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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.

ObjectiveCommunity-based reports regarding the association between the estimated glomerular filtration rate (eGFR) and dementia risk show conflicting results. The aim of this study is to investigate the links among kidney function, kidney function decline, and dementia incidence.MethodsWe analyzed the association of eGFR with the risk of dementia (defined as a new dementia diagnosis or initiation of dementia treatments) among 329,822 residents of Stockholm who accessed health care during 2006 to 2011, were ≥65 years of age, had no history of dementia, or underwent kidney replacement therapy. We also estimated the rate of eGFR decline among 205,622 residents with repeated eGFR measurements during the first year of observation and investigated its association with subsequent dementia risk.ResultsWe detected 18,983 cases of dementia (5.8% of participants) over a median follow-up of 5 years. Dementia incidence rates were progressively higher with lower eGFR: from 6.56/1,000 person-years in those with eGFR of 90 to 104 mL/min to 30.28/1,000 person-years in those with eGFR 2 mL/min/1.73 m2/y) within 1 year was associated with higher dementia risk. Risk magnitudes were stronger for vascular dementia than for Alzheimer dementia. As many as 10% (95% CI 6%–14%) of dementia cases could be attributed to eGFR 2, a proportion higher than that attributed to other dementia risk factors such as cardiovascular disease and diabetes.ConclusionsBoth lower kidney function and steeper kidney function decline are associated with the development of dementia.

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 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.

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.

BackgroundFrailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its predictive ability for adverse outcomes in geriatric patients.MethodsEHRs were extracted for 18,225 geriatric patients with unplanned admissions between 1/3/2020 and 17/6/2021 from nine geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modelled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression.Results13,188 patients were included in analyses (mean age 83.1 years). A 10% increment in the eFI was associated with higher risks of in-hospital (odds ratio: 5.34; 95% confidence interval: 4.20-6.82), 30-day (hazard ratio [HR]: 3.28; 2.91-3.69), and 6-month mortality (HR: 2.70; 2.52-2.90) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the best predictive accuracy for in-hospital mortality, yielding an area under receiver operating characteristic curve of 0.813. Higher eFI also predicted a longer length of stay, but had a rather poor discrimination for 30-day readmission.ConclusionsAn EHR-based eFI has good predictive accuracy for adverse outcomes, suggesting that it can be used in risk stratification in geriatric patients.

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.

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.

IntroductionAlzheimer’s disease (AD) is the most prevalent form of dementia with symptoms of deteriorating cognitive functions and memory loss, partially as a result of a decrease in cholinergic neurotransmission. The disease is incurable and treatment with cholinesterase inhibitors (ChEIs) is symptomatic. Choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), has been proven recently to be present in both cerebrospinal fluid (CSF) and plasma. As ChAT plays a role in regulating the extracellular ACh levels, it may have an impact on prognosis and cognitive performance in AD patients.ObjectivesTo measure ChAT activity and its protein concentration in CSF and plasma from patients with AD, mild cognitive impairment (MCI), or Subjective cognitive impairment (SCI).MethodsPlasma and CSF samples were obtained from 21 AD, 32 MCI, and 30 SCI patients. The activity and protein levels of ChAT and acetylcholinesterase (AChE), the enzyme catalyzing the hydrolysis of ACh, were analyzed using an integrated activity and protein concentration ELISA-like assay. A Cholinergic Index was calculated as the ratio of ChAT to AChE activities in CSF. The data were analyzed in relation to dementia biomarkers and cognitive performance of the patients.ResultsThe CSF ChAT activity was significantly higher (55–67%) in MCI patients compared to AD and SCI cases. The CSF Cholinergic Index was 41 and 22% lower in AD patients than in MCI and SCI subjects, respectively. This index correlated positively with the Aβ42/p-tau ratio in CSF in SCI but negatively with that in AD and MCI. The ChAT activity and protein levels in plasma exhibited significant differences with the pattern of AD>>MCI>SCI.ConclusionThis is the first study investigating soluble levels of the key cholinergic enzyme, ChAT, in both plasma and CSF of individuals at different clinical stages of dementia. Although further validation is needed, the overall pattern of the results suggests that in the continuum of AD, the cholinergic signaling exhibits an inverse U-shape dynamic of changes in the brain that greatly differs from the changes observed in the plasma compartment.

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

BackgroundThe majority of individuals with dementia will suffer from psychological and behavioral symptoms of dementia (BPSD). There is limited number of studies investigating BPSD in different types of dementia.ObjectivesTo 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 (UNS) in individuals residing in long-term care facilities.MethodsWe 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.ResultsThe 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 (in FTD), agitation (VaD, in PDD, unspecified dementia), elation/euphoria (in DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD); irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (in Mixed, VaD, unspecified dementia), sleep and night-time behavior changes (in unspecified dementia). Higher risk of delusions (in DLB), hallucinations (in DLB, PDD), apathy (VaD, FTD), disinhibition (in FTD) and appetite and eating abnormalities (in FTD) were also found in comparison to AD.ConclusionsBPSD was common in all types of dementia, with the most common symptoms being aberrant motor behavior, agitation, and irritability. Additionally, presentation of BPSD differ in different dementia types.

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.

Background and Aims Research regarding COVID-19 and acute kidney injury (AKI) in older adults is scarce. We evaluated the risk factors and outcomes of AKI in hospitalized older adults with and without COVID-19. Method Observational study of patients admitted to two geriatric clinics in the Stockholm Region of Sweden during the first wave of the COVID-19 pandemic 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 (ORs) for AKI were obtained from logistic regressions. The hazard ratios (HRs) for the risk of in-hospital death were calculated from Cox proportional hazard regression models. Results We analyzed 316 older patients hospitalized for COVID-19 and 876 patients for non-COVID-19 diagnoses. The mean age was 83±9 years, 57% were women, and mean baseline kidney function as depicted by estimated glomerular filtration rate (eGFR) was 62±23 ml/min/1.73m2. AKI occurred in 92 (29%) of patients with COVID-19 vs. 159 (18%) without COVID-19. The severity of AKI was significantly worse in patients with COVID-19 compared with non-COVID patients. The odds for developing AKI were higher in patients with COVID-19 (adjusted OR, 1.70; 95% CI, 1.04-2.76), low baseline kidney function [4.19 (2.48-7.05), for eGFR 30 ∼ Conclusion Geriatric patients hospitalized with COVID-19 had a higher incidence of AKI compared with patients hospitalized with other diagnoses. AKI and COVID-19 were associated with in-hospital death. Optimal management of AKI may improve the outcome of COVID-19 in geriatric patients.

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.

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.

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)

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.

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.

Objective:To compare access to intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) and its outcomes in patients with and without dementia.Methods:This was a longitudinal cohort study of the Swedish dementia and stroke registries. Patients with preexisting dementia who had AIS from 2010 to 2014 (n = 1,356) were compared with matched patients without dementia (n = 6,755). We examined access to thrombolysis and its outcomes at 3 months (death, residency, and modified Rankin Scale [mRS] score). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic and ordinal logistic regression.Results:The median age at stroke onset was 83 years in both groups. IVT was administered to 94 (7.0%) patients with dementia and 639 (9.5%) patients without dementia. The OR of receiving IVT was 0.68 (95% CI 0.54–0.86) for patients with dementia. When the analysis was repeated exclusively among patients independent in everyday activities, dementia status was no longer significant (OR 0.79, 95% CI 0.60–1.06). However, differences persisted in patients ≤80 years of age (OR 0.58, 95% CI 0.36–0.94). In patients who received thrombolysis, the incidence of symptomatic intracerebral hemorrhage (sICH; 7.4% vs 7.3%) and death at 3 months (22.0% vs 18.8%) did not differ significantly between the 2 groups. However, mRS score and accommodation status were worse among patients with dementia after 3 months in adjusted analyses (both p < 0.001). Unfavorable outcomes with an mRS score of 5 to 6 were doubled in patients with dementia (56.1% vs 28.1%).Conclusions:Younger patients with dementia and AIS are less likely to receive IVT. Among patients receiving thrombolysis, there are no differences in sICH or death, although patients with dementia have worse accommodation and functional outcomes at 3 months.

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.

BACKGROUNDThe 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 clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain.METHODSStructural 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-months 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.RESULTSAll AD subtypes showed reduced basal forebrain volume as compared with controls. Limbic-predominant subtype showed fastest basal forebrain atrophy rate, whereas minimal atrophy subtype did not show significant volume decline over time. Atrophy rates of hippocampus and precuneus also differed across subtypes. The NGF treatment seemed to slow the rate of atrophy in precuneus and hippocampus, particularly in the hippocampal-sparing AD subtype.CONCLUSIONSThe cholinergic system is differentially affected in distinct atrophy subtypes of AD, possibly contributing to their differential response to cholinergic treatment. Our findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratifying by subtype.Trial registrationClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010 - https://clinicaltrials.gov/ct2/show/NCT01163825

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.

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.

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.

Resumen: Introducción: La neurodegeneración en enfermedad de Alzheimer (EA) empieza décadas antes que la demencia y algunos pacientes con deterioro cognitivo leve presentan una importante carga lesional. La ausencia de información sobre la fisiopatología temprana de la enfermedad dificulta la búsqueda de estrategias terapéuticas.La queja cognitiva subjetiva (QCS) agrupa a sujetos con quejas mnésicas sin déficits significativos en test neuropsicológicos. Es un síndrome heterogéneo sobre el que no existe consenso, pero algunos de estos pacientes podrían representar el estadio más precoz de EA. Método: Realizamos una revisión bibliográfica para resumir el estado del conocimiento actual sobre quejas cognitivas subjetivas. Resultados: Aunque a nivel individual no presenten enfermedad objetivable, a nivel de grupo los pacientes con QCS rinden peor en test neuropsicológicos que la población general y tienen mayor incidencia de declive cognitivo futuro. La depresión y la comorbilidad psiquiátrica desempeñan un papel pero no son la única causa de quejas cognitivas. Estudios con resonancia magnética muestran un patrón de atrofia hipocampal similar al del deterioro cognitivo leve amnésico y en resonancia funcional hay aumento de activación en tareas cognitivas que podrían representar una compensación ante pérdida de función. Los pacientes con QCS presentan un patrón tipo EA de marcadores betaamiloide (Aβ42) y tau con mayor frecuencia que la población general. Conclusiones: Las quejas mnésicas son un síntoma relevante y podrían predecir EA. La heterogeneidad de los pacientes y de los ensayos clínicos ha dificultado la definición del síndrome. En el futuro, una definición estandarizada y estudios longitudinales con un seguimiento suficiente, y centrados en variables cuantificables, podrían clarificar aspectos tempranos de la EA. Abstract: Introduction: Neurodegeneration in Alzheimer disease (AD) begins decades before dementia and patients with mild cognitive impairment (MCI) already demonstrate significant lesion loads. Lack of information about the early pathophysiology in AD complicates the search for therapeutic strategies.Subjective cognitive impairment is the description given to subjects who have memory-related complaints without pathological results on neuropsychological tests. There is no consensus regarding this heterogeneous syndrome, but at least some of these patients may represent the earliest stage in AD. Method: We reviewed available literature in order to summarise current knowledge on subjective cognitive impairment. Results: Although they may not present detectable signs of disease, SCI patients as a group score lower on neuropsychological tests than the general population does, and they also have a higher incidence of future cognitive decline. Depression and psychiatric co-morbidity play a role but cannot account for all cognitive complaints. Magnetic resonance imaging studies in these patients reveal a pattern of hippocampal atrophy similar to that of amnestic mild cognitive impairment and functional MRI shows increased activation during cognitive tasks which might indicate compensation for loss of function. Prevalence of an AD-like pattern of beta-amyloid (Aβ42) and tau proteins in cerebrospinal fluid is higher in SCI patients than in the general population. Conclusions: Memory complaints are relevant symptoms and may predict AD. Interpatient variability and methodological differences between clinical studies make it difficult to assign a definition to this syndrome. In the future, having a standard definition and longitudinal studies with sufficient follow-up times and an emphasis on quantifiable variables may clarify aspects of early AD. Palabras clave: Quejas cognitivas subjetivas, Amiloide, Biomarcadores, Deterioro cognitivo subjetivo, Enfermedad de Alzheimer, Estadio preclínico de enfermedad de Alzheimer, Keywords: Subjective cognitive impairment, Amyloid, Biomarkers, Subjective cognitive complaints, Alzheimer disease, Preclinical stage of Alzheimer disease

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.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

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.

Objective To assess all-cause mortality patients with dementia treated with typical and atypical antipsychotic drugs (APDs). Design Registry-based cohort study. Setting and participants A total of 58,412 patients diagnosed with dementia and registered in the Swedish Dementia Registry were included in the study. Of the study sample, 2526 of the patients were prescribed APDs. Of these, 602 patients were prescribed typical APDs and 1833 patients were prescribed atypical APDs. Ninety-one patients were prescribed both typical and atypical APDs. Measurements All-cause mortality based on Swedish Cause of Death Register. Adjusted hazard ratios of mortality were calculated according to class of APDs (typical or atypical) prescribed. Final models were adjusted for age at dementia diagnosis, sex, Charlson comorbidity index, living arrangement, and Mini-Mental State Examination. Results In the adjusted models, use of APDs at the time of dementia diagnosis was associated with increased mortality risk in the total cohort (hazard ratio = 1.4; 95% confidence interval 1.3–1.5). After stratifying for dementia types, increased mortality risks associated with APDs were found in patients with Alzheimer's disease, mixed dementia, unspecified dementia, and vascular dementia. Higher risk for mortality was found with typical APDs in patients with mixed and vascular dementia and with atypical APDs in patients with Alzheimer's disease, mixed, unspecified, and vascular dementia. Furthermore, in patients with Alzheimer's disease who had typical APDs, use lower risk of death emerged in comparison with patients with atypical APDs. Conclusions/Implications Both the use of atypical and typical APDs increased the risk of death in patients with dementia even after adjusting for differences in basic characteristics between groups. Although we cannot rule out the influence of residual confounding, these results would seem to add to studies suggesting caution in APD prescription for patients with dementia. Funding Agencies|Swedish Brain Power network; Swedish Associations of Local Authorities and Regions; Gun och Bertil Stohnes Stiftelse; CIMED grant; Alzheimerfonden; Swedish Research Council [Drn 2012-2291, Drn 2016-02317]; Stockholm County Council (ALF project)

Introduction: Patients with dementia may be at a higher risk for death from stroke. We aimed to describe characteristics of dementia patients that died from ischemic stroke (IS) in Sweden. Methods: A retrospective longitudinal analysis of prospectively collected data of patients registered into the Swedish Dementia Registry was conducted. Data on causes of death, drugs and comorbidities were acquired from the Swedish nationwide health registers. Deaths were attributed to stroke if the death certificate contained stroke as a cause of death and the patient had a stroke registered in Riksstroke, the Swedish Stroke Register, in the year preceding death. Demographic data at the time of dementia diagnosis was compared between patients dying from IS and registered in Riksstroke, patients dying from IS without being registered in Riksstroke and those dying from other causes. Results: Out of 49823 patients diagnosed with dementia between 2007 and 2014 in primary care or specialist clinics, 14170 (28.4%) had died by the end of 2014. Of these 1180 (8.3%) had IS in their death certificate, of which 459 (38.9%) had been registered in Riksstroke. In patients who died of IS the most common type of dementia was vascular dementia while those died from other causes were most often diagnosed with Alzheimer’s dementia (AD). Patients who died from IS and were registered in Riksstroke had higher MMSE score compared to other groups. Patients who died from IS took more cardiovascular medications. There were no differences in the use of antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, anxiolytics, or hypnotics between the groups. Conclusions: There was a relatively high number of patients who died from IS as shown in their death certificate but had not been registered in Riksstroke in the year before death. This creates concerns on the accuracy of death certificate stroke diagnoses, particularly for deaths taking place outside hospitals.