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Background: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. Objective: To characterize BPSD in Alzheimer’s disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. Methods: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. Results: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. Conclusion: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer’s disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). Methods: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n = 18) or placebo (n = 15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

Background: In Sweden, 2,296,000 firearms were legally owned by private persons in 2017 and there were 150,000 persons living with a dementia diagnosis. A proportion of these persons owning a firearm may pose safety concerns. Objective: The aim was to describe firearm ownership in persons with dementia in Sweden and examine which characteristics are explaining physicians’ decision to report a person to the police as unsuitable to possess a firearm. Methods: This was a registry-based observational study. 65,717 persons with dementia registered in the Swedish Dementia Registry were included in the study. Logistic regression was used to evaluate which of the persons’ characteristics were most important in predicting the likelihood of being reported as unsuitable to possess a firearm. Relative importance of predictors was quantified using standardized coefficients (SC) and dominance analysis (DA). Results: Out of 53,384 persons with dementia, 1,823 owned a firearm and 419 were reported to the police as unsuitable owners. Firearm owners were predominantly younger, males, living alone, and without assistance of homecare. The most important predictors of being reported to the police were: living with another person (SC = 0.23), frontotemporal dementia (SC = 0.18), antipsychotics prescription (SC = 0.18), being diagnosed in a memory/cognitive clinic (SC = –0.27), female gender (SC = 0.18), mild (SC = –0.25) and moderate (SC = –0.21) dementia, and hypnotics prescription (SC = 0.17). Conclusion: Firearm owners with dementia were mostly younger males who were still living more independent lives. The decision to remove a weapon was not solely based on a diagnosis of dementia but a combination of factors was considered.

Background Periodontal disease has been proposed as a putative etiological factor for dementia. The aim of this investigation was to compare the incidence of dementia in individuals with or without deep probing pocket depths (DPPD), serving as a proxy for periodontitis. Methods In this cohort study, conducted in Sweden, we identified 7992 individuals with DPPD and 29,182 matched individuals without DPPD (non-DPPD), using the Swedish Quality Registry for Caries and Periodontal Diseases (SKaPa). The two groups were followed for incident dementia (mean follow-up time was 7.6 years) based on data from the Swedish Dementia Registry (SveDem). The exposure-outcome relationship was explored by applying the Royston-Parmar (RP) flexible parametric survival model. Results The incidence of dementia in the two groups was similar. In the DPPD group 137 (1.7%) developed dementia and 470 (1.6%) in the non-DPPD group. The incidence rate of dementia was estimated to be 2.3 per 1000 person-years (95% confidence interval [CI] 1.9 to 2.7) in the DPPD group and 2.1 per 1000 person-years (95% CI 1.9 to 2.3) in the non-DPPD group. The RP model disclosed no association between DPPD and dementia incidence after controlling for potential confounders (the exponentiated coefficient was estimated to 1.13 [95% CI = 0.39 to 3.24]). Conclusion In this sample, no association was revealed between deep probing pocket depths and the incidence of dementia.

Background The effect of calcium channel blockers (CCB) on mortality and ischaemic stroke risk in dementia patients is understudied. Objectives To calculate the risk of death and ischaemic stroke in dementia patients treated with CCBs, considering individual agents and dose response. Methods Longitudinal cohort study with 18 906 hypertensive dementia patients from the Swedish Dementia Registry (SveDem), 2008–2014. Other Swedish national registries contributed information on comorbidities, dispensed medication and outcomes. Individual CCB agents and cumulative defined daily doses (cDDD) were considered. Results In patients with hypertension and dementia, nifedipine was associated with increased mortality risk (aHR 1.32; CI 1.01–1.73; P

Background Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. Objective Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. Methods We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naive subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Results Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11-1.31] and lower probability of DPP-4i (0.72 [0.66-0.79]), GLP-1a (0.51 [0.41-0.63]), and SGLT-2i dispensation (0.44 [0.36-0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (-0.58%), GLP-1a (-0.13%), and SGLT-2i (-0.21%) dispensation in dementia patients compared to dementia-free controls. Conclusion Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects.

Background Older adults with dementia often have poor oral health. Chronic use of xerogenic medications may contribute to adverse dental outcomes. Objective To investigate the impact of xerogenic medication classes on the predicted risk for dental interventions in people with dementia. Methods This was a population-based cohort study involving 30,955 individuals registered in the Swedish Dementia Registry (SveDem) from 2008 to 2015. Data were linked with other national registers. The exposure was xerogenic medication classes used in the three years prior to dementia diagnosis (baseline). The primary outcome was the composite of number of tooth extractions and dental restorations over the three-year follow-up period. Secondary outcomes included the number of tooth extractions and number of dental restorations. Poisson regression models were used to estimate the association between the exposure and outcomes. Analyses were adjusted for age, gender, Mini-Mental State Examination, living arrangement, dementia disorder, average number of medications, Charlson's comorbidity index, number of dental visits, and number of teeth. Results After adjusting for potential covariates, the use of urological drugs (incidence rate ratio [IRR] 1.16, 95% CI 1.04-1.28), proton pump inhibitors (IRR 1.13, 95% CI 1.04-1.23), and opioids (IRR 1.19, 95% CI 1.06-1.34) were significantly associated with the primary composite outcome. Conclusion The use of specific classes of xerogenic medications was associated with an increased risk for tooth extractions and restorations in people with dementia. The risks and benefits of xerogenic medications, in the context of oral health, should be carefully assessed in this vulnerable population.

INTRODUCTION: Loss to follow-up in dementia studies is common and related to cognition, which worsens over time. We aimed to (1) describe dropout and missing cognitive data in the Swedish dementia registry, SveDem; (2) identify factors associated with dropout; and (3) estimate propensity scores and use them to adjust for dropout.METHODS: Longitudinal cognitive data were obtained from 53,880 persons from the SveDem national quality dementia registry. Inverse probability of censoring weights (IPCWs) were estimated using a logistic regression model on dropout.RESULTS: The mean annualized rate of change in Mini-Mental State Examination (MMSE) in those with a low MMSE (0 to 10) was likely underestimated in the complete case analysis (+1.5 points/year) versus the IPCW analysis (-0.3 points/year).DISCUSSION: Handling dropout by IPCWs resulted in plausible estimates of cognitive decline. This method is likely of value to adjust for biased dropout in longitudinal cohorts of dementia.

Background The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. Methods Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. Results All AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient. Conclusions The cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype. Trial registration ClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010.

Objective We performed a systematic review and meta-analysis to study the relationship between cognitive functioning and phenotypic frailty status. Methods We searched Pubmed, Cochrane Library and Epistemonikos from 2000 until March 2022, and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Samples included both sexes, age ≥55 years, assessed with standardized measures of the different cognitive domains and the frailty phenotype model and analyzing the relationship between the frailty subtypes pre-frail, frail and robust and specific cognitive function. Results Eleven studies published from 2008 until March 2022 fulfilled the inclusion criteria, and 10 were included in our meta-analyses. Sample sizes varied from 104 to 4649 individuals. Mean Mini-Mental State Examination (MMSE) scores ranged from 17.0 to 27.6, with mean difference (MD) of −2.55 (95% confidence interval [CI] −3.32, −1.78) in frail compared to robust, MD −1.64 (95% CI −2.21, −1.06) in frail compared to prefrail and MD −0.68 (95% CI −0.94, −0.43) in prefrail compared to robust. In subgroup analyses, frail persons had lower scores in the memory domain with standardized mean difference (SMD) −1.01 (95% CI −1.42, −0.59). Conclusion MMSE scores were significantly lower in frail compared to robust and prefrail persons and in prefrail compared to robust persons. Subgroup analysis of memory revealed significantly poorer scores in frail compared to robust. The results indicate a strong relationship between physical frailty and cognitive impairment suggesting incorporation of cognitive function in frailty assessments.

We compared the prevalence of COVID-19 and related mortality in nursing homes (NHs) in 14 countries until October 2021. We explored the relationship between COVID-19 mortality in NHs with the average size of NHs and with the COVID-19 deaths at a population level.The total number of COVID-19 cases and COVID-19-related deaths in all NHs as well as the total number of NHs and NH beds were provided by representatives of 14 countries. The population level respective figures in each country were provided up to October 2021.There was a wide variation in prevalence of COVID-19 cases and deaths between countries. We observed a significant correlation between COVID-19 deaths in NHs and that of the total population and between the mean size of NHs and COVID-19 deaths.Side-by-side comparisons between countries allow international sharing of good practice to better enable future pandemic preparedness.

Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients.

Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimers dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression. Funding Agencies|StratNeuro (the Strategic Research Area Neuroscience-Karolinska Institutet, Umea University); StratNeuro (Kungliga Tekniska hogskolan); Center for Innovative Medicine Foundation (CIMED) [FoUI-963369]; Swedish Research Council [2019-01059, 2022-01428, 2016-02317, 2020-02014]; Stockholm County Council; Karolinska Institutet; Swedish Heart and Lung Foundation [20190587]; Westman Foundation

Introduction The COVID-19 pandemic has caused large disruptions to healthcare systems. Refocus on COVID-19 related care might have contributed to indirect effects on other healthcare areas. Care focused on acute conditions have been negatively affected although research into the effects on chronic and care intensive patient groups such as patients with dementia diseases is lacking. In this study we evaluated dementia diagnosis trends in Sweden during 2015–2020 according to International Classification of Disease version 10 coding of common dementia diseases. Methods Regional and national statistics in the form of International Classification of Disease version 10 coding, COVID-19 incidence, mortality data, and population census data were collected from the National Institute of Health and Welfare. Logistic regression analysis was performed to identify trends of dementia diagnosis during 2015–2020. Correlation test was performed between COVID-19 incidence, mortality rates, and dementia coding. Results Dementia diagnosis incidence has been declining since 2015 and further decline was noted in many regions in Sweden during 2020. As COVID-19 incidence increased, fewer cases of dementia were diagnosed, a decrease that differentially impacted women and those who were advanced in age. Conclusions Dementia diagnosis incidence in Sweden has been on a decline since 2015. The COVID-19 pandemic caused a further larger decline in dementia diagnosis incidence during 2020. COVID-19 incidence, but not mortality, was associated with decrease in dementia diagnosis incidence. There might be a large number of undiagnosed patients with dementia and healthcare reforms should be enacted to address this. Women and elderly are particularly vulnerable groups.

Background The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia. Methods Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer’s disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout. Results Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (−1.00, −1.95; −0.04) and sulfonylureas (−1.19; −2.33; −0.04) was associated with larger point-wise decrements in MMSE with annual intervals. Conclusions In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted.

We thank Dr. Fischereder for the comments on our study.1 Our goal was to explore the association between kidney function and the risk of dementia, not to imply causation. Although the underlying mechanisms remain unclear, they do not preclude our findings from being plausible. Subsequent studies confirm an association between cognitive impairment and markers of kidney dysfunction.2,3 Experimental evidence suggests that uremia-induced chronic inflammation, oxidative stress, hypercoagulation, vitamin-D deficiency, klotho deficiency, hyperparathyroidism, anemia, and impaired peripheral amyloid-β clearance may lead to dementia.4 Besides, chronic kidney disease (CKD) may be a risk mediator for other conditions that cause dementia, such as smoking, hypertension, diabetes, and lipid disorders.4 It is important to note that our study reported similar associations in persons with and without diabetes or hypertension.

Alzheimer’s disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients’ CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches.

Nerve growth factor (NGF) is an essential neurotrophic factor for the development and maintenance of the central and the peripheral nervous system. NGF deficiency in the basal forebrain precedes degeneration of basal forebrain cholinergic neurons in Alzheimer's disease, contributing to memory decline. NGF mediates neurotrophic support via its high‐affinity receptor, the tropomyosin‐related kinase A (TrkA) receptor, and mediates mitogenic and differentiation signals via the extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2). However, the molecular mechanisms underlying the different NGF/TrkA/ERK signalling pathways are far from clear. In this study, we have investigated the role of human NGF and three NGF mutants, R100E, W99A and K95A/Q96A, their ability to activate TrkA or ERK1/2, and their ability to induce proliferation or differentiation in human foetal dorsal root ganglion (DRG) neurons or in PC12 cells. We show that the R100E mutant was significantly more potent than NGF itself to induce proliferation and differentiation, and significantly more potent in activation of ERK1/2 in DRG neurons. The W99A and K95A/Q96A mutants, on the other hand, were less effective than the wild‐type protein. An unexpected finding was the high efficacy of the K95A/Q96A mutant to activate TrkA and to induce differentiation of DRG neurons at elevated concentrations. These data demonstrate an NGF mutant with improved neurotrophic properties in primary human neuronal cells. The R100E mutant represents an interesting candidate for further drug development in Alzheimer's disease and other neurodegenerative disorders., The nerve growth factor (NGF) mutant R100E is more potent to induce proliferation, differentiation (anti‐β‐tubulin green staining) and phosphorylation of ERK1/2 (red staining) than wild‐type NGF in human foetal dorsal root ganglion (DRG) neurons after a 4‐day treatment. The NGF double mutant K95A/Q96A is more efficient to induce neuronal differentiation than wild‐type NGF in DRG neurons at high concentrations (>3 μg/ml). We show enhanced functional response in human nerve cells with NGF mutants.

Trials of supplementation with omega-3 fatty acids (ω3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω3-FAs in relation to brain atrophy and cognitive decline.We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of ω3-FAs supplementation on cognitive performance in moderate AD.This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE≥15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA.We found significant interactions between ω3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels11.7μmol/L, ω3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo.The effect of ω3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of ω3-FA on cognition.

Age-dependent progressive neurodegeneration and associated cognitive dysfunction represent a serious concern worldwide. Currently, dementia accounts for the fifth highest cause of death, among which Alzheimer's disease (AD) represents more than 60% of the cases. AD is associated with progressive cognitive dysfunction which affects daily life of the affected individual and associated family. The cognitive dysfunctions are at least partially due to the degeneration of a specific set of neurons (cholinergic neurons) whose cell bodies are situated in the basal forebrain region (basal forebrain cholinergic neurons, BFCNs) but innervate wide areas of the brain. It has been explicitly shown that the delivery of the neurotrophic protein nerve growth factor (NGF) can rescue BFCNs and restore cognitive dysfunction, making NGF interesting as a potential therapeutic substance for AD. Unfortunately, NGF cannot pass through the blood-brain barrier (BBB) and thus peripheral administration of NGF protein is not viable therapeutically. NGF must be delivered in a way which will allow its brain penetration and availability to the BFCNs to modulate BFCN activity and viability. Over the past few decades, various methodologies have been developed to deliver NGF to the brain tissue. In this chapter, NGF delivery methods are discussed in the context of AD.

There is currently no effective treatment for the most common of the dementia disorders, Alzheimer's disease (AD). It has been known for decades that the central cholinergic system is important for memory. The cholinergic neurons in the basal forebrain with its cortical and hippocampal projections degenerate in AD and thus contribute to the cognitive decline characteristic of AD. This knowledge led to the development of the currently approved treatment for AD, with inhibitors of acetylcholine-esterase targeting the cholinergic system with beneficial but mild effects. In recent years, other approaches to influence the degenerating cholinergic system in AD focusing on nerve growth factor (NGF) have been undertaken. NGF is required for the survival and function of the basal forebrain cholinergic neurons, the most important being the nucleus basalis of Meynert (nbM). Since there is a lack of NGF and its receptors in the AD forebrain, the hypothesis is that local delivery of NGF to the nbM could revive the cholinergic circuitry and thereby restore cognitive functions. Since NGF does not pass through the blood-brain barrier, approaches involving cerebral injections of genetically modified cells or viral vectors or implantation of encapsulated cells in the nbM in AD patients have been used. These attempts have been partially successful but also have limitations, which are presented and discussed here. In conclusion, these trials point to the importance of further development of NGF-related therapies in AD.

Background & Aims: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19. Methods: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression. Results: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMIDe två sista författarna delar sistaförfattarskapet

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment.

OBJECTIVES To externally validate a model for medication-related dental outcomes in (a) a general older population with dementia and (b) a matched population without dementia. SUBJECTS AND METHODS This validation study used population-based data from seven Swedish national registers (2008-2017). Individuals aged 60+ with dementia were matched to those without dementia on age, gender, and county of residence at the date of diagnosis (index date). The exposure was continuous use of xerogenic medications during the 3-year period before index date. The primary outcome was the number of tooth extraction and restorative procedures within 3 years after index date. RESULTS A total of 334,220 individuals were included in the final sample. In the dementia cohort, the use of urological drugs (incidence rate ratio [IRR] 1.08, 95% CI 1.03-1.13), respiratory medicines (IRR 1.10, 95% CI 1.04-1.17), and proton-pump inhibitors (IRR 1.09, 95% CI 1.05-1.13) was associated with the primary outcome. In the non-dementia cohort, respiratory medicines (IRR 1.03, CI 1.00-1.05), proton-pump inhibitors (IRR 1.06, CI 1.04-1.08), opioids (IRR 1.05, CI 1.03-1.07), and antidepressants (IRR 1.06, CI 1.04-1.08) were associated with the primary outcome. CONCLUSIONS Although there were differences in prescription patterns, the model performed similarly in both those with and without dementia.

Alzheimer's disease (AD) develops into dementia after several years, and subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are used as intermediary diagnoses of increasing severity. Inflammation is an important part of AD pathology and provides potential novel biomarkers and treatment targets.To identify novel potential biomarkers of AD in cerebrospinal fluid (CSF) and create a molecular pattern of inflammatory factors providing differentiation between AD and SCI.We analyzed 43 inflammatory-related mediators in CSF samples from a cohort of SCI and AD cases vetted for confounding factors (Training cohort). Using multivariate analysis (MVA), a model for discrimination between SCI and AD was produced, which we then applied to a larger nonvetted cohort (named Test cohort). The data were analyzed for factors showing differences between diagnostic groups and factors that differed between the vetted and non-vetted cohorts. The relationship of the factors to the agreement between model and clinical diagnosis was investigated.A good MVA model able to discriminate AD from SCI without including tangle and plaque biomarkers was produced from the Training cohort. The model showed 50% agreement with clinical diagnosis in the Test cohort. Comparison of the cohorts indicated different patterns of factors distinguishing SCI from AD. As an example, soluble interleukin (IL)-6Rα showed lower levels in AD cases in the Training cohort, whereas placental growth factor (PlGF) and serum amyloid A (SAA) levels were higher in AD cases of the Test cohort. The levels of p-tau were also higher in the Training cohort.This study provides new knowledge regarding the involvement of inflammation in AD by indicating different patterns of factors in CSF depending on whether potential confounding comorbidities are present or not, and presents sIL-6Rα as a potential new biomarker for improved diagnosis of AD.

Background Research regarding COVID-19 and acute kidney injury (AKI) in older adults is scarce. We evaluated risk factors and outcomes of AKI in hospitalized older adults with and without COVID-19. Methods Observational study of patients admitted to two geriatric clinics in Stockholm from March 1st to June 15th, 2020. The difference in incidence, risk factors and adverse outcomes for AKI between patients with or without COVID-19 were examined. Odds ratios (OR) for the risk of AKI and in-hospital death were obtained from logistic regression. Results Three hundred-sixteen older patients were hospitalized for COVID-19 and 876 patients for non-COVID-19 diagnoses. AKI occurred in 92 (29%) patients with COVID-19 vs. 159 (18%) without COVID-19. The odds for developing AKI were higher in patients with COVID-19 (adjusted OR, 1.70; 95% confidence interval [CI] 1.04–2.76), low baseline kidney function as depicted by estimated glomerular filtration rate (eGFR) [4.19 (2.48–7.05), for eGFR 30 to 10 mg/L). Compared to patients without COVID-19 and without AKI, the risk of in-hospital death was highest in patients with COVID-19 and AKI [OR 80.3, 95% CI (27.3–235.6)], followed by COVID-19 without AKI [16.3 (6.28–42.4)], and by patients without COVID-19 and with AKI [10.2 (3.66–28.2)]. Conclusions Geriatric patients hospitalized with COVID-19 had a higher incidence of AKI compared to patients hospitalized for other diagnoses. COVID-19 and reduced baseline kidney function were risk factors for developing AKI. AKI and COVID-19 were associated with in-hospital death.

Objectives Evidence is lacking on how treatment of comorbidities improves outcomes in patients with dementia. In this study, we evaluated temporal changes in the management of comorbidities in relation to survival rates in incident dementia over a 10-year period in Sweden. Design Observational cohort study. Setting and Participants A total of 40,219 patients with recently diagnosed dementia in memory clinics from the Swedish Dementia Registry (SveDem) from 2008 to 2017. Methods In 1-year blocks, pharmacological treatment of dementia and comorbidities in relationship to risk for fractures, major cardiovascular events (MACE), and death were analyzed using Cox models. Standardized Incidence Ratios (SIR) of death are presented. Results After standardization for demographics and comorbidities, the risk of fracture, MACE, and mortality decreased by 16%, 23%, and 28%, respectively, between 2008 and 2016. Each year decreased the risk of fracture by 3% (hazard ratio 0.97, 95% confidence interval 0.96–0.99), MACE by 4% (0.96, 0.95–0.97), and death by 5% (0.95, 0.93–0.97). Adjustment for changes in medication use attenuated these associations. Compared with the general population, the risk of death declined by 11%, corresponding to standardized incidence rate ratio, between 2008 and 2016. Conclusions and Implications Over 10 years, a reduction in the short-term risks of fracture, MACE, and death in patients with dementia was associated with changes in drug prescribing practices. These improvements seem to be partly explained by progressive implementation of dementia diagnostic, treatment guidelines, and general management of comorbidities.

ObjectiveCholinesterase inhibitors (ChEIs) and memantine are the only approved pharmacological treatments for Alzheimer’s disease (AD). Recent literature suggests reductions in cardiovascular burden and risk of stroke in ChEI users. However, the clinical effectiveness of these drugs in patients with diabetes mellitus (DM) and dementia has not been evaluated.Research design and methodsWe conducted a registry-based open-cohort study of 22 660 patients diagnosed with AD and mixed-pathology dementia registered in the Swedish Dementia Registry until December 2015. Information on drug use, comorbidity and mortality was extracted using the linkage with the National Patient Registry, the Prescribed Drug Registry and the Cause of Death Registry. In total, 3176 (14%) patients with DM and 19 484 patients without DM were identified. Propensity-score matching, Cox-regression and competing-risk regression models were applied to produce HRs with 95% CIs for differences in all-cause, cardiovascular and diabetes-related mortality rates in ChEI users and non-users.ResultsAfter matching the ChEI use in patients with DM was associated with 24% all-cause mortality reduction (HR 0.76 (95% CI 0.67 to 0.86)), compared with 20% reduction (0.80 (0.75 to 0.84)) in non-DM users. Donepezil and galantamine use were associated with a reduced mortality in both patients with DM (0.84 (0.74 to 0.96); 0.80 (0.66 to 0.97)) and patients without DM (0.85 (0.80 to 0.90); 0.93 (0.86 to 0.99)). Donepezil was further associated with reduction in cardiovascular mortality, however only in patients without DM (0.84 (0.75 to 0.94)). Rivastigmine lowered mortality only in the whole-cohort analysis and in patients without DM (0.82 (0.75 to 0.89)). Moreover, ChEI use was associated with 48% reduction in diabetes-related mortality (HR 0.52 (0.32 to 0.87)) in the whole-cohort analysis. Last, low and high doses were associated with similar benefit.ConclusionsWe found reductions in mortality in patients with DM and AD or mixed-pathology dementia treated with ChEIs, specifically donepezil and galantamine were associated with largest benefit. Future studies should evaluate whether ChEIs help maintain self-management of diabetes in patients with dementia.

Background: Dementia presents barriers to the collaboration between individuals and the healthcare system. Caregivers perform multiple functions helping patients with basic and instrumental activities but also communicating and mediating the dyads’ needs within the broader social group. Interventions focusing on caregivers show that caregiver burden can be reduced, improving patient outcomes in a cost-effective way, but the generalisation of these findings is limited by several factors such as low participation rates of caregivers in studies. There is a global push to increase patient participation in health care, but this can be difficult for patients with dementia. Caregiver participation has arisen as a substitute, but there is a lack of standardised definitions, goals and outcome measurement tools for this participation. Methods: In 2015, the Swedish Association of Local Authorities and Regions commissioned a study on possibilities of increasing caregiver participation within the Swedish Dementia Registry (SveDem). This discussion paper updates and adapts that report, aiming to broadly summarise the caregiving phenomenon in order to provide a backdrop for clinicians seeking to understand the legal, ethical and practical considerations of caregiver participation in dementia. Relevant literature on caregiver participation is presented, and its definition, extent and practical implementation are discussed. Discussion: The Swedish legal framework compels care providers to facilitate patient and caregiver participation in dementia and provides support to caregivers through the local level of government, but further work is needed to clarify and define the extension and form that this participation must take in clinical practice. Advanced directives are one step in extending patient participation to the period of advanced dementia. Conclusion: Little research exists on caregiver participation. There is a need to develop a framework for caregiver and patient participation to determine the extent, type and form that such participation should take in health care, research and quality initiatives pertaining to persons with dementia. (Less)

Calderón-Larrañaga A, Vetrano DL, Ferrucci L, Mercer SW, Marengoni A, Onder G, Eriksdotter M, Fratiglioni L. (Karolinska Institutet-Stockholm University, Stockholm, Sweden; Catholic University of the Sacred Heart, Rome, Italy; National Institutes of Health, Baltimore, MD, USA; University of Glasgow, Glasgow, UK; University of Brescia, Brescia, Italy; Karolinska Institutet, Stockholm, Sweden; Stockholm Gerontology Research Center, Stockholm, Sweden; Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy). Multimorbidity and functional impairment– bidirectional interplay, synergistic effects and common pathways. This review discusses the interplay between multimorbidity (i.e. co-occurrence of more than one chronic health condition in an individual) and functional impairment (i.e. limitations in mobility, strength or cognition that may eventually hamper a person’s ability to perform everyday tasks). On the one hand, diseases belonging to common patterns of multimorbidity may interact, curtailing compensatory mechanisms and resulting in physical and cognitive decline. On the other hand, physical and cognitive impairment impact the severity and burden of multimorbidity, contributing to the establishment of a vicious circle. The circle may be further exacerbated by people’s reduced ability to cope with treatment and care burden and physicians’ fragmented view of health problems, which cause suboptimal use of health services and reduced quality of life and survival. Thus, the synergistic effects of medical diagnoses and functional status in adults, particularly older adults, emerge as central to assessing their health and care needs. Furthermore, common pathways seem to underlie multimorbidity, functional impairment and their interplay. For example, older age, obesity, involuntary weight loss and sedentarism can accelerate damage accumulation in organs and physiological systems by fostering inflammatory status. Inappropriate use or overuse of specific medications and drug–drug and drug–disease interactions also contribute to the bidirectional association between multimorbidity and functional impairment. Additionally, psychosocial factors such as low socioeconomic status and the direct or indirect effects of negative life events, weak social networks and an external locus of control may underlie the complex interactions between multimorbidity, functional decline and negative outcomes. Identifying modifiable risk factors and pathways common to multimorbidity and functional impairment could aid in the design of interventions to delay, prevent or alleviate age-related health deterioration; this review provides an overview of knowledge gaps and future directions.

Alzheimer's disease (AD) is characterized by early degeneration of cholinergic neurons and decreased levels of nerve growth factor (NGF). Thus, increasing the NGF levels by for instance encapsulated cell bio-delivery (ECB) is a potential treatment strategy. The results from our previous first-in-human studies on ECB of NGF to the basal forebrain cholinergic neurons were promising, but indicated some variability of long-term viability of the encapsulated cells and associated reduced NGF-release. Here we studied the effect of amyloid beta-peptides (Aβ), interleukin 1-beta (IL-1β), and CSF from AD, Lewy body dementia (LBD) or subjective cognitive impairment (SCI) patients on the NGF overproducing cell line NGC-0295. At physiological concentrations, neither Aβ40 nor Aβ42 had any major impact on cell viability or NGF-production. In contrast, IL-1β dose-dependently affected NGF-production over time. Exposure of NGF-producing cells to CSF from AD patients showed significantly reduced NGF-release as compared to CSF from LBD or SCI patients. By mass spectrometry we found 3 proteins involved in inflammatory pathways to have an altered expression in AD CSF compared to LBD and SCI. Cell survival and NGF-release were not affected by Aβ. NGF-release was affected by IL-1β, suggesting that inflammation has a negative effect on ECB cells.

Introduction The e4 allele of the apolipoprotein E ( APOE ) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied. Methods We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity. Results The e4 allele was associated with reduced longevity as e4 versus e3 homozygotes lived on average 2.6 years shorter ( P = .006). In AD, e4 carriers lived 1.0 years shorter than noncarriers ( P = .028). The e4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders. Discussion The APOE e4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common.

Background The number of drugs prescribed for old people has been rising in recent decades. With increasing age and multiple medications, the risk of complications and drug prescription complexity increases. Multiple changes to prescriptions could be a factor that improves treatment quality. Objectives Our objective was to investigate trends in drug prescriptions and factors that contribute to prescription changes. Specific objectives were to find out whether high numbers of prescription changes are significantly correlated with age, sex, comorbidity, length of care episode, and number of drugs. Methods Data were extracted from geriatric clinic records in Stockholm in 2005, 2010, and 2015. Indicators for good drug therapy were used to assess the effects of prescription changes on quality, using an index of inappropriate drug use (IDU). Data were analyzed with Student’s t-test, PR test, Wilcoxon’s rank sum test, and linear regression. Results Patients had more comorbidities and used more drugs but had shorter hospital stays and significantly fewer prescription changes in 2015 than in 2005. Length of care episode was significantly associated with prevalence of prescription changes. Our model showed that, for each day by which the length of care episode decreased, the number of prescription changes decreased by 8%. The number of prescription changes was negatively correlated to the IDU index score. Conclusions The study showed that more prescription changes were associated with longer care episodes and improved drug prescribing quality as per the IDU index. Given prescription changes are regarded as a quality factor in geriatric care, quality may have decreased along with the length of care episodes between 2005 and 2015.

Introduction The aim of this study was to investigate the association between acetylcholinesterase inhibitor (AChEI) use and risk of ischemic stroke and death in people with dementia. Methods A cohort study of 44,288 people with dementia registered in the Swedish Dementia Registry from 2007 to 2014. Propensity score-matched competing risk regression models were used to compute hazard ratios and 95% confidence intervals for the association between time-dependent AChEI use and risk of stroke and death. Results Compared with matched controls, AChEI users had a lower risk of stroke (hazard ratio: 0.85, 95% confidence interval: 0.75–0.95) and all-cause death (hazard ratio: 0.76, 95% confidence interval: 0.72–0.80). After considering competing risk of death, high doses (≥1.33 defined daily doses) of AChEI remained significantly associated with reduced stroke risk. Discussion The use of AChEIs in people with dementia may be associated with reduced risk of ischemic stroke and death. These results call for a closer examination of the cardiovascular effects of AChEIs.

We thank Dr. Kuschpel for the comment on our article.1 We agree that people with Alzheimer disease (AD) who received cholinesterase inhibitors (ChEIs) and those who did not differed significantly, so we controlled for the unbalanced comorbidity and medication in our propensity score–matching cohort. The result was a well-matched cohort in the distribution of observed comorbidities. We also acknowledge the possibility of residual and unknown confounders, although we did not have more information about comorbidity severity. Our group has previously reported an association between ChEIs and reductions in myocardial infarction, stroke, and mortality.2 In an RCT study by Hager et al., the 2-year mortality rate with the use of galantamine compared with the placebo group was similar to our findings, substantially reduced by 42%. The articles referenced by the commenter were meta-analyses of clinical trials, one of which addressed vascular dementia and not AD.4,5 Most clinical trials on the subject have been relatively short, from 6 months to 1 year. It is possible that short- and long-term mortality effects vary—a possibility that exceeds the scope of this study but is a possible research question for future studies. Given that this is a cohort study, it is difficult to completely exclude the possibility of bias, as we have acknowledged. The numbers in the abstract match the numbers for the propensity score-matched cohort from Table 2. We chose this as our main analysis and presented the imputed results as sensitivity analyses.

Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

Medical decision-making capacity (MDC) is known to decline in individuals with Alzheimer's disease (AD). The vignette method uses hypothetical information as a prerequisite for measuring the capacity to make well-informed decisions to clinical trials. Our aim was to investigate if adapted vignettes can help individuals with mild AD to assimilate information, make decisions and express them in an understandable way, compared to corresponding decisions based on linguistically more demanding vignettes, as measured by the Swedish Linguistic Instrument for Medical Decision-making (LIMD). Two vignettes from LIMD were altered linguistically with the aim to facilitate understanding for individuals with AD. An experimental within-subject design was used to study the influence on MDC of readability (original/adapted vignettes) and content (two different clinical trials). We included 24 patients with mild AD in this prospective study, which read all four vignettes along with a few other tests. This allowed us to investigate the association between MDC and cognitive function. Adapted vignettes did not yield significant differences regarding MDC as compared with original vignettes using a two-way repeated measures analysis of variance. A difference was found between the two clinical trials where LIMD score was significantly higher for Kidney disease than hypertension vignettes. Our results indicate that adapted vignettes may not improve MDC for individuals with mild AD. MDC was affected by which clinical trial the vignettes regarded, which implies that other factors affecting MDC need to be investigated, like length of text and vocabulary used.

In this study, we explored life satisfaction and sense of coherence in relation to biopsychosocial variables in individuals at risk for the development of familial Alzheimer's disease. Forty nine individuals (response rate: 96%) were interviewed. Life satisfaction was found to be high for the majority of participants. Those who were older than the expected age of onset of disease, those

Background Many people with Alzheimer's disease (AD) live alone in their own homes. There is a lack of knowledge about whether these individuals receive the same quality of diagnostics and treatment for AD as patients who are cohabiting. Objectives To investigate the diagnostic work-up and treatment of community-dwelling AD patients who live alone. Methods We performed a cross-sectional cohort study based on data from the Swedish Dementia Registry (SveDem). We studied patients diagnosed with AD between 2007 and 2015 (n = 26,163). Information about drugs and comorbidities was acquired from the Swedish Prescribed Drug Register and the Swedish Patient Register. Results 11,878 (46%) patients lived alone, primarily older women. After adjusting for confounders, living alone was inversely associated with receiving computed tomography (OR 0.90; 95% CI 0.82-0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83-0.99), and lumbar puncture (OR 0.86; 95% CI 0.80-0.92). Living alone was also negatively associated with the use of cholinesterase inhibitors (OR 0.81; 95% CI 0.76; 0.87), memantine (OR 0.77; 95% CI 0.72; 0.83), and cardiovascular medication (OR 0.92; 0.86; 0.99). On the other hand, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08; 1.22), antipsychotics (OR 1.41; 95% CI 1.25; 1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02; 1.17). Conclusions Solitary living AD patients do not receive the same extent of care as those who are cohabiting.

Survival in patients with dementia is variable. Statins are a cornerstone of cardiovascular prevention. However, the effect of statins on mortality and risk for stroke in patients with dementia is not clear.The aim of the study was to analyse the association between the use of statins and the risk of all-cause death and first ischemic stroke in patients diagnosed with dementia.A longitudinal cohort study of 48 771 patients based on combined Swedish registries was conducted. The association between the incident use of statins one year prior to dementia diagnosis, allcause mortality and first ischemic stroke was examined using propensity score-matched flexible parametric or Cox hazard survival models and is presented with hazard ratios and corresponding 95% confidence intervals.After propensity score matching, incident users of statins (n=1412) had a lower risk of all-cause death (HR 0.82, 95% CI 0.74-0.91) and ischemic stroke (HR 0.62, 95% CI 0.43-0.89) compared to matched non-users (n=4482). In stratified analysis, the protective association between incident statin use and survival was observed in men, patients older than 75 years, with Alzheimer's disease and vascular dementia. Furthermore, we observed a protective association between incident use of statins and first ischemic stroke risk in men, patients older than 75 years and with mixed dementia. There was a graded association between cumulative doses of statins and mortality.The use of statins might be beneficial for the survival and ischemic stroke risk in patients with dementia in a dose-dependent manner.

Background There remains a lack of large-scale clinical studies of cognitive impairment that aim to increase diagnostic and prognostic accuracy as well as validate previous research findings. The MemClin project will amass large quantities of cross-disciplinary data allowing for the construction of robust models to improve diagnostic accuracy, expand our knowledge on differential diagnostics, strengthen longitudinal prognosis, and harmonise examination protocols across centres. The current article describes the Memory Clinic (MemClin) project’s study-design, materials and methods, and patient characteristics. In addition, we present preliminary descriptive data from the ongoing data collection. Methods Nine out of ten memory clinics in the greater Stockholm area, which largely use the same examination methods, are included. The data collection of patients with different stages of cognitive impairment and dementia is coordinated centrally allowing for efficient and secure large-scale database construction. The MemClin project rest directly on the memory clinics examinations with cognitive measures, health parameters, and biomarkers. Results Currently, the MemClin project has informed consent from 1543 patients. Herein, we present preliminary data from 835 patients with confirmed cognitive diagnosis and neuropsychological test data available. Of those, 239 had dementia, 487 mild cognitive impairment (MCI), and 104 subjective cognitive impairment (SCI). In addition, we present descriptive data on visual ratings of brain atrophy and cerebrospinal fluid markers. Conclusions Based on our current progress and preliminary data, the MemClin project has a high potential to provide a large-scale database of 1200–1500 new patients annually. This coordinated data collection will allow for the construction of improved diagnostic and prognostic models for neurodegenerative disorders and other cognitive conditions in their naturalistic setting.

Background: Stroke and dementia are frequent comorbidities. Dementia possibly increases total costs of stroke care, especially cost of institutionalization and informal medical care. However, stroke rehabilitation costs in dementia patients are understudied. Objective: To estimate inpatient stroke rehabilitation costs for Swedish dementia patients in comparison with non-dementia patients. Methods: A longitudinal cohort study with linked data from the Swedish Dementia Register and the Swedish Stroke Register was conducted. Patients diagnosed with dementia who suffered a first ischemic stroke between 2010 and 2014 (n = 138) were compared with non-dementia patients (n = 935). Cost analyses were conducted from a Swedish health care perspective. The difference of rehabilitation costs between the two groups was examined via simple linear regression (before and after matching by propensity scores of dementia) and multiple linear regression. Results: Mean inpatient rehabilitation costs for dementia and non-dementia patients were SEK 103,693/$11,932 and SEK 130,057/$14,966, respectively (median SEK 92,183/$10,607 and SEK 106,365/$12,239) (p = 0.001). Dementia patients suffered from more comorbidities and experienced lower functioning, compared to non-dementia patients. The inpatient rehabilitation cost for patients with known dementia was 0.84 times the cost in non-dementia individuals. Conclusion: Dementia diagnosis was significantly associated with lower inpatient stroke rehabilitation costs. This might be explained by physicians’ beliefs on the limited effectiveness of rehabilitation in dementia patients. Further research on cost-effectiveness of stroke rehabilitation and patients’ satisfaction with stroke rehabilitation is necessary.

Background: Recurrent ischemic stroke (IS) increases the risk of cognitive decline. To lower the risk of recurrent IS, secondary prevention is essential. Objective: Our aim was to compare post-discharge secondary IS prevention and its maintenance up to 3 years after first IS in patients with and without Alzheimer’s disease and other dementia disorders. Methods: Prospective open-cohort study 2007–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who experienced an IS (n = 1410; 332 [23.5%] with Alzheimer’s disease) were compared with matched non-dementia IS patients (n = 7150). We analyzed antiplatelet, anticoagulant, blood pressure lowering, and statin treatment as planned medication initiation at discharge and actual dispensation of medications at first, second, and third year post-stroke. Results: At discharge, planned initiation of medication was higher in patients with dementia compared to non-dementia patients for antiplatelets (OR with 95% CI for fully adjusted models 1.23 [1.02–1.48]) and lower for blood pressure lowering medication (BPLM; 0.57 [0.49–0.67]), statins (0.57 [0.50–0.66]), and anticoagulants (in patients with atrial fibrillation – AF; 0.41 [0.32–0.53]). When analysis for antiplatelets was stratified according to the presence of AF, ORs for receiving antiplatelets remained significant only in the presence of AF (in the presence of AF 1.56 [1.21–2.01], in patients without AF 0.99 [0.75–1.33]). Similar trends were observed in 1st, 2nd, and 3rd year post-stroke. Conclusions: Dementia was a predictor of lower statin and BPLM use. Patients with dementia and AF were more likely to be prescribed antiplatelets and less likely to receive anticoagulants.

Objective To investigate the factors that increase the risk of discontinuing dental care utilisation after dementia is diagnosed in a population in Stockholm County, Sweden. Background As the progression of dementia results in a deteriorating ability to maintain good oral health, it is important to identify people at risk of discontinued dental care after being diagnosed with dementia. Materials and methods This study is a register-based longitudinal study. Data were extracted from the Swedish Dementia Registry (SveDem), the Swedish National Patient Register, the Dental Health Register and the Municipal Dental Care Register (Stockholm County Council). The data included people using both general public dental services and care-dependent individuals. Dental visits three years before and after dementia had been diagnosed were analysed. Results In total, 10 444 people were included in the analysis, of which 19% did not have dental visits recorded after they were diagnosed with dementia. A logistic regression model, adjusted for relevant factors, showed that the factors associated with a greater risk for discontinued dental attendance were fewer remaining teeth (OR = 0.96, 95% CI = 0.95, 0.97) and living alone compared to living with another adult (OR = 1.23, 95% CI = 1.05, 1.43). People with Parkinson's disease dementia had a lower risk (OR = 0.40, 95% CI = 0.19, 0.84) than people with Alzheimer's disease. Conclusion Patients, dental and healthcare personnel, and family members should all be aware of these risk factors so that appropriate support and oral care for people with dementia can be delivered.

OBJECTIVE: To describe temporal changes in treatment, care, and short-term mortality outcomes of geriatric patients during the first wave of the COVID-19 pandemic. DESIGN: Observational study. SETTING AND PARTICIPANTS: Altogether 1785 patients diagnosed with COVID-19 and 6744 hospitalized for non-COVID-19 causes at 7 geriatric clinics in Stockholm from March 6 to July 31, 2020, were included. METHODS: Across admission month, patient vital signs and pharmacological treatment in relationship to risk for in-hospital death were analyzed using the Poisson regression model. Incidence rates (IRs) and incidence rate ratios (IRRs) of death are presented. RESULTS: In patients with COVID-19, the IR of mortality were 27%, 17%, 10%, 8%, and 2% from March to July, respectively, after standardization for demographics and vital signs. Compared with patients admitted in March, the risk of in-hospital death decreased by 29% [IRR 0.71, 95% confidence interval (CI) 0.51-0.99] in April, 61% (0.39, 0.26-0.58) in May, 68% (0.32, 0.19-0.55) in June, and 86% (0.14, 0.03-0.58) in July. The proportion of patients admitted for geriatric care with oxygen saturation

Background: Early-onset dementia (EOD) is a rare condition, with an often atypical clinical presentation, and it may therefore be challenging to diagnose. Specialized memory clinics vary in the type of patients seen, diagnostic procedures applied, and the pharmacological treatment given. The aim of this study was to investigate quality-of-care indicators in subjects with EOD from 3 tertiary memory clinics in 3 European countries.Methods: We included 1325 newly diagnosed EOD patients, ages 65 years or younger, between January 1, 2007 and December 31, 2013, from the Danish Dementia Registry (Rigshospitalet, Copenhagen), the Swedish Dementia Registry ("SveDem", Karolinska University Hospital, Stockholm), and the Amsterdam Dementia Cohort (VU University Medical Center).Results: The frequency of EOD among all dementia patients was significantly lower in Copenhagen (410, 20%) and Stockholm (284, 21%) compared with Amsterdam (631, 48%). Not all quality indicator targets were met, such as the time to diagnosis, the mini-mental state examination score available, and the prescription of cholinesterase inhibitors. Cerebrospinal fluid sampling, registered in 2 sites, was performed in over 80% of the subjects.Conclusions: In tertiary referral centers in Copenhagen, Stockholm, and Amsterdam, quality indicators were not always met for patients with EOD. Results partly reflect differences in referral pattern, the application of diagnostic criteria, and local best practices. Standardized international procedures for patients with EOD may reduce this variability.

Malaltia d'Alzheimer; Demència; Epidemiologia Enfermedad de Alzheimer; Demencia; Epidemiología Alzheimer's disease; Dementia; Epidemiology The aim of this study was to compare the frequency of dementia diagnoses from two dementia registries in Europe. Patients registered between 2007 and 2013 in the Swedish Dementia Registry (SveDem; Sweden) and in the Registry of Dementias of Girona (ReDeGi; North-East of Spain) were selected. We compared sociodemographic data, Mini-Mental State Examination (MMSE) scores, dementia subtype, and medication consumption of 22,384 cases from SveDem and 5,032 cases from ReDeGi. The average age (78.1 years SveDem versus 79.7 years ReDeGi) and the gender (female 58.2% SveDem versus 61.5% ReDeGi) did not greatly differ. MMSE score at diagnosis was higher for SveDem cases (22.1 versus 17.8). Alzheimer’s disease (AD) accounted for the main dementia subtype (36.6% SveDem versus 55.6% ReDeGi). The proportion of vascular dementia (VaD) and mixed dementia was higher in SveDem (18.8% versus 6.4% and 24.9 versus 13.4%), with an odds ratio (OR) and 95% confidence interval (CI) for SveDem relative to the ReDeGi of 3.41 (3.03–3.84) for VaD, and 2.15 (1.97–2.35) for mixed dementia. This was at the expense of a lower frequency of AD in SveDem (OR 0.41; 95% CI 0.39–0.44). Other dementia diagnoses such as frontotemporal dementia or dementia with Lewy bodies did not significantly differ between registries (2.3% versus 2.9%; 1.9 versus 3.1%). Large differences in medication consumption at the time of dementia diagnosis were detected (4.7 treatments SveDem versus 6.8 ReDeGi). Northern and southern European dementia cohorts differ in demographic characteristics, MMSE score at diagnosis, and drug treatment profile.

To investigate whether acetylcholinesterase inhibitor (AChEI) use prevents or delays subsequent initiation of psychotropic medications in people with Alzheimer's disease (AD) and Lewy body dementia (LBD).Cohort study of 17,763 people with AD and LBD, without prior psychotropic use at time of dementia diagnosis, registered in the Swedish Dementia Registry from 2007 to 2015. Propensity score-matched regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-dependent AChEI use and risk of psychotropic initiation.Compared with matched comparators, AChEI users had a lower risk of antipsychotic (HR: 0.85, 95%CI: 0.75-0.95) and anxiolytic (HR: 0.76, 95%CI: 0.72-0.80) initiation. In subanalyses, this association remained significant at higher AChEI doses, and in AD but not LBD. There were no associations between AChEI use and initiation of antidepressants or hypnotics.AChEI use may be associated with lower risk of antipsychotic and anxiolytic initiation in AD, particularly at higher doses. Further investigation into aceytylcholinesterase inhibitors in behavioral and psychological symptoms of dementia management in LBD is warranted.

Background Whether dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are distinct disorders or two subtypes of the same entity, is not yet fully understood. There is a dearth of knowledge on differences in longitudinal clinical outcomes between DLB and PDD. Objective We aimed to compare longitudinal trend of cognitive decline, mortality, and their determinant factors between patients with DLB and PDD. Methods At baseline, we recruited 1110 DLB, and 764 PDD patients registered in the Swedish dementia registry (SveDem) during 2007-2015. Cognitive status was assessed at baseline and each follow-up visit by mini-mental state examination (MMSE). At least one follow-up MMSE was available for 411 (37.0%) DLB and 229 (30.0%) PDD patients. Rate of cognitive decline and mortality risk were compared between the two groups. Results After an average of 2-years, the rate of cognitive decline did not differ between DLB (1.1 MMSE unit/year) and PDD (1.2 MMSE unit/year) groups (p = 0.970). There was no significant difference in the median survival time between DLB (4.0 years) and PDD (4.1 years) groups (Log rank p = 0.614). Antipsychotic drug use in DLB and larger number of medications in PDD were the most important determinants of faster annual cognitive decline. Conclusions Our findings from real-world clinical practice demonstrated that the rate of cognitive decline and mortality do not differ significantly between DLB and PDD at least over 2 years, yet, various factors might determine clinical outcome in these two groups. It seems that DLB and PDD are probably similar synucleinopathies, with phenotypical variations in the order of manifestations rather than course of progression and clinical outcome.

Background. Anticholinergic burden is associated with poorer cognitive and functional outcomes in people with dementia. However, the impact of anticholinergics on significant adverse outcomes such as stroke has not been studied previously. Objective. To investigate the association between total anticholinergic cognitive burden (ACB) and risk of stroke and death in people with different dementia subtypes. Methods. This was a cohort study of 39107 people with dementia and no prior history of stroke registered in the Swedish Dementia Registry (SveDem) from 2008 – 2014. Data were extracted from the Swedish Prescribed Drug Register, the Swedish National Patient Register and the Swedish Total Population Register. Competing risk regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying ACB score and risk of stroke and all-cause mortality. Results. During a mean follow-up period of 2.31 (standard deviation 1.66) years, 11224 (28.7%) individuals had a stroke or died. Compared with non-users of anticholinergic medications, ACB score of 1 (HR 1.09, 95%CI 1.04 – 1.14) and ACB score of ≥2 (HR 1.20, 95%CI 1.14 – 1.26) increased the risk of developing the composite outcome of stroke and death. When stratifying by dementia disorder, the association remained significant in Alzheimer’s disease, mixed dementia and vascular dementia. Conclusions. The use of anticholinergic medicines may be associated with an increased risk of stroke and death in people with dementia. A dose-response relationship was observed. Careful consideration should be made when prescribing medications with anticholinergic properties to people with dementia.