Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. OBJECTIVE: To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. METHODS: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. RESULTS: Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. CONCLUSION: In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.

Implementation of a multicomponent intervention sign to reduce delirium in orthopaedic inpatients (MIND-ORIENT): a quality improvement project.

Delirium is a serious and common condition that leads to significant adverse health outcomes for hospitalised older adults. It occurs in 30%-55% of patients with hip fractures and is one of the most common postoperative complications in older adults undergoing orthopaedic surgery. Multicomponent, non-pharmacological interventions can reduce delirium incidence by up to 30% but are often challenging to implement as part of routine care. We identified a gap in the delivery of non-pharmacological interventions on an orthopaedic unit. This project aimed to implement a bedside sign on an orthopaedic unit to reduce the occurrence of delirium by prompting staff to use multicomponent evidence-based delirium prevention strategies for at-risk older adults. Quality improvement methods were used to integrate and optimise the use of a bedside 'delirium prevention' sign on an orthopaedic unit.The sign was implemented in four target rooms and sign completion rates increased from 47% to 83% (95% CI 71.7% to 94.9%; p<0.001) over a 10-month period. The sign did not have a significant impact on delirium prevalence. The mean Confusion Assessment Method (CAM)+ rate during the baseline period was 8% with an absolute increase in the intervention period to 11.4% (95% CI 7.2% to 15.8%; p=0.31). There were no significant shifts or trends in the run chart for the proportion of patients with CAM+ scores over time. The sign was well received by staff, who reported it was a worthwhile use of time and prompted use of non-pharmacological interventions. This quality improvement project successfully integrated a novel, low-cost, feasible and evidence-based approach into routine clinical care to support staff to deliver non-pharmacological interventions. Given the increased pressures on front-line staff in hospital, tools that reduce cognitive load at the bedside are important to consider when caring for a vulnerable older adult patient population.

Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice.

Recently, oestrogen receptors (ERs) have been implicated in rapid learning processes. We have previously shown that 17ß-estradiol, ERα and ERß agonists can improve learning within 40 min of drug administration in mice. However, oestrogen action at the classical receptors may only in part explain these rapid learning effects. Chronic treatment of a G-protein coupled oestrogen receptor (GPER) agonist has been shown to affect learning and memory in ovariectomized rats, yet little is known about its rapid learning effects. Therefore we investigated whether the GPER agonist G-1 at 1 µg/kg, 6 µg/kg, 10 µg/kg, and 30 µg/kg could affect social recognition, object recognition, and object placement learning in ovariectomized CD1 mice within 40 min of drug administration. We also examined rapid effects of G-1 on CA1 hippocampal dendritic spine density and length within 40 min of drug administration, but in the absence of any learning tests. Results suggest a rapid enhancing effect of GPER activation on social recognition, object recognition and object placement learning. G-1 treatment also resulted in increased dendritic spine density in the stratum radiatum of the CA1 hippocampus. Hence GPER, along with the classical ERs, may mediate the rapid effects of oestrogen on learning and neuronal plasticity. To our knowledge, this is the first report of GPER effects occurring within a 40 min time frame.

Low doses of 17ß-estradiol rapidly improve learning and increase hippocampal dendritic spines.

While a great deal of research has been performed on the long-term genomic actions of estrogens, their rapid effects and implications for learning and memory are less well characterized. The often conflicting results of estrogenic effects on learning and memory may be due to complex and little understood interactions between genomic and rapid effects. Here, we investigated the effects of low, physiologically relevant, doses of 17ß-estradiol on three different learning paradigms that assess social and non-social aspects of recognition memory and spatial memory, during a transcription independent period of memory maintenance. Ovariectomized female CD1 mice were subcutaneously administered vehicle, 1.5 µg/kg, 2 µg/kg, or 3 µg/kg of 17ß-estradiol 15 minutes before social recognition, object recognition, or object placement learning. These paradigms were designed to allow the testing of learning effects within 40 min of hormone administration. In addition, using a different set of ovariectomized mice, we examined the rapid effects of 1.5 µg/kg, 2 µg/kg, or 3 µg/kg of 17ß-estradiol on CA1 hippocampal dendritic spines. All 17ß-estradiol doses tested impacted learning, memory, and CA1 hippocampal spines. 17ß-Estradiol improved both social and object recognition, and may facilitate object placement learning and memory. In addition, 17ß-estradiol increased dendritic spine density in the stratum radiatum subregion of the CA1 hippocampus, but did not affect dendritic spines in the lacunosum-moleculare, within 40 min of administration. These results demonstrate that the rapid actions of 17ß-estradiol have important implications for general learning and memory processes that are not specific for a particular type of learning paradigm. These effects may be mediated by the rapid formation of new dendritic spines in the hippocampus.

Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition.

Social Recognition is a fundamental skill that forms the basis of behaviors essential to the proper functioning of pair or group living in most social species. We review here various neurobiological and genetic studies that point to an interplay of oxytocin (OT), arginine-vasopressin (AVP), and the gonadal hormones, estrogens and testosterone, in the mediation of social recognition. Results of a number of studies have shown that OT and its actions at the medial amygdala seem to be essential for social recognition in both sexes. Estrogens facilitate social recognition, possibly by regulating OT production in the hypothalamus and the OT receptors at the medial amygdala. Estrogens also affect social recognition on a rapid time scale, likely through nongenomic actions. The mechanisms of these rapid effects are currently unknown but available evidence points at the hippocampus as the possible site of action. Male rodents seem to be more dependent on AVP acting at the level of the lateral septum for social recognition than female rodents. Results of various studies suggest that testosterone and its metabolites (including estradiol) influence social recognition in males primarily through the AVP V1a receptor. Overall, it appears that gonadal hormone modulation of OT and AVP regulates and fine tunes social recognition and those behaviors that depend upon it (e.g., social bonds, social hierarchies) in a sex specific manner. This points at an important role for these neuroendocrine systems in the regulation of the sex differences that are evident in social behavior and of sociality as a whole.