Long-term effects of cholinesterase inhibitors and memantine on cognitive decline, cardiovascular events, and mortality in dementia with Lewy bodies: An up to 10-year follow-up study.

INTRODUCTION: We aimed to assess the impact of cholinesterase inhibitors (ChEIs) and memantine on cognition, major adverse cardiovascular events (MACE) and mortality in dementia with Lewy bodies (DLB). METHODS: A total of 1,095 incident DLB patients from the Swedish Registry on cognitive/dementia disorders were included. Using an inverse probability of treatment weighting, the effect of initiating ChEI or memantine within 90 days of DLB diagnosis and nonuse was evaluated on cognitive trajectories and risks of MACE and death. RESULTS: The use of ChEIs significantly slowed cognitive decline at follow-ups (Mini-Mental State Examination [MMSE] -0.39 points/y; 95% confidence interval [CI], -0.96 to 0.18) compared to memantine (-2.49 points/y; -4.02 to -0.97) and nonuse (-2.50 points/y; -4.28 to -0.73). Treatment groups did not differ in MACE events. ChEI use was associated with lower risk of death in the first year after DLB diagnosis (adjusted hazard ratio [HR] 0.66, 95% CI 0.46, 0.94). DISCUSSION: Our findings illuminate the potential benefits of ChEI treatment in DLB patients. HIGHLIGHTS: Cholinesterase inhibitors slow cognitive decline over a 5-year follow-up period when compared to both memantine treatment and nonuse in patients with dementia with Lewy bodies. Cholinesterase Inhibitors reduce risk of mortality within the initial year, but this effect is not sustained after 1 year in patients with dementia with Lewy bodies.

Acute Kidney Injury and Its Association With Dementia and Specific Dementia Types: Findings From a Population-Based Study in Sweden.

BACKGROUND AND OBJECTIVES: Preclinical studies suggest that acute kidney injury (AKI) results in biochemical and pathologic changes in the brain. We aimed to explore the association between experiencing AKI and subsequent risks of developing dementia. METHODS: We conducted a study involving individuals aged 65 years and older in Stockholm from 2006 to 2019, who were free from dementia diagnosis and had data on kidney function. The exposure was an episode of AKI (time varying), ascertained by issued clinical diagnoses and transient creatinine elevations according to Kidney Disease Improving Global Outcomes criteria. The outcome was all-cause dementia and specific types of dementia, ascertained by clinically confirmed cases in the Swedish registry of cognitive/dementia disorders, the presence of 2 issued dementia diagnoses in outpatient care, or initiation of specific antidementia medications. We investigated associations with dementia through Cox proportional hazard regression by AKI, severity levels of AKI, AKI recurrence, and setting (community-acquired or hospital-acquired AKI). RESULTS: We included 305,122 individuals with a median age of 75 ± 8 years (56.6% women). During a median follow-up of 12.3 (interquartile range 8.7-13.3) years, there were 79,888 individuals (26%) suffering from at least 1 episode of AKI and 47,938 incident cases (16%) of dementia. The rate of dementia cases was 37.0 per 1,000 person-years (95% CI 36.2-37.8) after developing AKI, which was approximately 2 times higher than the rate observed during the periods before AKI (17.3, 95% CI 17.2-17.5). After multivariable adjustment, developing AKI was associated with a 49% higher rate of subsequent dementia (adjusted hazard ratio hazard ratio [HR] 1.49, 95% CI 1.45-1.53). This pattern was consistent across dementia types, with HRs of 1.88 (95% CI 1.53-2.32), 1.47 (1.38-1.56), and 1.31 (1.25-1.38) for dementia with Lewy bodies and Parkinson disease with dementia, vascular dementia, and Alzheimer dementia, respectively. Risk associations were stronger in magnitude across more severe AKIs and in hospital-acquired vs community-acquired AKI. DISCUSSION: Individuals who experienced an AKI were at increased risk of receiving a diagnosis of dementia.

COVID-19 Pandemic and Stroke Care in Patients with Dementia Compared to Other Stroke Patients.

OBJECTIVES: The primary objective of this study was to examine the impact of the COVID-19 pandemic on the quality of stroke care for patients with preexisting dementia, compared with patients who had only stroke. The secondary aim was to investigate how the quality of stroke care changed during the pandemic and post-pandemic periods compared with the pre-pandemic period in patients with preexisting dementia. DESIGN: A registry-based, nationwide cohort study in Sweden. SETTING AND PARTICIPANTS: We included patients with a first stroke between 2019 and 2022, both with and without dementia. The study periods were defined as follows: pre-pandemic (January 1, 2019, to February 29, 2020), COVID-19 pandemic (March 1, 2020, to February 24, 2022), and post-COVID-19 pandemic period (February 25, 2022, to September 19, 2022). The outcomes examined were the following quality indicators of stroke care, suggested by the national guideline of stroke care in Sweden: stroke admission site, performance of swallowing assessment, reperfusion treatment, assessment for rehabilitation, and early supported discharge. METHODS: The associations were studied through group comparisons and binary logistic regressions. RESULTS: Of the 21,795 patients with strokes, 1357 had documented preexisting dementia, and 20,438 had stroke without a dementia diagnosis. Throughout all study periods, a significantly lower proportion of patients with stroke with preexisting dementia, compared with stroke-only patients, received reperfusion treatment, assessments for rehabilitation, and early supported discharge from stroke units. In the subgroup of stroke patients with preexisting dementia, no significant associations were found regarding the quality indicators of stroke care before, during, and after the pandemic. CONCLUSIONS AND IMPLICATIONS: Disparities in quality of stroke care were observed between stroke patients with preexisting dementia and those with only stroke during the COVID-19 pandemic. However, there were no statistically significant differences in stroke care for patients with dementia across the pandemic.

Effectiveness of integrated person-centered interventions for older people's care: Review of Swedish experiences and experts' perspective.

Older adults have multiple medical and social care needs, requiring a shift toward an integrated person-centered model of care. Our objective was to describe and summarize Swedish experiences of integrated person-centered care by reviewing studies published between 2000 and 2023, and to identify the main challenges and scientific gaps through expert discussions. Seventy-three publications were identified by searching MEDLINE and contacting experts. Interventions were categorized using two World Health Organization frameworks: (1) Integrated Care for Older People (ICOPE), and (2) Integrated People-Centered Health Services (IPCHS). The included 73 publications were derived from 31 unique and heterogeneous interventions pertaining mainly to the micro- and meso-levels. Among publications measuring mortality, 15% were effective. Subjective health outcomes showed improvement in 24% of publications, morbidity outcomes in 42%, disability outcomes in 48%, and service utilization outcomes in 58%. Workshop discussions in Stockholm (Sweden), March 2023, were recorded, transcribed, and summarized. Experts emphasized: (1) lack of rigorous evaluation methods, (2) need for participatory designs, (3) scarcity of macro-level interventions, and (4) importance of transitioning from person- to people-centered integrated care. These challenges could explain the unexpected weak beneficial effects of the interventions on health outcomes, whereas service utilization outcomes were more positively impacted. Finally, we derived a list of recommendations, including the need to engage care organizations in interventions from their inception and to leverage researchers' scientific expertise. Although this review provides a comprehensive snapshot of interventions in the context of Sweden, the findings offer transferable perspectives on the real-world challenges encountered in this field.

[Oral diseases and dementia]. / Möjliga samband mellan orala sjukdomar och demens.

The aging population makes the increase in cognitive disorders a challenge. One of the risk factors is old age, but also oral diseases, especially periodontitis, have been linked to an increased risk of dementia, especially Alzheimer's disease (AD), although research studies show varying correlations. Dental care utilization also decreases after a dementia diagnosis. The periodontal diseases are inflammatory disorders and common in the adult population. Periodontitis leads to loss of the supporting tissue of the tooth and, if untreated, to loss of teeth. Inflammation also plays a role in AD, the most common form of dementia. The reason for an association could be that periodontitis may lead to a spread of pro-inflammatory mediators and oral microorganisms to the brain. Another explanation suggests that chewing may stimulate nerve impulses and increase the blood flow to the brain. Fewer teeth could lead to less stimulation and reduced blood flow. In conclusion, oral diseases and dementia appear to be associated. Whether this connection constitutes a causal connection is more uncertain.

Immigration and access to dementia diagnostics and treatment: A nationwide study in Sweden.

•Compared to Swedish-born people, foreign-born people were less likely to receive dementia diagnostic tests.•Being born in Africa or Europe was associated with lower chance of receiving cholinesterase inhibitors.•Asian-born people had higher chance of receiving cholinesterase inhibitors, but were less likely to receive memantine.•Disparities existed in dementia diagnostics and treatment between Swedish-born and foreign-born people, but were not consistent after adjusting for MMSE scores.

Cholinesterase inhibitors are associated with reduced mortality in patients with Alzheimer's disease and previous myocardial infarction.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are the first-line symptomatic pharmacologic treatment for patients with mild-to-moderate Alzheimer's disease (AD). Although the target organ for this group of drugs is the brain, inhibition of the enzyme may affect cardiac function through vagotonic and anti-inflammatory effects. OBJECTIVE: To assess the impact of ChEIs on outcomes in patients with AD who have experienced myocardial infarction (MI) prior to the AD diagnosis. METHODS: Patients who had experienced MI before they were diagnosed with AD or Alzheimer's mixed dementia between 2008 and 2018 were identified from the Swedish Dementia Registry (SveDem, www.svedem.se), which was linked to the National Patient Registry to obtain data on MI and mortality. Cox proportional hazards regression model among a propensity score-matched dataset was performed to assess the association between ChEI treatment and clinical outcomes. RESULTS: Of 3198 patients with previous MI and a diagnosis of AD or mixed dementia, 1705 (53%) were on treatment with ChEIs. Patients treated with ChEIs were more likely to be younger and have a better overall cardiovascular (CV) risk profile. The incidence rate of all-cause death (per 1000 patient-years) in the propensity-matched cohort of 1016 ChEI users and 1016 non-users was 168.6 in patients on treatment with ChEIs compared with 190.7 in patients not on treatment with ChEIs. In this propensity-matched cohort, treatment with ChEIs was associated with a significantly lower risk of all-cause death (adjusted hazard ratio 0.81, 95% confidence interval 0.71-0.92) and a greater reduction with higher doses of ChEIs. While in the unadjusted analysis, ChEIs were associated with a lower risk of both CV and non-CV death, only the association with non-CV death remained significant after accounting for baseline differences. CONCLUSION: Treatment with ChEIs was associated with a significantly reduced risk of all-cause death, driven by lower rates of non-CV death in a nationwide cohort of patients with previous MI and a diagnosis of AD or mixed dementia. These associations were greater with higher ChEI doses. CONDENSED ABSTRACT: We assessed the association between cholinesterase inhibitors (ChEIs) and clinical outcomes in a nationwide cohort of patients with previous myocardial infarction (MI) and a diagnosis of Alzheimer's disease (AD) or mixed dementi. In propensity-matched analysis, treatment with ChEIs was associated with a 19% reduction in all-cause death driven by non-cardiovascular death. The reduction in all-cause death was greater with the higher doses of ChEIs.

Predicting sojourn times across dementia disease stages, institutionalization, and mortality.

INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.

Statins and cognitive decline in patients with Alzheimer's and mixed dementia: a longitudinal registry-based cohort study.

BACKGROUND: Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer's disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms. OBJECTIVE: To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment. METHODS: A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users. RESULTS: Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent. CONCLUSIONS: Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses.

Psychiatric Disorders Before and After Dementia Diagnosis.

Importance: Little is known about the specific timing and sequence of incident psychiatric comorbidities at different stages of dementia diagnosis. Objectives: To examine the temporal risk patterns of psychiatric disorders, including depression, anxiety, stress-related disorders, substance use disorders, sleep disorders, somatoform/conversion disorders, and psychotic disorders, among patients with dementia before, at the time of, and after receipt of a diagnosis. Design, Setting, and Participants: This population-based, nationwide cohort study analyzed data from 796 505 participants obtained from 6 registers between January 1, 2000, and December 31, 2017, including the Swedish registry for cognitive/dementia disorders. Patients with dementia were matched on year of birth (±3 years), sex, and region of residence with up to 4 controls. Data were analyzed between March 1, 2023, and August 31, 2023. Exposures: Any cause of dementia and dementia subtypes. Main Outcomes and Measures: Flexible parametric survival models to determine the time-dependent risk of initial diagnosis of psychiatric disorders, from 7 years prior to dementia diagnosis to 10 years after diagnosis. Subgroup analysis was conducted for psychiatric drug use among persons receiving a diagnosis of dementia from January 1, 2011, to December 31, 2012. Results: Of 796 505 patients included in the study (mean [SD] age at diagnosis, 80.2 [8.3] years; 448 869 (56.4%) female), 209 245 had dementia, whereas 587 260 did not, across 7 824 616 person-years. The relative risk of psychiatric disorders was consistently higher among patients with dementia compared with control participants and began to increase from 3 years before diagnosis (hazard ratio, [HR], 1.72; 95% CI, 1.67-1.76), peaked during the week after diagnosis (HR, 4.74; 95% CI, 4.21-5.34), and decreased rapidly thereafter. Decreased risk relative to controls was observed from 5 years after diagnosis (HR, 0.93; 95% CI, 0.87-0.98). The results were similar for Alzheimer disease, mixed dementia, vascular dementia and unspecified dementia. Among patients with dementia, markedly elevated use of psychiatric medications was observed in the year leading up to the dementia diagnosis and peaked 6 months after diagnosis. For example, antidepressant use was persistently higher among patients with dementia compared with controls, and the difference increased from 2 years before dementia diagnosis (15.9% vs 7.9%, P < .001), peaked approximately 6 months after dementia diagnosis (29.1% vs 9.7%, P < .001), and then decreased slowly from 3 years after diagnosis but remained higher than controls 5 years after diagnosis (16.4% vs 6.9%, P < .001). Conclusions and Relevance: The findings of this cohort study that patients with dementia had markedly increased risks of psychiatric disorders both before and after dementia diagnosis highlight the significance of incorporating psychiatric preventative and management interventions for individuals with dementia across various diagnostic stages.

The Impact of Educational Attainment and Income on Long-Term Care for Persons with Alzheimer's Disease and Other Dementias: A Swedish Nationwide Study.

BACKGROUND: Long-term care improves independence and quality of life of persons with dementia (PWD). The influence of socioeconomic status on access to long-term care was understudied. OBJECTIVE: To explore the socioeconomic disparity in long-term care for PWD. METHODS: This registry-based study included 14,786 PWD, registered in the Swedish registry for cognitive and dementia disorders (2014-2016). Education and income, two traditional socioeconomic indicators, were the main exposure. Outcomes were any kind of long-term care, specific types of long-term care (home care, institutional care), and the monthly average hours of home care. The association between outcomes and socioeconomic status was examined with zero-inflated negative binomial regression and binary logistic regression. RESULTS: PWD with compulsory education had lower likelihood of receiving any kind of long-term care (OR 0.80, 95% CI 0.68-0.93), or home care (OR 0.83, 95% CI 0.70-0.97), compared to individuals with university degrees. Their monthly average hours of home care were 0.70 times (95% CI 0.59-0.82) lower than those of persons with university degrees. There was no significant association between education and the receipt of institutional care. Stratifying on persons with Alzheimer's disease showed significant association between lower education and any kind of long-term care, and between income and the hours of home care. CONCLUSIONS: Socioeconomic inequalities in long-term care existed in this study population. Lower-educated PWD were less likely to acquire general long-term care, home care and had lower hours of home care, compared to their higher-educated counterparts. Income was not significantly associated with the receipt of long-term care.

Temporal trends in hospitalizations and 30-day mortality in older patients during the COVID pandemic from March 2020 to July 2021.

BACKGROUND: A reduction in mortality risk of COVID-19 throughout the first wave of the pandemic has been reported, but less is known about later waves. This study aimed to describe changes in hospitalizations and mortality of patients receiving inpatient geriatric care for COVID-19 or other causes during the pandemic. METHODS: Patients 70 years and older hospitalized in geriatric hospitals in Stockholm for COVID-19 or other causes between March 2020-July 2021 were included. Data on the incidence of COVID-positive cases and 30-day mortality of the total ≥ 70-year-old population, in relation to weekly hospitalizations and mortality after hospital admissions were analyzed. Findings The total number of hospitalizations was 5,320 for COVID-19 and 32,243 for non-COVID-cases. In COVID-patients, the 30-day mortality rate was highest at the beginning of the first wave (29% in March-April 2020), reached 17% at the second wave peak (November-December) followed by 11-13% in the third wave (March-July 2021). The mortality in non-COVID geriatric patients showed a similar trend, but of lower magnitude (5-10%). During the incidence peaks, COVID-19 hospitalizations displaced non-COVID geriatric patients. INTERPRETATION: Hospital admissions and 30-day mortality after hospitalizations for COVID-19 increased in periods of high community transmission, albeit with decreasing mortality rates from wave 1 to 3, with a probable vaccination effect in wave 3. Thus, the healthcare system could not compensate for the high community spread of COVID-19 during the pandemic peaks, which also led to displacing care for non-COVID geriatric patients.

Natural Course of Aortic Stenosis in Older Subjects: Effects of COVID-19.

OBJECTIVE: Both aortic stenosis (AS) and COVID-19 affect the morbidity and mortality burden among older adults. The aim of the study was to examine whether aortic stenosis (AS) affects the prognosis after SARS-CoV-2 infection and whether COVID-19 affects AS prognosis, in a cohort of older adults hospitalized with and without COVID-19. DESIGN: Observational study. SETTING AND PARTICIPANTS: Patients admitted to 9 geriatric clinics in Stockholm from March 2020 to November 2021. METHODS: AS and COVID-19 diagnoses were identified by electronic health records; the outcomes were mortality at 30 days and any time during a median follow-up of 630 days. The associations between AS, COVID-19, and mortality were assessed by using Royston-Parmar models adjusting for age, sex, comorbidities, and admission waves. RESULTS: Among 28,974 patients, 85 had concomitant AS and COVID-19, 529 had only AS, and 5033 had only COVID-19. Both at 30 days and at any time, as compared to patients without, concomitant AS and COVID-19 subjects had a higher mortality rate (438.4 per 100 py, 95% CI 296.2-648.8, and 72.9, 95% CI 53.7-99.0, respectively) and a higher death risk (adjusted HR 5.5, 95% CI 3.7-8.2; and 2.8, 95% CI 2.1-3.9). AS patients presented increased mortality HR both in the presence and absence of COVID-19 at 30 days (1.6, 95% CI 1.1-2.4; and 1.6, 95% CI 1.2-2.2, respectively) and at any time (1.6, 95% CI 1.1-2.1; 1.4, 95% CI 1.2-1.7, respectively). CONCLUSIONS AND IMPLICATIONS: AS was a significant mortality risk factor, independent of concomitant COVID-19. Careful AS management should always be pursued, even in acute and post-acute phases of COVID-19.

Precision medicine in neurodegeneration: the IHI-PROMINENT project.

Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer's disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.

Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to AppNL-G-F knock-in Alzheimer mice.

BACKGROUND: Alzheimer's disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (AppNL-G-F). METHODS: ECB's containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old AppNL-G-F mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings. RESULTS: The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-ß (Aß) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. CONCLUSIONS: The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies.

External Causes of Death From Death Certificates in Patients With Dementia.

OBJECTIVES: We aim to analyze the risk of death from specific external causes, including falls, complications of medical and surgical care, unintentional injuries, and suicide, in dementia patients. DESIGN: Swedish nationwide cohort study integrating 6 registers from May 1, 2007, through December 31, 2018, including the Swedish Registry for Cognitive/Dementia Disorders (SveDem). SETTING AND PARTICIPANTS: Population-based study. Patients diagnosed with dementia from 2007 to 2018 and up to 4 controls matched on year of birth (±3 years), sex, and region of residence. METHODS: The exposures of this study were diagnosis of dementia and dementia subtypes. Number of deaths and causes of mortality were obtained from death certificates compiled into the Cause of Death Register. Hazard ratios (HRs) and 95% CIs were estimated using Cox and flexible models, adjusted for sociodemographics, medical and psychiatric disorders. RESULTS: The study population included 235,085 patients with dementia [96,760 men (41.2%); mean age 81.5 (SD 8.5) years] and 771,019 control participants [341,994 men (44.4%); mean age 79.9 (SD 8.6) years], over 3,721,687 person-years. Compared with control participants, patients with dementia presented increased risk for unintentional injuries (HR 3.30, 95% CI 3.19-3.40) and falls (HR 2.67, 95% CI 2.54-2.80) during old age (≥75 y), and suicide (HR 1.56, 95% CI 1.02-2.39) in middle age (<65 y). Suicide risk was 5.04 times higher (HR 6.04, 95% CI 4.22-8.66) in patients with both dementia and 2 or more psychiatric disorders relative to controls (incidence rate per person-years, 1.6 vs 0.3). For dementia subtypes, frontotemporal dementia had the highest risks of unintentional injuries (HR 4.28, 95% CI 2.80-6.52) and falls (HR 3.83, 95% CI 1.98-7.41), whereas subjects with mixed dementia were less likely to die from suicide (HR 0.11, 95% CI 0.03-0.46) and complications of medical and surgical care (HR 0.53, 95% CI 0.40-0.70) compared to controls. CONCLUSIONS AND IMPLICATIONS: Suicide risk screening and psychiatric disorders management in early-onset dementia and early interventions for unintentional injuries and falls prevention in older dementia patients should be provided.

Machine learning algorithms for identifying predictive variables of mortality risk following dementia diagnosis: a longitudinal cohort study.

Machine learning (ML) could have advantages over traditional statistical models in identifying risk factors. Using ML algorithms, our objective was to identify the most important variables associated with mortality after dementia diagnosis in the Swedish Registry for Cognitive/Dementia Disorders (SveDem). From SveDem, a longitudinal cohort of 28,023 dementia-diagnosed patients was selected for this study. Sixty variables were considered as potential predictors of mortality risk, such as age at dementia diagnosis, dementia type, sex, body mass index (BMI), mini-mental state examination (MMSE) score, time from referral to initiation of work-up, time from initiation of work-up to diagnosis, dementia medications, comorbidities, and some specific medications for chronic comorbidities (e.g., cardiovascular disease). We applied sparsity-inducing penalties for three ML algorithms and identified twenty important variables for the binary classification task in mortality risk prediction and fifteen variables to predict time to death. Area-under-ROC curve (AUC) measure was used to evaluate the classification algorithms. Then, an unsupervised clustering algorithm was applied on the set of twenty-selected variables to find two main clusters which accurately matched surviving and dead patient clusters. A support-vector-machines with an appropriate sparsity penalty provided the classification of mortality risk with accuracy = 0.7077, AUROC = 0.7375, sensitivity = 0.6436, and specificity = 0.740. Across three ML algorithms, the majority of the identified twenty variables were compatible with literature and with our previous studies on SveDem. We also found new variables which were not previously reported in literature as associated with mortality in dementia. Performance of basic dementia diagnostic work-up, time from referral to initiation of work-up, and time from initiation of work-up to diagnosis were found to be elements of the diagnostic process identified by the ML algorithms. The median follow-up time was 1053 (IQR = 516-1771) days in surviving and 1125 (IQR = 605-1770) days in dead patients. For prediction of time to death, the CoxBoost model identified 15 variables and classified them in order of importance. These highly important variables were age at diagnosis, MMSE score, sex, BMI, and Charlson Comorbidity Index with selection scores of 23%, 15%, 14%, 12% and 10%, respectively. This study demonstrates the potential of sparsity-inducing ML algorithms in improving our understanding of mortality risk factors in dementia patients and their application in clinical settings. Moreover, ML methods can be used as a complement to traditional statistical methods.

Comparing three neuropsychological subgrouping approaches in subjective and mild cognitive impairment from a naturalistic multicenter study.

Subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are two clinical groups with an increased risk to develop dementia, but they are highly heterogeneous. This study compared three different approaches to subgroup SCI and MCI patients and investigated their capacity to disentangle cognitive and biomarker heterogeneity. We included 792 patients from the MemClin-cohort (142 SCI and 650 MCI). Biomarkers included cerebrospinal fluid measures of beta-amyloid-42 and phosphorylated tau, as well as visual ratings of medial temporal lobe atrophy and white matter hyperintensities on magnetic resonance imaging. We found that a more inclusive approach identified individuals with a positive beta-amyloid-42 biomarker; a less inclusive approach captured individuals with higher medial temporal lobe atrophy; and a data-driven approach captured individuals with high white matter hyperintensities burden. The three approaches also captured some neuropsychological differences. We conclude that choice of approach may differ depending on the purpose. This study helps to advance our current understanding of the clinical and biological heterogeneity within SCI and MCI, particularly in the unselected memory clinic setting.