Risk Of Adverse Cognitive Outcomes Research Articles

Hippocampal volumes and cognitive performance in children born extremely preterm with and without low-grade intraventricular haemorrhage

Children born extremely preterm, especially those with intraventricular haemorrhage (IVH), are at increased risk of adverse cognitive outcomes during childhood. The present study aimed to explore the effects of IVH (grades I–II) on hippocampal volumes, and their correlates with cognitive performance. The sample consisted of 94 participants, including 54 children born extremely preterm (19 with IVH, grades I–II), and 40 children born at term. All participants underwent a magnetic resonance imaging study at the age of 10 (Mage = 10.20 years; SDage = 0.78), and 74 of them (45 extremely preterm and 29 full-term) carried out a cognitive assessment at 12 years old. Children born extremely preterm had lower scores in cognitive performance compared to their full-term peers. Significant positive partial correlations were observed between global bilateral hippocampus, left CA-field, and left subiculum volumes with processing speed in the full-term group, while no significant correlations were found in the extremely preterm group. Moderation analyses in the extremely preterm sample revealed that low-grade IVH moderated the relationship between right hippocampal volume and full-IQ (F(4,40) = 5.42, p = 0.001, R2 = 0.35). Having greater right hippocampal volume had a protective effect on full-IQ in those children born extremely preterm with low-grade IVH.

Association of social participation and psychological resilience with adverse cognitive outcomes among older Chinese adults: A national longitudinal study

BackgroundLimited epidemiological evidence exists regarding the association of social participation and psychological resilience with cognitive health. This study aimed to comprehensively investigate the effects of social participation and psychological resilience on adverse cognitive outcomes among older adults in China. MethodsWe used two waves (2011 and 2014) of data from the Chinese Longitudinal Survey of Health and Longevity (CLHLS), and 9765 respondents were eligible for the subsequent screening for the present prospective analysis. The Cox proportional hazards model was utilized to examine the association of social participation and psychological resilience with cognitive impairment, cognitive decline and greater cognitive decline. The restricted cubic spline plots were applied to clarify the dose–response relationships between them. ResultsCompared to those with low social participation, participants with high social participation had a lower hazard ratio (HR) of 0.72 (95 % confidence interval [CI]: 0.59–0.89) for cognitive impairment, 0.85 (95 % CI: 0.76–0.94) for cognitive decline and 0.78 (95 % CI: 0.67–0.90) for greater cognitive decline. Participants with high psychological resilience had an HR of 0.77 (95 % CI: 0.63–0.95) for cognitive impairment 0.85 (95 % CI: 0.76–0.94) for cognitive decline and 0.85 (95 % CI: 0.73–0.98) for greater cognitive decline compared with those with low psychological resilience. Similar effects were observed for social participation score and psychological resilience score. The dose–response analysis also showed that the risk of adverse cognitive outcomes decreased gradually with increasing social participation scores and psychological resilience scores. Additionally, the multiplicative interaction between social participation and psychological resilience was not significant. LimitationAll information was collected by self-report, which may lead to biases in the process of information collection. ConclusionIn this study, social participation and psychological resilience were independently associated with a lower risk of adverse cognitive outcomes, and therefore both need to be considered as broader measures to preserve cognitive health among older Chinese adults.

Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child.

To provide an updated summary and appraisal of work from 2019 to 2022 examining risks of selective serotonin reuptake inhibitor (SSRI) use in pregnancy. Perinatal SSRI exposure does not increase risk of major malformations or gestational diabetes after accounting for underlying maternal illness. SSRIs are associated with small increase in risk of pre-eclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, and neonatal intensive care unit admissions, though absolute risk of these outcomes is low. While data suggests no increased risk of neurodevelopmental disorders in offspring, mixed evidence indicates increased risk of adverse cognitive outcomes and affective disorders. Recent evidence suggest low absolute risk of clinically relevant negative outcomes with perinatal SSRI exposure when compared to untreated perinatal depression. However, study design and ability to control for confounding remains an ongoing research challenge, highlighting need for ongoing rigorous study design and analysis.

Cannabis Use and Subjective Cognitive Decline Among Middle-Aged and Older Adults

Cannabis is the most commonly-used drug in the US, with older adults being the fastest-growing group of users. National surveys among 50+ adults found poorer executive function among current or past cannabis users, but better performance with daily users. However, there is little evidence linking levels of cannabis use and subjective cognitive decline (SCD) among middle-age and older adults. This study sought to examine the association between levels of cannabis use in the past 30 days and SCD during the past 12 months using Behavioral Risk Factor Surveillance System (BRFSS) data (2016-2019) from 45+ individuals while controlling for demographics, chronic conditions, exercise, general and mental health. Logit models with SCD as outcome were estimated using complex survey weights. Multiple group analyses examined differences across age groups: 45-64 vs. 65+. Levels of cannabis use in the past 30 days were categorized as: no use, 1-4 days, 5-20 days; and 21-30 days. Adjusted results indicated that those who reported no cannabis use were from 35% to 47% less likely to report SCD compared to cannabis users at all levels: 1-4 days (OR=0.65, 95%CI=0.46, 0.92); 5-20 days (OR=0.53, 95%CI=0.36,0.78); 21-30 days (OR=.61, 95%CI=0.45,0.83). In multi-group analyses, levels of cannabis use effects on SCD remained statistically significant in the 45-64 age group, but not in the 65+ group. Further research targeting SCD is needed to design interventions particularly for middle-age cannabis users whose health has been compromised by disease or age-related vulnerabilities and are at greater risk for adverse cognitive outcomes from cannabis use.

The utility of the brief ECT cognitive screen (BECS) for early prediction of cognitive adverse effects from ECT: A CARE network study

Although highly effective, electroconvulsive therapy (ECT) often produces cognitive side effects which can be a barrier for patients. Monitoring cognitive side effects during the acute course is therefore recommended to identify patients at increased risk for adverse outcomes. The Brief ECT Cognitive Screen (BECS) is a brief instrument designed to measure emerging cognitive side effects from ECT. The aim of this study was to examine the clinical utility of the BECS for predicting adverse cognitive outcomes in real world clinic settings. The study included data collated from four participating sites in the Clinical Alliance for ECT and Related treatments (CARE) network. The BECS was administered at pre ECT and post 3 or 4 ECT. The primary outcome was a ≥4 point decrease on the Montreal Cognitive Assessment (MoCA) from pretreatment to post ECT. Logistic multiple regression analyses examined the BECS and other relevant clinical and demographic and treatment factors as predictors. The final analysis included 623 patients with diverse indications for ECT including 53.6% with major depression and 33.7% with schizophrenia or schizoaffective disorder. A higher total score on the BECS significantly predicted decline in Total Scores on the MoCA [B = 0.25 (0.08), p = 0.003], though not decline in MoCA Delayed Recall scores (p > 0.1). Other significant predictors included higher pretreatment MoCA Total Scores and female gender for verbal anterograde memory decline. This study confirmed that the BECS has clinical utility for identifying patients with both reduced and increased risk for adverse cognitive outcomes from ECT.

Investigating the associations of trajectories of depressive symptoms and self‐perceived health and incident dementia: An unsupervised machine learning approach

AbstractBackgroundRisk factors for dementia show inter‐individually varying trajectories over the lifespan. However, risk factors have been mainly investigated with one time‐point assessments. New research suggests that certain risk factor trajectories are associated with increased risk of adverse cognitive outcomes (Demnitz et al., 2020 [https://doi.org/10.1101/2020.05.20.20106963]; Singh‐Manoux et al., 2018 [https://doi.org/10.1016/j.jalz.2017.06.2637]). However, it remains unclear how sequential and simultaneous changes of risk factors alter the individual risk for developing dementia. Testing the joint contribution of trajectories of depressive symptoms and self‐perceived health on incidence of dementia, we hypothesized that consistently poor as well as deteriorating trajectories increase the risk for incident dementia, and explored possible interactions of the trajectories.MethodA total of 5,326 respondents to the SHARE survey, mean age 73.9 years, and 6 complete follow‐ups spanning ∼13 years, answered the EURO‐D depression scale, self‐perceived health (SPH) (t1‐t5), and self‐reported dementia diagnosis at last follow‐up (t6). To investigate the predictive ability of distinct longitudinal trajectories, we applied unsupervised statistical learning methods (K‐means cluster modelling). Clusters indicated distinct risk factor trajectories, which were used as exposures in stepwise logistic regressions to predict incident dementia, controlling for age, gender, education, and country.ResultCluster analysis revealed five distinct trajectories each for SPH and EURO‐D, with varying dementia incidence. In stepwise logistic regressions, respondents with trajectories “consistently poor health” and “consistently high depression” showed elevated risk of dementia (OR = 4.02 [1.39, 14.75] and OR = 2.26 [1.03, 4.95], respectively) compared to the combined baseline risk for “consistently low depression” and “consistently good health”. Interactions were not significant. However, respondents with the combination of “consistently high depression” and “consistently poor health” showed increased risk (N = 246; 6.1% dementia).ConclusionApplying unsupervised machine learning is helpful to incorporate longitudinal information on depressive symptoms and self‐perceived health and model these risk factors longitudinally to test their contribution to explain incidence of dementia. The predictive ability of the trajectories of depressive symptoms and self‐perceived health for dementia indicates the potential for improving the identification of people at risk for developing dementia in late life by exploiting trajectory information readily accessible through regular medical check‐ups in old age.

The relationship between chronic health conditions and cognitive deficits in children, adolescents, and young adults with down syndrome: A systematic review.

Individuals with Down syndrome are predisposed to a number of chronic health conditions, but the relationship between these conditions and cognitive ability is not clear. The primary objective of this systematic review is to assess this relationship by evaluating studies that measure cognitive performance in the context of Down syndrome-associated chronic health conditions. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Studies included in this review (1) included children, adolescent, and young adult participants with Down syndrome and one or more co-occurring health conditions; (2) were quantitative; and (3) reported outcomes related to both chronic health conditions and cognitive performance. A set of predetermined chronic health conditions that are common in Down syndrome (e.g. sleep disorders, congenital heart disease, thyroid disease, seizure disorders, and pulmonary hypertension) were selected based on prevalence rates in Down syndrome. Fifteen studies met inclusion criteria. The majority these of studies assessed cognitive performance in association with sleep disorders (47%) and congenital heart disease (47%). Fewer studies reported on the effect of thyroid disease (7%) and seizure disorders (7%) on cognitive ability. None of the studies reported cognitive outcomes related to pulmonary hypertension. Of the chronic health conditions evaluated, associations between sleep disorders and cognitive dysfunction were most common among individuals with Down syndrome. Individuals with Down syndrome exhibit deficits in cognitive ability, particularly related to attention, executive function and verbal processing. These deficits may be further exacerbated by the presence of chronic health conditions, particularly sleep disorders. Individuals with Down syndrome and co-occurring sleep disorders may benefit from early interventions to mitigate their risk for adverse cognitive outcomes.

Central SBP and executive function in children and adolescents with primary and secondary hypertension.

The aims of the study were to assess executive function performance in children and adolescents with primary and secondary hypertension, and to investigate for associations with central SBP and ambulatory blood pressure. Forty-six pediatric patients with secondary hypertension because of kidney diseases and 46 patients with primary hypertension underwent ambulatory blood pressure monitoring, pulse wave analysis, and assessment of executive function using Behavior Rating Inventory of Executive Function. Results for comparisons are presented as mean (SD). Analysis of covariance was performed to examine the effect of blood pressure parameters and hypertension cause. Patients with secondary hypertension had higher T scores in parent and self-reported Metacognition Indices compared with those with primary hypertension (51.2 ± 8.9 vs. 47.6 ± 7.5, P = 0.05 and 49.6 ± 9.1 vs. 42.1 ± 7.9, P = 0.001, respectively), but did not differ in Behavior Regulation Index T scores, as well as in mean arterial pressure z-score. Patients with secondary hypertension had higher central SBP z-scores (P = 0.05). Adjustment for central SBP attenuated differences in parent Metacognition Index between groups. Central SBP z-score associated with parent Metacognition (B = 0.95, 95% CI 0.02-1.87), Behavior Regulation (B = 1.14, 95% CI 0.07-2.21), and self-reported Metacognition Indices T scores (B = 1.48, 95% CI 0.39-2.56), independent of mean arterial pressure z-score, age, sex, socioeconomic status, hypertension cause, and antihypertensive treatment. Central SBP associates with executive function performance in youth with hypertension and could have complementary role to ambulatory blood pressure for identifying children at risk for adverse cognitive outcomes.

Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players

Emerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ε4 (APOE ε4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown. To determine whether the APOE ε4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players. A total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data. At each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4). Verbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState. A total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (β = -0.59; 95% CI, -0.93 to -0.25; P = .001). There was no main association of APOE ε4 with verbal memory (β = 0.09; 95% CI, -0.24 to 0.42; P = .58). However, there was a significant association of APOE ε4 and heading with performance on the ISRL task (χ2 = 7.22; P = .03 for overall interaction). In APOE ε4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ε4 negative, β = -0.36; 95% CI, -0.75 to 0.03; APOE ε4 positive, β = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ε4 negative, β = -0.13; 95% CI, -0.54 to 0.29; APOE ε4 positive, β = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ε4-negative players. This study suggests that the APOE ε4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.

Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia?

While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration—differences which future work may reveal to improve geriatric patient monitoring.

Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age

To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years. We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment. Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins. Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

Long-term cognitive and school outcomes of late-preterm and early-term births: a systematic review.

Children born before full term (39-41 weeks' gestation) are at increased risk of adverse cognitive outcomes. Risk quantification is important as late-preterm (LPT; 34-36 weeks) and early-term (ET; 37-38 weeks) births are common. This review analyses the effect of LPT and ET births on long-term cognitive and educational outcomes. The primary outcome was general cognitive ability. Secondary outcomes included verbal/non-verbal intelligence quotient, subject-specific school performance and special educational needs. The search strategy included Medline and Embase from January 1975 to June 2013. Eligible studies investigated specified outcomes and included suitable gestational age participants assessed at 2 years and older. Outcome measures and socio-demographic descriptors were extracted, and data meta-analysed where possible. Eight studies compared ET birth with full-term birth. Fourteen studies compared LPT birth with either term birth (>37 weeks, n = 12 studies) or full-term birth (39-41 weeks, n = 2 studies). Substantial between-study heterogeneity existed. LPT and ET children underperformed in most outcomes compared with their term/full-term counterparts, respectively. For example, LPT children had an increased risk of lower general cognitive ability (adjusted risk ratio 1.38 [95% confidence interval 1.06-1.79]), and full-term children performed 5% of a standard deviation higher (z-score 0.05 [0.02, 0.08]) than ET children. Poorer outcomes persist into adulthood; term cohorts performed 5% of a standard deviation higher than LPT cohorts (z-score 0.05 [0.04, 0.07]), and full-term cohorts performed 3% of a standard deviation higher than ET cohorts (z-score 0.03 [0.02, 0.04]). This review critically examines the knowledge around long-term cognitive outcomes of LPT and ET births, demonstrating multiple, small, adverse differences between LPT/ET and term/full-term births.

Risk of Dementia Among Elderly Nursing Home Patients Using Paroxetine and Other Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment for depression. Among the SSRIs, paroxetine has strong anticholinergic properties and may lead to increased risk of adverse cognitive outcomes among elderly patients. This study evaluated the comparative risk of dementia associated with use of paroxetine and other SSRIs among elderly nursing home patients. A retrospective cohort study using propensity score matching was conducted with 2007-2010 Minimum Data Set-linked Medicare data. The study population included elderly nursing home patients with depression who were new users of SSRIs. Patients were followed for a maximum of two years after index SSRI use. The risk of dementia was modeled by using a robust Cox proportional hazards model to account for clustering within matched users of paroxetine and other SSRIs. The unmatched cohort included 19,952 new users of SSRIs; 1,898 used paroxetine, and 18,054 used other SSRIs. In the propensity-matched cohort of 3,796 patients, the unadjusted incidence of dementia was 7.5% for users of paroxetine and 8.6% for users of other SSRIs. There was no difference in the risk of dementia for users of paroxetine or other SSRIs. These study findings remained robust in multiple sensitivity analyses involving various measures of dementia. Compared with use of other SSRIs, use of paroxetine was not associated with higher risk of dementia among elderly nursing home patients with depression. Future studies are needed to evaluate the impact of paroxetine on other cognition measures.

Pregnancy and epilepsy.

This review encompasses issues regarding the management of women with epilepsy and pregnancy, including preconception planning, antiepileptic drug (AED) effects on the exposed offspring, and consequences of seizures during pregnancy, with an emphasis on counseling points and risk management. In utero valproate exposure continues to show the highest risk of congenital malformations and of adverse cognitive outcomes, including autism, compared to other AEDs. In utero topiramate exposure is associated with facial clefts. In utero exposure to lamotrigine, carbamazepine, phenytoin, and levetiracetam has been evaluated in large numbers of offspring, and all of these AEDs have a low risk of major congenital malformations, near 2.5%. The risk of major congenital malformations due to in utero AED exposure is dose associated. Folic acid taken at the time of conception decreases the risk of adverse cognitive outcomes. AED polytherapy may adversely affect fertility, and in utero exposure of AED polytherapy is associated with infants who are small for their gestational age. Seizure freedom before pregnancy is a good predictor of remaining seizure free during pregnancy. Counseling points are complex for managing women with epilepsy contemplating pregnancy, including evaluation of AED choice and dose. The physician must have knowledge of the issues to enable an honest discussion and appropriate decision making in partnership with the patient.

ECT efficacy and treatment course: A systematic review and meta-analysis of twice vs thrice weekly schedules

Electroconvulsive therapy (ECT) guidelines, across various regulatory bodies, lack consensus as to the optimal frequency of treatment for individual patients. Some authors postulate that twice weekly ECT may have a similar efficacy to thrice weekly, and may have a lower risk of adverse cognitive outcomes. We did a systematic review and a meta-analysis to assess the strength of associations between ECT frequency and depression scores, duration of treatment, number of ECTs, and remission rates. We searched on Medline, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (to December 2009), and searched reports to identify comparative studies of frequency of ECT. We did both random-effects (RE) and quality effect (QE) meta-analyses to determine the risk of various outcomes associated with lesser frequency as compared to the thrice weekly frequency. We analysed 8 datasets (7 articles), including 214 subjects. Twice-weekly frequency of ECT was associated with a similar change in depression score (QE model SMD -0.11 [-0.55-0.33] and RE model SMD -0.17 [-0.77-0.43]) as compared to thrice weekly ECT. The number of real ECT's trended towards fewer in the twice weekly group. There was a statistically significant longer duration of treatment with a twice weekly protocol (QE model 6.48 days [4.99-7.97] and RE model 4.78 days [0.74-8.82]). There was a statistically significant greater efficacy for thrice weekly ECT compared to once weekly ECT (QE model SMD 1.25 [-0.62-1.9] and RE model SMD 1.31 [0.6-2.02]). Twice weekly ECT is associated with similar efficacy to thrice weekly ECT, may require fewer treatments and may be associated with longer treatment duration when compared to thrice weekly. These epidemiological observations support the routine use of twice weekly ECT in acute courses, though choice of frequency should take into account individual patient factors. These observations have implications for resource utilisation e.g. costs of duration of admission vs cost of provision of ECT, as well as issues of access to inpatient beds and anaesthetist time.

In search of neuroprotective therapies based on the mechanisms of estrogens

Although estradiol is a neuroprotective factor, estrogen therapy in older women increases the risk of adverse cognitive outcomes and poses additional peripheral risks, requiring careful use of estrogenic compounds as treatments for neurodegenerative conditions or neural injury. Potential alternatives to estrogen therapy to promote neuroprotection might include treatment with molecules that are able to interact with estrogen receptors, with alternative mechanisms of action, or with molecules that induce local estradiol synthesis in the brain, or a combination of all. However, before considering the broad clinical applications, more basic research is required to clarify the mechanisms of action and potential risks of some of these estrogen-based treatments.