2+ stores may be depleted by treatment with EGTA, or by repeated drug additions in the absence of extracellular calcium.

The effect of histamine on cyclic AMP levels in guinea-pig tracheal smooth muscle.

Histamine (10(-5)--3 x 10(-4) M) increased the cylic AMP content of guinea-pig tracheal smooth muscle, the maximal effect being a 3-fold increase after 2-min incubation with 10(-4) histamine. Histamine-induced accumulation of cyclic AMP was not affected by propranolol or atropine, but was reduced by mepyramine. Aspirin and indomethacin abolished the cyclic AMP response to histamine and potentiated histamine-induced contractions of the smooth muscle. These results suggest that the elevation of cyclic AMP levels in response to histamine is mediated by prostaglandins, and represents an important negative feedback regulatory mechanism which modulates the contractile response of guinea-pig tracheal smooth muscle to histamine.