Table 9.

Knowledge gaps and areas for further research

	Knowledge gap(s)	Further research
General dementia-related research domainsa
Distinguishing progression of normal aging from pre-clinical cognitive decline	Physiology of normal aging/pathological neurodegenerative processes.	Large international population-based longitudinal studies of aging and dementia Contribution of vascular conditions, inflammation, oxidative stress, and the immune system to neurodegenerative processes causing dementia
Identification of the risk factors and risk reduction	Interactions of shared pathological pathways and risk factors.	Interactions of modifiable and non-modifiable dementia risk factors in population-based studies Feasibility, administration and effectiveness of interventions addressing dementia risk factors
Early diagnosis, biomarkers and disease monitoring	Effective strategies for cognitive surveillance; Early detection of cognitive impairment; Monitoring of disease progression.	Interventions for timely and accurate diagnosis of cognitive impairment or dementia at the primary health-care level. Better characterization of different dementia types Strategies for longitudinal surveillance of healthy individuals to distinguish (and timely diagnose) pre-clinical neurodegenerative diseases with cognitive impairment vs. normal aging Validation and standardization of available cerebrospinal fluid and brain imaging biomarkers of dementia for research and clinical use Development and validation of novel biological, genetic, behavioural or cognitive biomarkers with predictive value at pre-dementia stages
Prevention of cognitive impairment/dementia	Effective preventive strategies in general population.	Exploring single- and multi-domain approaches for primary and secondary prevention of dementia based on evidence on risk/protective factors and the relationship with other chronic diseases Prevention studies need to start in mid-life and have a long follow-up to identify ‘windows of opportunity’ for effective interventions
Pharmacological and non-pharmacological clinical–translational research on dementia diagnosis and treatment	Effective dementia-specific therapies are not available yet.	Identification, validation and implementation of better defined outcome measures for clinical trials of cognition, function and other biomarkers of neurodegenerative diseases causing dementia Improvement in differentiation of dementia types Improvement in the selection of patients eligible for clinical trials of cognitive impairment or dementia Investigation of combination therapies for dementia and diversification of investigational therapeutic approaches (pharmacological and non-pharmacological interventions)
AF-specific research domains
Association of AF with cognitive impairment or dementia	Underlying mechanisms beyond clinically overt strokes, silent strokes and aging are poorly understood.	Significance and contribution of cerebral hypoperfusion due to irregular heart rhythm and impaired cardiac function in AF patients, AF-associated hypercoagulability and OAC-related cerebral micro-bleeds to cognitive deterioration and development of dementia Association of AF burden (i.e. paroxysmal vs. non-paroxysmal AF) with cognitive status Potential role of atrial cardiomyopathy in the development of cognitive impairment/dementia
Time-course of cognitive impairment in AF patients	Mechanism(s) of accelerated development of dementia in AF patients.	Large prospective population-based studies on AF and non-AF patients to identify the time-course of cognitive deterioration by AF status and risk factors for accelerated dementia, thus providing a roadmap for prevention strategies Identification and validation of clinical predictors and biomarkers to identify AF patients at increased risk of cognitive impairment/dementia
Rhythm control and other strategies, including ablation, for AF burden reduction	Short- and long-term effects on cognitive function in AF patients	Better representation of elderly and other AF patients with, or at risk for cognitive impairment or dementia in future rhythm control and AF ablation studies Prospective investigation of the effects of rhythm control, AF ablation and other strategies for AF burden reduction on cognitive function and prevention, attenuation or delay of cognitive impairment/dementia Prospective investigation of the effects of different ablation energy sources (e.g. radiofrequency, cryoablation) on cognitive function
Pharmacological rate control therapies in AF; AV node ablation with permanent pacemaker implantation for rate control in AF	Short- and long-term effects on cognitive function in AF patients	Prospective investigation of the effects of strict vs. lenient rate control on cognitive function in AF patients including those with cognitive impairment or dementia Better representation of elderly and other AF patients with, or at risk for cognitive impairment or dementia in future prospective studies investigating the effects of AV node ablation with permanent pacemaker implantation on cognitive function and prevention, attenuation or delay of cognitive impairment or dementia
VKA, NOACs and non-pharmacological (LAAO) thromboprophylaxis in AF	Long-term effects on cognitive function in AF patients	Prospective studies of VKA, NOACs and LAAO long-term effects on cognitive function in AF patients with baseline normal cognitive status, cognitive impairment or dementia Assessment of benefits of VKA, NOACs for reduction of cognitive decline among patients with micro-haemorrhages Identification and validation of clinical/biomarker predictors of cognitive impairment/dementia in anticoagulated AF patients or those with LAAO Studies on the consequences of non-adherence or permanent OAC discontinuation in AF patients with cognitive impairment or dementia
Screening for asymptomatic AF	Asymptomatic AF-associated risk of cognitive impairment	Assessment of cognitive impairment and dementia in patients with asymptomatic AF Assessment of the effect of asymptomatic AF treatment on prevention, attenuation or delay of cognitive impairment or dementia
Early AF detection and treatment	Effects of early aggressive rhythm control on cognitive function	Studies with pre-specified primary endpoint of cognitive function Inclusion of elderly and other AF patients with, or at risk for cognitive impairment or dementia
Primary prevention of AF	Effective interventions for primary prevention (ongoing research)	Effects of dietary intervention, improved blood pressure control and other risk factors control on cognitive function in patients at risk of AF and cognitive impairment/dementia, and in non-AF patients with cognitive impairment/dementia
Other arrhythmia-specific research domains
SCD risk assessment and SCD prevention	Effective strategies in individuals with cognitive limitations	Improvement of non-invasive risk assessment and identification of screening tools applicable to older and other patients with, or at risk for cognitive impairment or dementia SCD prevention studies to include cognitive function endpoints
Catheter ablation of ventricular arrhythmias	Short and long-term effects in individuals with cognitive limitations	Better understanding of the role of catheter ablation of ventricular arrhythmias in older and other patients with, or at risk for cognitive impairment/dementia, including studies of competing risk of death caused by ventricular arrhythmias vs. other causes Further studies on the impact of left sided and trans-septal vs. trans-aortic access on cognitive function
ICD for primary and secondary prevention	Short- and long-term effects in patients with cognitive limitations	Studies on ICD implantation outcomes including procedural complications, QALY gain, healthcare costs and competing risk of death in patients with cognitive impairment or dementia Studies estimating life extension with ICD and end-of-life issues in patients with cognitive impairment or dementia Further research on impact of antitachycardia pacing vs. defibrillation on cognitive function
CRT	Effects in patients with cognitive limitations	Studies of the impact of CRT, with or without ICD, on QoL and cognitive function in patients with, or at risk for cognitive impairment or dementia

^aCompiled and modified from the Refs.^{131–133,185–187} (for details on the quality of care, delivery of care and services for individuals with dementia and public awareness and understanding see the cited documents).

AF, atrial fibrillation; AV, atrioventricular; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; LAAO, left atrial appendage occlusion; NOACs, non-vitamin K antagonist oral anticoagulants; OAC, oral anticoagulation; QALY, quality-adjusted life-years; QoL, quality of life; SCD, sudden cardiac death; VKA, vitamin K antagonist.