BACKGROUND: no studies have compared the predictive validity of different dementia risk prediction models in Australia. OBJECTIVES: (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models. METHODS: the Hunter Community Study (HCS) included 3,306 adults aged 55-85syears with a median follow-up of 7.1syears. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method. RESULTS: 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively. CONCLUSION: ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.
BACKGROUND: There has been limited research into potentially inappropriate medication (PIM) use and anticholinergic burden in patients attending memory clinics. OBJECTIVES: The aim of this study was to explore the use of PIMs related to cognitive impairment (PIMcog), anticholinergic cognitive burden (ACB) and concomitant use of anticholinergic medications with cholinesterase inhibitors (ChEIs) in patients attending memory clinics. METHODS: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study was performed. Participants were community-dwelling patients who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog were defined as any medication considered potentially inappropriate for patients with cognitive impairment according to the Beers or STOPP criteria. Clinically significant ACB was defined as total score of >/=3 on the ACB scale. RESULTS: A total of 964 patients, mean age 77.6 years, were included. PIMcog were used by 206 (21.4 %) patients. Anticholinergics and sedatives were the most common PIMcog. PIMcog use was associated with higher number of medications (adjusted OR 1.26; 95 % CI 1.19-1.33) and with not having completed secondary level education (adjusted OR 1.71; 95 % CI 1.01-2.89). One hundred and thirteen (11.7 %) patients had a clinically significant ACB score (>/=3). ChEIs were used by 575 patients and 65 (11.3 %) of these had an ACB score >/=3. There was no statistically significant difference in ChEI use between patients with and without an ACB score >/=3. CONCLUSION: PIMcog use, clinically significant anticholinergic burden, and concurrent use of anticholinergics with ChEIs were prevalent in patients attending memory clinics. Efforts are needed to improve prescribing for people with cognitive impairment.
The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.
A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. These selective pathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for beta-amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activity.
Title: Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses Baldwin HA, De Souza RJ, Sarna GS, Murray TK, Green AR, Cross AJ Ref: British Journal of Pharmacology, 103:1946, 1991 : PubMed
1. The concentration of tacrine (tetrahydroaminoacridine or THA) in plasma, regions of brain and cerebral extracellular fluid has been studied in the rat at various times following injection of a dose of 5 mg kg-1, i.p. 2. The peak plasma THA concentration was 2.46 nmol ml-1, and occurred 30 min post injection and clearance was first order (t1/2 = 90 min). The concentration in the brain peaked between 30-60 min, and was around 30 times plasma concentration (striatum peak concentration = 65 +/- 3 nmol g-1). Extracellular cerebral concentration measured by in vivo microdialysis was similar to plasma concentration with the peak occurring 100 min post-injection. 3. No evidence was obtained by in vivo dialysis for THA inducing dopamine release from striatum or 5-hydroxytryptamine (5-HT) release from the frontal cortex. Enhanced release of dopamine did occur after (+)-amphetamine (5 mg kg-1, i.p.) injection, while KCl (100 mM) in the probe released both dopamine and 5-HT. 4. Since the minimum plasma THA concentration achieved in this study was at least twice that found in the plasma of patients given THA for the treatment of dementia, these results suggest that monoamine release in the brain does not occur during therapy.
Title: Reversal by tetrahydroaminoacridine of scopolamine-induced memory and performance deficits in rats Murray TK, Cross AJ, Green AR Ref: Psychopharmacology (Berl), 105:134, 1991 : PubMed
The effects of the cholinesterase inhibitors physostigmine and tetrahydroaminoacridine (THA) on memory and performance deficits induced by scopolamine were studied using an operant delayed non-matching to position task. No effect was seen on the performance of rats when treated with either physostigmine (0.1 mg/kg IP) or THA (1 mg/kg IP) alone. However, the performance deficits induced in the task by scopolamine (0.03 mg/kg SC) were reversed by the same doses of the cholinesterase inhibitors.
Title: The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro Hunter AJ, Murray TK, Jones JA, Cross AJ, Green AR Ref: British Journal of Pharmacology, 98:79, 1989 : PubMed
1. The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2. Administration of THA (5-20 mg kg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg-1) administration. 3. THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4. In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 +/- 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 +/- 10 nM) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 +/- 1.4 nM). 5. Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600 nM) and M2 (Ki: 880 nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors. 6. It is concluded that THA is a reversible non-competitive inhibitor of cholinesterase with a long half life (compared with physostigmine). It also may antagonize muscarinic receptors at high doses. The long half life may account for its reported efficacy in the treatment of Alzheimer's disease.
Title: The mechanism of tetrahydroaminoacridine-evoked release of endogenous 5-hydroxytryptamine and dopamine from rat brain tissue prisms Robinson TN, De Souza RJ, Cross AJ, Green AR Ref: British Journal of Pharmacology, 98:1127, 1989 : PubMed
1 Tetrahydroaminoacridine (THA) is an acetylcholinesterase (AChE) inhibitor which may have a greater therapeutic effect in Alzheimer-type dementia (ATD) than other cholinergic agents. This suggests possible non-cholinergic properties. We have therefore studied the effects of THA on the release of endogenous 5-hydroxytryptamine (5-HT) from rat cortical prisms and dopamine from striatal prisms. 2 In the presence of K+ (1 mM), THA stimulated release of both 5-HT and dopamine. THA (100 microM)-evoked monoamine release was comparable, but not additive with the release produced by K+ (35 mM). The effect was not maximal at 1 mM THA. THA-evoked release of 5-HT was independent of the presence of Ca2+ in the external medium. 3 Drugs acting on the cholinergic system, nicotine, mecamylamine, atropine, oxotremorine, physostigmine and neostigmine (all 10 microM) had no effect on 5-HT and dopamine-release. 4-Aminopyridine (4-AP), a potent acetylcholine-releasing agent, had no effect on 5-HT release and was approximately 100 fold less active than THA on dopamine release. 4 Both THA and reserpine enhanced the release of 5-HT in the presence of the monoamine oxidase inhibitor, pargyline. Reserpine- but not THA-evoked release was abolished in the absence of pargyline. Reserpine (5 mg kg-1, i.p.) markedly depleted brain monoamine concentrations 3 h after injection, while THA (15 mg kg-1, i.p.) had no effect. 5 Chloroamphetamine and fenfluramine both released 5-HT in a Ca2(+)-independent manner and with a similar potency to THA, while (+)-amphetamine released dopamine with a similar potency to THA. The effects of the amphetamines were not maximal at 1 mM. However, unlike THA, chloroamphetamine-evoked release of 5-HT was additive with release evoked by K+ (35 mM). 6 Clomipramine (IC50 = 0.036 microM) and THA (IC50 = 19.9 microM) all inhibited the uptake of [3H]-5-HT into a P2 membrane preparation. However, none of these compounds inhibited [3H]-5-HT uptake into tissue prisms during the release experiments in which the reuptake inhibitor fluoxetine (5 microM) was present. 7 We conclude that THA does not release endogenous 5-HT through a cholinergic, reserpine- or amphetamine-like mechanism or through inhibition of reuptake. The possibility exists that the release may occur via blockade of 4-AP-insensitive K+ channels.
Title: Metabolic aspects of the toxicology of diazinon. I. Hepatic metabolism in the sheep, cow, pig, guinea-pig, rat, turkey, chicken and duck Machin AF, Rogers H, Cross AJ, Quick MP, Howell LC, Janes NF Ref: Pest Sci, 6:461, 1975 : PubMed
The phosphorothionate insecticide diazinon was incubated with liver microsomes from the sheep, cow, pig, guinea-pig, rat, turkey, chicken and duck. Metabolism by liver slices of most of these species was also examined. Hydroxydiazinon, isohydroxydiazinon, dehydrodiazinon, their oxons and diazoxon were identified and determined quantitatively or semi-quantitatively. An eighth metabolite was tentatively identified as the 6-aldehyde analogue of diazinon. Yields and rates of production of these metabolites varied greatly between species. Production of oxons was not generally correlated with susceptibility to diazinon poisoning, although it was lowest in the least susceptible animal, the sheep. The degradation of oxons by liver slices was too slow to explain the low toxicity of diazinon to the mammals. The relative importance of hepatic and extrahepatic metabolism in determining toxicity to vertebrates is discussed.
