Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF

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

Anticholinergic burden and risk of stroke and death in people with different types of dementia

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.FORTEAccepte

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

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

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

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

Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease

Depression and Alzheimer’s disease (AD) are among the most common clinical diagnosis in older people. The relation between depression and AD is complex: depression has been shown to be a risk factor, prodromal symptom and a consequence of AD. Increased understanding of the underlying mechanisms of depression in AD may lead to early detection and differential diagnosis, and is crucial for development of novel and mechanism-based treatments. The first two studies of this doctoral thesis are exploring the associations between depressive symptoms and biomarkers of amyloid deposition and neuronal injury in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD. The aims of the third study were to describe the use of antidepressants in patients with dementia and to explore the association between mortality risk and the use of antidepressants 3 years before the dementia diagnosis. CAIDE Dementia Risk Score is taking into account midlife risk and protective factors; age, educational level, gender, systolic blood pressure, body mass index, cholesterol level and physical activity and APOE genotyping, and can predict dementia over 20 years. The last study was focused on exploring the associations between CAIDE Dementia Risk Score and biomarkers of amyloid deposition, neuronal injury and small vessel pathology in SCI and MCI patients. Additionally we explored the capacity of CAIDE Dementia Risk Score to predict dementia in a memory clinic population. Data were obtained from Memory Clinic Karolinska University Hospital Huddinge Sweden (Study I, II and IV). In study III, two large national registries were merged: the Swedish Dementia Registry (SveDem) and the Swedish Prescribed Drug Register. In study I, analysis of the three different cerebrospinal fluid biomarkers; amyloid beta (CSF Aβ), total-tau (CSF t-tau), and phosphorylated-tau did not support the hypothesis that more severe amyloid or tau pathologies are associated with more severe depressive symptoms. In contrast, SCI and AD patients with depressive symptoms tended to have lower CSF p-tau levels and, in particular, lower CSF t-tau levels than those without depression, indicating less severe neuronal injury. In study II, we used two different analysis methods of MRI to measure medial temporal lobe atrophy and hippocampus volume. Using manual tracing of the hippocampi we found smaller left hippocampus volume in SCI patients with depressive symptoms compared to those without depressive symptoms. In contrast, AD patients with depressive symptoms had less medial temporal lobe atrophy compared with those without depressive symptoms. In study III, 20,050 patients with incident dementia diagnosed in memory clinics and registered in SveDem were included. Information on the total number of medication and all antidepressants dispensed at the time of dementia diagnosis and at the first, the second and the third year prior to dementia diagnosis was obtained from the Swedish Prescribed Drug Register. During a median follow up of 2 years, 5168 (25.8%) dementia patients died. At the time of dementia diagnosis, 5,004 (25.0%) patients were on antidepressant treatment. Use of antidepressant treatment for 3 consecutive years prior to a dementia diagnosis was associated with a lower mortality risk for all dementia disorders in general and particularly in AD. In study IV, a higher CAIDE Dementia Risk Score was associated with higher CSF t-tau levels, more severe medial temporal lobe atrophy and more severe white matter changes. For the CAIDE score including APOE, a score above 9 points was associated with lower CSF Aβ, more severe medial temporal lobe atrophy and more severe white matter changes. CAIDE Dementia Risk Score (version with APOE) performed better at predicting AD compared with CAIDE Dementia Risk Score without APOE. Conclusion: We found that depressive symptoms in patients with AD and SCI are not associated with more amyloid deposition nor more neuronal injury compared with AD and SCI patients without depressive symptoms. Thus our results are consistent with the hypothesis that the mechanisms underlying depression differ between older people with and without AD. Our results have shown that use of antidepressants in prodromal AD stages is associated with a lower mortality risk. Further longitudinal studies are needed to better understand the associations between the use of antidepressants and mortality risk in dementia

Dementia and psychotropic medications are associated with significantly higher mortality in geriatric patients hospitalized with COVID-19 : data from the StockholmGeroCovid project

Background: Dementia and psychotropic medications are discussed as risk factors for severe/lethal outcome of the coronavirus disease 2019 (COVID-19). We aimed to explore the associations between the presence of dementia and medication use with mortality in the hospitalized and discharged patients who suffered from COVID-19. Methods: We conducted an open-cohort observational study based on electronic patient records from nine geriatric care clinics in the larger Stockholm area, Sweden, between February 28, 2020, and November 22, 2021. In total, we identified 5122 hospitalized patients diagnosed with COVID-19, out of which 762 (14.9%) patients had concurrent dementia and 4360 (85.1%) were dementia-free. Patients’ age, sex, baseline oxygen saturation, comorbidities, and medication prescription (cardiovascular and psychotropic medication) were registered at admission. The hazard ratios (HRs) with 95% confidence intervals (CIs) of in-hospital, 30-day, 90-day, 365-day post-discharge, and overall mortal- ity during the follow-up were obtained. Then, the associations of dementia and medication use with mortality were determined using proportional hazards regression with time since entry as a time scale. Results: After adjustment, dementia was independently associated with 68% higher in-hospital mortality among COVID-19 patients compared to patients who were dementia-free at admission [HRs (95% CI) 1.68 (1.37–2.06)]. The increase was consistent post-discharge, and the overall mortality of dementia patients was increased by 59% [1.59 (1.40–1.81)]. In addition, the prescription of antipsychotic medication at hospital admission was associated with a 70% higher total mortality risk [1.70 (1.47–1.97)]. Conclusions: The clinical co-occurence of dementia and COVID-19 increases the short- and long-term risk of death, and the antipsychotics seem to further the risk increase. Our results may help identify high-risk patients in need of more specialized care when infected with COVID-19.Swedish Research Council (dnr: 2020-06101 WISER, 2021-013167, 2020-05805)National Institute for Neurological Research, Programme EXCELES (Project No. LX22NPO5107)European Union, Next Generation EUAlzheimerfondenKarolinska InstitutetPublishe

Periodontal conditions and incident dementia: a nationwide Swedish cohort study

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.Peer reviewe

Fast Alpha Activity in EEG of Patients With Alzheimer's Disease Is Paralleled by Changes in Cognition and Cholinergic Markers During Encapsulated Cell Biodelivery of Nerve Growth Factor.

Background Basal forebrain cholinergic neurons are dependent on nerve growth factor (NGF) for growth and survival and these cells are among the first to degenerate in Alzheimer's disease (AD). Targeted delivery of NGF has been suggested as a potential therapy for AD. This hypothesis was tested in a clinical trial with encapsulated cell biodelivery of NGF (NGF-ECB) in AD patients. Three of six patients showed improved biomarkers for cognition by the end of the study. Here, we report on the effects of targeted delivery of NGF on human resting EEG. Materials and methods NGF-ECB implants were implanted bilaterally in the basal forebrain of six AD patients for 12 months. EEG recordings and quantitative analysis were performed at baseline, 3 and 12 months of NGF delivery, and analyzed for correlation with changes in Mini-mental state examination (MMSE) and levels of the cholinergic marker choline acetyltransferase (ChAT) in cerebrospinal fluid (CSF). Results We found significant correlations between the topographic variance of EEG spectral power at the three study points (baseline, 3 and 12 months) and changes in MMSE and CSF ChAT. This possible effect of NGF was identified in a narrow window of alpha frequency 10-11.5 Hz, where a stabilization in MMSE score during treatment was related to an increase in EEG alpha power. A similar relation was observed between the alpha power and ChAT. More theta power at 6.5 Hz was on the contrary associated with a decrease in CSF ChAT during the trial period. Conclusion In this exploratory study, there was a positive correlative pattern between physiological high-frequency alpha activity and stabilization in MMSE and increase in CSF ChAT in AD patients receiving targeted delivery of NGF to the cholinergic basal forebrain

Dementia prevention : The potential long-term cost-effectiveness of the FINGER prevention program

Introduction The aim of this study was to estimate the potential cost-effectiveness of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) program. Methods A life-time Markov model with societal perspective, simulating a cohort of people at risk of dementia reflecting usual care and the FINGER program. Results Costs were 1,653,275 and 1,635,346 SEK and quality-adjusted life years (QALYs) were 8.636 and 8.679 for usual care and the FINGER program, respectively, resulting in savings of 16,928 SEK (2023 US$) and 0.043 QALY gains per person, supporting extended dominance for the FINGER program. A total of 1623 dementia cases were avoided with 0.17 fewer person-years living with dementia. The sensitivity analysis confirmed the conclusions in most scenarios. Discussion The model provides support that programs like FINGER have the potential to be cost-effective in preventing dementia. Results at the individual level are rather modest, but the societal benefits can be substantial because of the large potential target population.Peer reviewe