Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study

Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1-35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5-6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4-5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11-1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1-3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2-6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.Daniel H. J. Davis, Graciela Muniz Terrera, Hannah Keage, Terhi Rahkonen, Minna Oinas, Fiona E. Matthews ... et al

Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review.

BACKGROUND: Deposition of amyloid-beta (Abeta) in vessel walls of the brain as cerebral amyloid angiopathy (CAA) could be a major factor in the pathogenesis of dementia. Here we investigate the relationship between dementia and the prevalence of CAA in older populations. We searched the literature for prospective population-based epidemiological clinicopathological studies, free of the biases of other sampling techniques, which were used as a comparison. METHODS: To identify population-based studies assessing CAA and dementia, a previous systematic review of population-based clinicopathological studies of ageing and dementia was employed. To identify selected-sample studies, PsychInfo (1806-April Week 3 2008), OVID MEDLINE (1950-April Week 2 2008) and Pubmed (searched 21 April 2008) databases were searched using the term "amyloid angiopathy". These databases were also employed to search for any population-based studies not included in the previous systematic review. Studies were included if they reported the prevalence of CAA relative to a dementia classification (clinical or neuropathological). RESULTS: Four population-based studies were identified. They showed that on average 55-59% of those with dementia displayed CAA (of any severity) compared to 28-38% of the non-demented. 37-43% of the demented displayed severe CAA in contrast to 7-24% of the non-demented. There was no overlap in the range of these averages and they were less variable and lower than those reported in 38 selected sample studies (demented v non-demented: 32-100 v 0-77% regardless of severity; 0-50 v 0-11% for severe only). CONCLUSION: CAA prevalence in populations is consistently higher in the demented as compared to the non-demented. This supports a significant role for CAA in the pathogenesis of dementia

Antarctic Protected Areas

The system of protected sites established for Antarctic terrestrial environments by the Antarctic Treaty is examined - protection of sites is one of the measures available to Contracting Parties to the Treaty for the preservation and conservation of the Antarctic Environment. Protected sites are categorised: site designations are described and weaknesses are identified in terms of site selection criteria, land-use planning concepts, site management, and logistic and political pressures. Emphasis is given to practical remedies for these deficiencies which can be implemented under the Antarctic Treaty. Four options for the future operation of protected sites are discussed. These are (a) to maintain the status quo, (b) to revise selectively existing Treaty provisions, (c) to declare a 'World Park', and (d) to introduce a new protected site classification based on the Biosphere Reserve concept. Such options are not mutually exclusive and emphasise the need for Treaty Parties to take a more positive approach to the setting aside of protected sites and to their management. It is concluded that improvements to the protected site system hinge on parallel development of (a) a conservation strategy linking conservation measures for the. Antarctic terrestrial environment with those for the marine environment, (b) the establishment of an active Antarctic Treaty Secretariat to oversee the implementation and operation of recommendations on nature conservation, and (c) expansion of the Scientific Cormnittee on Antarctic Research (SCAR) Secretariat to enable it to be more actively involved in site selection, monitoring, and environmental impact assessment. The system of protected sites established for Antarctic terrestrial environments by the Antarctic Treaty is examined protection of sites is one of the measures available to Contracting Parties to the Treaty for the preservation and conservation of the Antarctic Environment. Protected sites are categorised: site designations are described and weaknesses are identified in terms of site selection criteria, land-use planning concepts, site management , and logistic and political pressures. Emphasis is given to practical remedies for these deficiencies which can be implemented under the Antarctic Treaty. Four options for the future operation of protected sites are discussed . These are (a) to maintain the status quo, (b) to revise selectively existing Treaty provisions, (c) to declare a 'World Park', and (d) to introduce a new protected site classification based on the Biosphere Reserve concept. Such options are not mutually exclusive and emphasise the need for Treaty Parties to take a more positive approach to the s e tting aside of protected sites and to their management. It is concluded that improvements to the protected site system hinge on parallel development of (a) a conservation strategy linking conservation measures for the · Antarctic terrestrial environment with those for the marine environment, (b) the establishment of an active Antarctic Treaty Secretariat to oversee the implementation and operation of recommendations on nature conservation, and (c) expansion of the Scientific Conunittee on Antarctic Research (SCAR) Secretariat to enable it to be more actively involved in site selection, monitoring, and environmental impact assessment.Digitisation of this thesis was sponsored by Arcadia Fund, a charitable fund of Lisbet Rausing and Peter Baldwin

Identifying New Factors Associated With Cognitive Decline and Delirium After Transcatheter Aortic Valve Implantation: A Study Protocol

Background: Transcatheter aortic valve implantation (TAVI) has become the standard-of-care for treatment of severe symptomatic aortic stenosis and is also being increasingly recommended for low-risk patients. While TAVI boasts positive post-procedural outcomes, it is also associated with cognitive complications, namely delirium and cognitive decline. There is a pressing need for accurate risk tools which can identify TAVI patients at risk of delirium and cognitive decline, as risk scores designed for general cardiovascular surgery fall short. The present effect-finding exploratory study will assess the utility of various measures in the context of aging and frailty in predicting who will and who will not develop delirium or cognitive impairment following TAVI. The measures we propose include gait, visual symptoms, voice, swallowing, mood and sleep. Methods: This is an observational prospective cohort study focused on identifying pre-procedural risk factors for the development of delirium and cognitive decline following TAVI. Potential risk factors will be measured prior to TAVI. Primary outcomes will be post-procedure cognitive decline and delirium. Secondary outcomes include activities of daily living, quality of life, and mortality. Delirium presence will be measured on each of the first 2 days following TAVI. All other outcomes will be assessed at 3-, 6-, and 12-months post-operatively. A series of logistic regressions will be run to investigate the relationship between potential predictors and outcomes (presence vs. absence of either delirium or cognitive decline). Discussion: This study will assess the strengths of associations between a range of measures drawn from frailty and aging literature in terms of association with cognitive decline and delirium following TAVI. Identified measures can be used in future development of TAVI risk prediction models, which are essential for the accurate identification of cognitive at-risk patients and successful application of pre-procedural interventions. Clinical Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry. [https://bit.ly/2PAotP5], [ACTRN12618001114235]

Cross-Sectional Study of Sleep Quantity and Quality and Amnestic and Non-Amnestic Cognitive Function in an Ageing Population: The English Longitudinal Study of Ageing (ELSA)

Background The aim was to investigate the association between sleep disturbances and cognitive function in younger and older individuals from an ageing population. Methods 3,968 male and 4,821 female white participants, aged 50 years and over, from the English Longitudinal Study of Ageing (ELSA) were studied. Information on sleep quality and quantity as well as both amnestic (memory, ACF) and non-amnestic (non-memory, nACF) function was available at Wave 4 (2008). Analysis of covariance was used to evaluate the relationship between sleep and cognitive function. Results After adjustment for multiple confounders in the younger group (50–64 years) duration of sleep explained 15.2% of the variance in ACF (p = 0.003) and 20.6% of nACF (p = 0.010). In the older group (65+ years) the estimates were 21.3% (p<0.001) and 25.6% (p<0.001), respectively. For sleep quality, there was a statistically significant association between sleep quality and both ACF (p<0.001) and nACF (p<0.001) in the older age group, but not in the younger age group (p = 0.586 and p = 0.373, respectively; interaction between age and sleep quality in the study sample including both age groups: p<0.001 for ACF and p = 0.018 for nACF). Sleep quality explained between 15.1% and 25.5% of the variance in cognition. The interaction with age was independent of duration of sleep. At any level of sleep duration there was a steeper association between sleep quality and ACF in the older than the younger group. Conclusions The associations between sleep disturbances and cognitive function vary between younger and older adults. Prospective studies will determine the temporal relationships between sleep disturbances and changes in cognition in different age groups

Meta-Analysis of Prevalence and Risk Factors for Cognitive Decline and Improvement After Transcatheter Aortic Valve Implantation

Changes to cognition, both decline and improvement, are commonly reported after transcatheter aortic valve implantation (TAVI). However, previous systematic reviews and meta-analyses have missed these subgroups by assessing whole-group-averages for cognitive outcomes. We sought to pool estimates to identify the prevalence of cognitive decline and improvement after TAVI, as well as associated factors for these outcomes. A systematic review identified 15 articles appropriate for meta-analysis. When robust cognitive change definitions were employed, the pooled prevalence of incident cognitive impairment up to 1-, 1 to 6-, and ≥6-months post-TAVI was 7%, 14%, and 12%, respectively. For cognitive improvement, the prevalence from 1 to 6 months and ≥6 months after TAVI was estimated to be 19% and 11%, respectively. Two factors were associated with these cognitive outcomes: (1) using a cerebral embolic protection device was associated with decreased prevalence of cognitive decline up to 1-week post-TAVI; (2) baseline cognitive impairment had a large association with post-TAVI cognitive improvement. In conclusion, cognitive decline and cognitive improvement are experienced by approximately 7% to 19% of patients after TAVI, respectively. Those with the lowest cognitive performance pre-TAVI appear to have the most to gain in terms of cognitive improvement post-TAVI. Identifying further predictive factors for cognitive decline and improvement post-TAVI will facilitate a personalized-medicine approach for cognitive care and prognosis

Factors associated with cognitive decline and delirium after transcatheter aortic valve implantation: Preliminary evidence

Background: Transcatheter aortic valve implantation (TAVI) has become the standard for treating severe symptomatic aortic stenosis in those with prohibitive surgical risk. Cognitive complications, including delirium and cognitive decline are common following TAVI, yet an understanding of pre-procedural factors associated with these outcomes is lacking. This prospective observational study set out to identify geriatric pre-procedural factors associated with post-procedural delirium and cognitive decline in patients undergoing TAVI. / Methods: Cognitive outcomes of TAVI patients aged ≥60 years (N=32) were measured over one-year post-TAVI. Pre-procedural measures included frailty, gait, visual symptoms, voice pitch, dysphagia, blink rate, mood, and sleep. Primary outcomes were post-procedural delirium and cognitive decline. / Results: Delirium was present in 25% of patients over two days following TAVI and 26% experienced cognitive decline in the year post-TAVI. Daily physical activity was a protective factor against cognitive decline, and worse baseline visual memory was associated with delirium. While non-significant and with very large confidence intervals, moderate to large effect sizes were found for associations between slowed gait speed, pre-existing atrial fibrillation, and dysphagia for delirium, and slower gait speed, higher blink rate, pre-existing atrial fibrillation for cognitive decline. / Conclusion: Though underpowered, measures of considerable effect size were identified (although non-significant and with large variability). In larger studies, these novel geriatric factors could further be explored for predicting cognitive complications following TAVI. Improvement of risk prediction for cognitive decline and delirium following TAVI could assist with early identification of those at risk, informing clinical decision-making and allowing for targeted intervention to reduce post-procedural incidence of these complications

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline