GRID1/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1/5 receptor signaling and excitatory synapses.

The ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is involved in synapse formation, function, and plasticity. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allow the formation of trans-synaptic bridges, and trigger transmembrane signaling. Despite wide expression in the nervous system, pathogenic GRID1 variants have not been characterized in humans so far. We report homozygous missense GRID1 variants in five individuals from two unrelated consanguineous families presenting with intellectual disability and spastic paraplegia, without (p.Thr752Met) or with (p.Arg161His) diagnosis of glaucoma, a threefold phenotypic association whose genetic bases had not been elucidated previously. Molecular modeling and electrophysiological recordings indicated that Arg161His and Thr752Met mutations alter the hinge between GluD1 cerebellin and D-serine binding domains and the function of this latter domain, respectively. Expression, trafficking, physical interaction with metabotropic glutamate receptor mGlu1, and cerebellin binding of GluD1 mutants were not conspicuously altered. Conversely, upon expression in neurons of dissociated or organotypic slice cultures, we found that both GluD1 mutants hampered metabotropic glutamate receptor mGlu1/5 signaling via Ca2+ and the ERK pathway and impaired dendrite morphology and excitatory synapse density. These results show that the clinical phenotypes are distinct entities segregating in the families as an autosomal recessive trait, and caused by pathophysiological effects of GluD1 mutants involving metabotropic glutamate receptor signaling and neuronal connectivity. Our findings unravel the importance of GluD1 receptor signaling in sensory, cognitive and motor functions of the human nervous system.

White matter fibre density in the brain's inhibitory control network is associated with falling in low activity older adults.

Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and ßIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and ßIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Multicenter evaluation of the Toxoplasma gondii Real-TM (Sacace) kit performance for the molecular diagnosis of toxoplasmosis.

The molecular detection of Toxoplasma gondii DNA is a key tool for the diagnosis of disseminated and congenital toxoplasmosis. This multicentric study from the Molecular Biology Pole of the French National Reference Center for toxoplasmosis aimed to evaluate Toxoplasma gondii Real-TM PCR kit (Sacace). The study compared the analytical and clinical performances of this PCR assay with the reference PCRs used in proficient laboratories. PCR efficiencies varied from 90% to 112%; linearity zone extended over four log units (R2 > 0.99) and limit of detection varied from 0.01 to ≤1 Tg/mL depending on the center. Determined on 173 cryopreserved DNAs from a large range of clinical specimens, clinical sensitivity was 100% [106/106; 95 confidence interval (CI): 96.5%-100%] and specificity was 100% (67/67; 95 CI: 94.6%-100%). The study revealed two potential limitations of the Sacace PCR assay: the first was the inconsistency of the internal control (IC) when added to the PCR mixture. This point was not found under routine conditions when the IC was added during the extraction step. The second is a lack of practicality, as the mixture is distributed over several vials, requiring numerous pipetting operations. Overall, this study provides useful information for the molecular diagnosis of toxoplasmosis; the analytical and clinical performances of the Sacace PCR kit were satisfactory, the kit having sensitivity and specificity similar to those of expert center methods and being able to detect low parasite loads, at levels where multiplicative analysis gives inconsistently positive results. Finally, the study recommends multiplicative analysis in particular for amniotic fluids, aqueous humor, and other single specimens.

Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Primary care payment models and avoidable hospitalizations in Ontario, Canada: A multivalued treatment effects analysis.

Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early- to mid-2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non-incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a two-stage estimation strategy on a balanced panel of 3710 primary care physicians (1158 blended-fee-for-service (FFS), 1388 blended-capitation models, and 1164 interprofessional team-based practices). First, we account for the differences in physician practices using a generalized propensity score based on a multinomial logit regression model, corresponding to three primary care payment models. Second, we use fractional regression models to estimate the average treatment effects on the treated outcome (i.e., avoidable hospitalizations). The capitation-based model sometimes increases avoidable hospitalizations due to angina (by 7 per 100,000 patients) and congestive heart failure (40 per 100,000) relative to the blended-FFS-based model. Switching capitation physicians into interprofessional teams mitigates this effect, reducing avoidable hospitalizations from congestive heart failure by 30 per 100,000 patients and suggesting better access to primary care and chronic disease management in team-based practices.

Nutrition is associated with differences in multisensory integration in healthy older adults.

Diet can influence cognitive functioning in older adults and is a modifiable risk factor for cognitive decline. However, it is unknown if an association exists between diet and lower-level processes in the brain underpinning cognition, such as multisensory integration. We investigated whether temporal multisensory integration is associated with daily intake of fruit and vegetables (FV) or products high in fat/sugar/salt (FSS) in a large sample (N = 2,693) of older adults (mean age = 64.06 years, SD = 7.60; 56% female) from The Irish Longitudinal Study on Ageing (TILDA). Older adults completed a Food Frequency Questionnaire from which the total number of daily servings of FV and FSS items respectively was calculated. Older adults' susceptibility to the Sound Induced Flash Illusion (SIFI) measured the temporal precision of audio-visual integration, which included three audio-visual Stimulus Onset Asynchronies (SOAs): 70, 150 and 230 ms. Older adults who self-reported a higher daily consumption of FV were less susceptible to the SIFI at the longest versus shortest SOAs (i.e. increased temporal precision) compared to those reporting the lowest daily consumption (p = .013). In contrast, older adults reporting a higher daily consumption of FSS items were more susceptible to the SIFI at the longer versus shortest SOAs (i.e. reduced temporal precision) compared to those reporting the lowest daily consumption (p < .001). The temporal precision of multisensory integration is differentially associated with levels of daily consumption of FV versus products high in FSS, consistent with broader evidence that habitual diet is associated with brain health.

Cardiovascular disease and the risk of incident falls and mortality among adults aged ≥ 65 years presenting to the emergency department: a cohort study from national registry data in Denmark.

BACKGROUND: Falls cause 58% of injury-related Emergency Department (ED) attendances. Previous research has highlighted the potential role of cardiovascular risk factors for falls. This study investigated the impact of cardiovascular disease (CVD) risk on three-year incident falls, with presentation to the ED, and mortality. METHODS: A matched cohort study design was employed using national registry data from 82,292 adults (33% male) aged ≥ 65 years living in Denmark who attended the ED in 2013. We compared age and gender matched ED attendees presenting with a fall versus another reason. The cohort was followed for three-year incident falls, with presentation to the ED, and mortality. The impact of falls-related CVDs was also examined. RESULTS: Three-year incident falls was twofold higher among age and gender matched ED attendees aged ≥ 65 years presenting with a fall versus another reason at baseline. A presentation of falls with hip fracture had the highest percentage of incident falls in the 65-74 age group (22%) and the highest percentage mortality in all age groups (27-62%). CVD was not a significant factor in presenting with a fall at the ED, nor did it contribute significantly to the prediction of three-year incident falls. CVD was strongly associated with mortality risk among the ED fall group (RR = 1.81, 95% CI: 1.67-1.97) and showed interactions with both age and fall history. CONCLUSION: In this large study of adults aged ≥ 65 years attending the ED utilising data from national administrative registers in Denmark, we confirm that older adults attending the ED with a fall, including those with hip fracture, were at greatest risk for future falls. While CVD did not predict incident falls, it increased the risk of mortality in the three-year follow up with advancing age. This may be informative for the provision of care pathways for older adults attending the ED due to a fall.

Frailty on the island of Ireland: evidence from the NICOLA and TILDA studies.

BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.

Examining mental health and autonomic function as putative mediators of the relationship between sleep and trajectories of cognitive function: findings from the Irish longitudinal study on ageing (TILDA).

OBJECTIVES: This study investigates the mediating roles of autonomic function and mental health in the association between sleep and cognitive decline in adults aged 50 and above. METHOD: A total of 2,697 participants with observations on sleep and mediators at baseline and repeated measures of cognitive function (MMSE) were included. Clusters of individuals with similar cognitive trajectories (high-stable, mid-stable and low-declining) were identified. Multinomial logistic regressions were used to estimate the likelihood of membership to each trajectory group based on sleep duration and disturbance. Finally, mediation analysis tested potential mediating effects of autonomic function and mental health underpinning the sleep-cognition relationship. RESULTS: Short (p = .028), long (p =.019), and disturbed sleep (p =.008) increased the likelihood of a low-declining cognitive trajectory. Mental health measures fully attenuated relationships between cognitive decline and short or disturbed sleep but not long sleep. No autonomic function mediation was observed. CONCLUSION: Older adults with short or disturbed sleep are at risk of cognitive decline due to poor mental health. Individuals with long sleep are also at risk, however, the acting pathways remain to be identified. These outcomes have clinical implications, potentially identifying intervention strategies targeting mental health and sleep as prophylactic measures against dementia.

Were Frailty Identification Criteria Created Equal? A Comparative Case Study on Continuous Non-Invasively Collected Neurocardiovascular Signals during an Active Standing Test in the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: In this observational study, we compared continuous physiological signals during an active standing test in adults aged 50 years and over, characterised as frail by three different criteria, using data from The Irish Longitudinal Study on Ageing (TILDA). METHODS: This study utilised data from TILDA, an ongoing landmark prospective cohort study of community-dwelling adults aged 50 years or older in Ireland. The initial sampling strategy in TILDA was based on random geodirectory sampling. Four independent groups were identified: those characterised as frail only by one of the frailty tools used (the physical Frailty Phenotype (FP), the 32-item Frailty Index (FI), or the Clinical Frailty Scale (CFS) classification tree), and a fourth group where participants were not characterised as frail by any of these tools. Continuous non-invasive physiological signals were collected during an active standing test, including systolic (sBP) and diastolic (dBP) blood pressure, as well as heart rate (HR), using digital artery photoplethysmography. Additionally, the frontal lobe cerebral oxygenation (Oxy), deoxygenation (Deoxy), and tissue saturation index (TSI) were also non-invasively measured using near-infrared spectroscopy (NIRS). The signals were visualised across frailty groups and statistically compared using one-dimensional statistical parametric mapping (SPM). RESULTS: A total of 1124 participants (mean age of 63.5 years; 50.2% women) were included: 23 were characterised as frail only by the FP, 97 by the FI, 38 by the CFS, and 966 by none of these criteria. The SPM analyses revealed that only the group characterised as frail by the FI had significantly different signals (p < 0.001) compared to the non-frail group. Specifically, they exhibited an attenuated gain in HR between 10 and 15 s post-stand and larger deficits in sBP and dBP between 15 and 20 s post-stand. CONCLUSIONS: The FI proved to be more adept at capturing distinct physiological responses to standing, likely due to its direct inclusion of cardiovascular morbidities in its definition. Significant differences were observed in the dynamics of cardiovascular signals among the frail populations identified by different frailty criteria, suggesting that caution should be taken when employing frailty identification tools on physiological signals, particularly the neurocardiovascular signals in an active standing test.

Connectome-based predictive modelling of cognitive reserve using task-based functional connectivity.

Cognitive reserve supports cognitive function in the presence of pathology or atrophy. Functional neuroimaging may enable direct and accurate measurement of cognitive reserve which could have considerable clinical potential. The present study aimed to develop and validate a measure of cognitive reserve using task-based fMRI data that could then be applied to independent resting-state data. Connectome-based predictive modelling with leave-one-out cross-validation was applied to predict a residual measure of cognitive reserve using task-based functional connectivity from the Cognitive Reserve/Reference Ability Neural Network studies (n = 220, mean age = 51.91 years, SD = 17.04 years). This model generated summary measures of connectivity strength that accurately predicted a residual measure of cognitive reserve in unseen participants. The theoretical validity of these measures was established via a positive correlation with a socio-behavioural proxy of cognitive reserve (verbal intelligence) and a positive correlation with global cognition, independent of brain structure. This fitted model was then applied to external test data: resting-state functional connectivity data from The Irish Longitudinal Study on Ageing (TILDA, n = 294, mean age = 68.3 years, SD = 7.18 years). The network-strength predicted measures were not positively associated with a residual measure of cognitive reserve nor with measures of verbal intelligence and global cognition. The present study demonstrated that task-based functional connectivity data can be used to generate theoretically valid measures of cognitive reserve. Further work is needed to establish if, and how, measures of cognitive reserve derived from task-based functional connectivity can be applied to independent resting-state data.

Twenty-five years of research on syncope.

Over the last 25 years, the Europace journal has greatly contributed to dissemination of research and knowledge in the field of syncope. More than 400 manuscripts have been published in the journal. They undoubtedly improved our understanding of syncope. This symptom is now clearly differentiated from other forms of transient loss of consciousness. The critical role of vasodepression and/or cardioinhibition as final mechanisms of reflex syncope is emphasized. Current diagnostic approach sharply separates between cardiac and autonomic pathways. Physiologic insights have been translated, through rigorously designed clinical trials, into non-pharmacological or pharmacological interventions and interventional therapies. The following manuscript is intended to give the reader the current state of the art of knowledge of syncope by highlighting landmark contributions of the Europace journal.

EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA).

There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research.

The bi-directional association between loneliness and depression among older adults from before to during the COVID-19 pandemic.

BACKGROUND: Older adults have both the highest risk of contracting SARS-CoV-2 and in many jurisdictions have had additional restrictions placed on the social interactions. As a result, the COVID-19 pandemic has led to increased depression and loneliness among older adults. Using data from an established cohort of older adults, the aims of this study was to describe changes in loneliness and depression and to examine the directionality of the association between depression and loneliness over a 5-year period that included the early months of the pandemic. METHODS: Data were from The Irish Longitudinal Study on Ageing (TILDA), a large cohort of community-dwelling adults aged 54+. We applied an auto-regressive cross-lagged panel modelling approach to estimate the effect of depression on loneliness and vice versa over three time points. RESULTS: Both depression and loneliness increased significantly in the early months of the pandemic. While the association between loneliness and depression was bi-directional, loneliness was a stronger predictor of depression. CONCLUSION: The strength and bi-directionality of the association between loneliness and depression suggests that interventions to alleviate loneliness may also help reduce depressive symptoms and vice versa.

Eight-year longitudinal falls trajectories and associations with modifiable risk factors: evidence from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: The label 'faller' and the associated stigma may reduce healthcare-seeking behaviours. However, falls are not inevitably progressive and many drivers are modifiable. This observational study described the 8-year longitudinal trajectories of self-reported falls in The Irish Longitudinal Study on Ageing (TILDA) and studied associations with factors, including mobility, cognition, orthostatic hypotension (OH), fear of falling (FOF) and use of antihypertensive and antidepressant medications. METHODS: Participants aged ≥50 years at each wave were categorised by whether they averaged ≥2 falls in the previous year (recurrent fallers) or not (≤1 fall). Next-wave transition probabilities were estimated with multi-state models. RESULTS: 8,157 (54.2% female) participants were included, of whom 586 reported ≥2 falls at Wave 1. Those reporting ≥2 falls in the past year had a 63% probability of moving to the more favourable state of ≤1 fall. Those reporting ≤1 fall had a 2% probability of transitioning to ≥2 falls. Besides older age and higher number of chronic conditions, factors that increased the risk of transitioning from ≤1 fall to ≥2 falls were lower Montreal Cognitive Assessment score, FOF and taking antidepressants. Conversely, male sex, higher timed up and go time, the presence of OH and being on antidepressants reduced the probability of improving from ≥2 falls to ≤1 fall. CONCLUSION: The majority of recurrent fallers experienced favourable transitions. Improvements in cognitive and psychological status, psychotropic prescribing, mobility and OH may help improve trajectories. Findings may help combat stigma associated with falling and promote preventative healthcare-seeking behaviours.

The use of the World Guidelines for Falls Prevention and Management's risk stratification algorithm in predicting falls in The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: the aim of this study was to retrospectively operationalise the World Guidelines for Falls Prevention and Management (WGFPM) falls risk stratification algorithm using data from The Irish Longitudinal Study on Ageing (TILDA). We described how easy the algorithm was to operationalise in TILDA and determined its utility in predicting falls in this population. METHODS: participants aged ≥50 years were stratified as 'low risk', 'intermediate' or 'high risk' as per WGFPM stratification based on their Wave 1 TILDA assessments. Groups were compared for number of falls, number of people who experienced one or more falls and number of people who experienced an injury when falling between Wave 1 and Wave 2 (approximately 2 years). RESULTS: 5,882 participants were included in the study; 4,521, 42 and 1,309 were classified as low, intermediate and high risk, respectively, and 10 participants could not be categorised due to missing data. At Wave 2, 17.4%, 43.8% and 40.5% of low-, intermediate- and high-risk groups reported having fallen, and 7.1%, 18.8% and 18.7%, respectively, reported having sustained an injury from falling. CONCLUSION: the implementation of the WGFPM risk assessment algorithm was feasible in TILDA and successfully differentiated those at greater risk of falling. The high number of participants classified in the low-risk group and lack of differences between the intermediate and high-risk groups may be related to the non-clinical nature of the TILDA sample, and further study in other samples is warranted.

Assessing cognitive function in longitudinal studies of ageing worldwide: some practical considerations.

Over 55 million people live with dementia worldwide. With 40% of modifiable risk factors estimated to contribute to dementia, the potential for prevention is high, and preventive measures, at an early stage of cognitive decline, are likely to positively influence future dementia trends. Countries need reliable health data and adequate measurement tools to quantify, monitor and track early changes in cognitive capacity in the general population. Many cognitive tests exist; however, there is no consensus to date about which instruments should be employed, and important variations in measurement have been observed. In this narrative review, we present a number of cognitive tests that have been used in nationally representative population-based longitudinal studies of ageing. Longitudinal panel studies of ageing represent critical platforms towards capturing the process of cognitive ageing and understanding associated risk and protective factors. We highlight optimal measures for use at a population level and for cross-country comparisons, taking into consideration instrument reliability, validity, duration, ease of administration, costs, literacy and numeracy requirements, adaptability to sensory and fine motor impairments and portability to different cultural and linguistic milieux. Drawing upon the strengths and limitations of each of these tests, and the experience gained and lessons learnt from conducting a nationally representative study of ageing, we indicate a comprehensive battery of tests for the assessment of cognitive capacity, designed to facilitate its standardised operationalisation worldwide.

Randomised controlled trials of antihypertensive therapy: does exclusion of orthostatic hypotension alter treatment effect? A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Management of antihypertensive therapy is challenging in patients with symptomatic orthostatic hypotension, a population often excluded from randomised controlled trials of antihypertensive therapy. In this systematic review and meta-analysis, we sought to determine whether the association of antihypertensive therapy and adverse events (e.g. falls, syncope), differed among trials that included or excluded patients with orthostatic hypotension. METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing blood pressure lowering medications to placebo, or different blood pressure targets on falls or syncope outcomes and cardiovascular events. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall in subgroups of trials that excluded patients with orthostatic hypotension and trials that did not exclude patients with orthostatic hypotension, and tested P for interaction. The primary outcome was fall events. RESULTS: 46 trials were included, of which 18 trials excluded orthostatic hypotension and 28 trials did not. The incidence of hypotension was significantly lower in trials that excluded participants with orthostatic hypotension (1.3% versus 6.2%, P < 0.001) but not incidences of falls (4.8% versus 8.8%; P = 0.40) or syncope (1.5% versus 1.8%; P = 0.67). Antihypertensive therapy was not associated with an increased risk of falls in trials that excluded (OR 1.00, 95% CI; 0.89-1.13) or included (OR 1.02, 95% CI; 0.88-1.18) participants with orthostatic hypotension (P for interaction = 0.90). CONCLUSIONS: The exclusion of patients with orthostatic hypotension does not appear to affect the relative risk estimates for falls and syncope in antihypertensive trials.

The 'Bermuda Triangle' of orthostatic hypotension, cognitive impairment and reduced mobility: prospective associations with falls and fractures in The Irish Longitudinal Study on Ageing.

BACKGROUND: Orthostatic hypotension (OH), cognitive impairment (Cog) and mobility impairment (MI) frequently co-occur in older adults who fall. This study examines clustering of these three geriatric syndromes and ascertains their relationship with future falls/fractures in a large cohort of community-dwelling people ≥ 65 years during 8-year follow-up. METHODS: OH was defined as an orthostatic drop ≥ 20 mmHg in systolic blood pressure (from seated to standing) and/or reporting orthostatic unsteadiness. CI was defined as Mini Mental State Examination ≤ 24 and/or self-reporting memory as fair/poor. MI was defined as Timed Up and Go ≥12 s. Logistic regression models, including three-way interactions, assessed the longitudinal association with future falls (explained and unexplained) and fractures. RESULTS: Almost 10% (88/2,108) of participants had all three Bermuda syndromes. One-fifth of participants had an unexplained fall during follow-up, whereas 1/10 had a fracture. There was a graded relationship with incident unexplained falls and fracture as the number of Bermuda syndromes accumulated. In fully adjusted models, the cluster of OH, CI and MI was most strongly associated with unexplained falls (odds ratios (OR) 4.33 (2.59-7.24); P < 0.001) and incident fracture (OR 2.51 (1.26-4.98); P = 0.045). Other clusters significantly associated with unexplained falls included OH; CI and MI; MI and OH; CI and OH. No other clusters were associated with fracture. DISCUSSION: The 'Bermuda Triangle' of OH, CI and MI was independently associated with future unexplained falls and fractures amongst community-dwelling older people. This simple risk identification scheme may represent an ideal target for multifaceted falls prevention strategies in community-dwelling older adults.