[Informal care for dementia according to type of service]. / Informelle Pflege bei Demenz nach Leistungsarten.

BACKGROUND: Dementia is a major challenge for society and its impact will grow in the future. Informal care is an essential part of dementia care. Previous studies considered informal care as a whole and not by its components. OBJECTIVE: We aimed to assess the degree of association between specific informal care services and dementia. MATERIAL AND METHODS: This analysis is based on data from the seventh wave of the AgeCoDe/AgeQualiDe study. Dementia was diagnosed based on the DSM-IV criteria. Severity of dementia was assessed and categorized by means of the Clinical Dementia Rating and eight individual informal care services were considered. Logistic regression models were used to assess associations. RESULTS: Of the 864 participants 18% suffered from dementia (very mild: 4%; mild: 6%; moderate: 5%; severe: 3%). All informal care services were significantly associated with dementia, with an emphasis on "supervision", "regulation of financial matters" and "assistance in the intake of medication". Considering different degrees of dementia severity, similar results arose from the analyses. All three aforementioned services showed a pronounced association with all degrees of dementia severity, except for supervision and very mild dementia. CONCLUSION: The provision of all types of informal care services is associated with dementia. The association is pronounced for services that can be more easily integrated into the daily routines of the informal caregiver. Policy makers who plan to integrate informal care into the general care arrangements for dementia should consider this.

[Longitudinal Predictors of the Need for Care]. / Einflussfaktoren auf die Pflegebedürftigkeit im Längsschnitt.

Background: Little is known about the longitudinal predictors of the need for care in old age. However, the knowledge of these factors is important for developing strategies for prevention or delay the need for care. Thus, we aimed at investigating the factors affecting the need for care in old age. Methods: In this population-based prospective cohort study (AgeCoDe, with n=3 217 individuals aged 75 years and above at baseline), the need for care was observed over 4.5 years. The need for care was quantified by the care level defined by the German Law (§ 15 SGB XI). Longitudinal predictors (sociodemographic variables, impairment in mobility/hearing/vision, dementia and depression) of the need for care were examined by using Random Effects Logit regressions. Results: Longitudinal regression analysis revealed that the probability of the need for care significantly increased with the occurrence of dementia (OR: 48.2), mobility impairments (aggravated walking, OR: 26.4; disability of walking, OR: 747.9) and age (e. g. 90 years and above vs.<80 years, OR: 32.3). The influence of family status, living conditions, visual impairment and depression on need for care was markedly smaller, and the effect of hearing impairments did not achieve statistical significance. Conclusion: In order to prevent or delay the need for care in old age, treatments should aim at preserving mobility and cognition. Due to demographic ageing, developing such programs is of major importance for health policy.

[Prevention of Alzheimer's dementia in Germany : A projection of the possible potential of reducing selected risk factors]. / Prävention von Alzheimer-Demenz in Deutschland : Eine Hochrechnung des möglichen Potenzials der Reduktion ausgewählter Risikofaktoren.

BACKGROUND: Current international projections suggest that reducing the prevalence of seven well-established risk factors, midlife hypertension and obesity, diabetes mellitus, depression, physical inactivity, smoking and low educational attainment, may also substantially reduce the prevalence of Alzheimer's dementia (AD). OBJECTIVE: Following the procedures of the international projections, in this study we aimed to provide projections of a corresponding potential for prevention specific for Germany. METHODS: For each risk factor separately and combined (with adjustment for the association between the risk factors) we calculated (1) the population attributable risk (PAR) for AD, (2) the corresponding total number of attributable AD cases and (3) the potential number of current AD cases that may have been prevented by a 10 %, 25 % and 50 % lower prevalence of the risk factors. RESULTS: According to the population projections 30.5 % of the current AD cases in Germany could be attributable to the risk factors considered (305,000 AD cases in total). The highest estimated impact on AD prevalence was found for physical inactivity (PAR = 21.7 %, 217,000 attributable cases) and smoking (PAR = 14.9 %, 149,000 cases). A 10-50 % reduction in the prevalence of all seven risk factors could have potentially prevented 23,000-130,000 of the current AD cases in Germany. CONCLUSION: The identified possible substantial potential for reducing AD prevalence should act as a strong additional incentive to reduce the seven risk factors in Germany.

Incident subjective memory complaints and the risk of subsequent dementia.

OBJECTIVE: In this study, we aimed to analyze the association between new-incident-subjective memory complaints (SMC) and risk of subsequent dementia in a general population sample aged 75+ years. METHOD: Data were derived from follow-up (FUP) waves I-V of the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate dementia-free survival times of individuals with and without incident SMC and multivariable Cox proportional hazards regression to assess the association between incident SMC and risk of subsequent dementia, controlled for covariates. RESULTS: Of 443 non-demented individuals, 58 (13.1%) developed dementia during a subsequent 5.4-year follow-up period. Participants with incident SMC showed a significantly higher progression to dementia (18.5% vs. 10.0%; P=0.010) and a significantly shorter mean dementia-free survival time than those without (6.2 vs. 6.8 years; P=0.008). The association between incident SMC and risk of subsequent dementia remained significant in the multivariable Cox analysis (adjusted hazard ratio=1.8; P=0.028). CONCLUSION: Our findings suggest higher progression to dementia and shorter dementia-free survival in older individuals with incident SMC. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia.

Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients.

OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (≥2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia.

Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene-environment interaction for the risk of dementia and Alzheimer's disease dementia.

BACKGROUND: As physical activity may modify the effect of the apolipoprotein E (APOE) ε4 allele on the risk of dementia and Alzheimer's disease (AD) dementia, we tested for such a gene-environment interaction in a sample of general practice patients aged ⩾75 years. METHOD: Data were derived from follow-up waves I-IV of the longitudinal German study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). The Kaplan-Meier survival method was used to estimate dementia- and AD-free survival times. Multivariable Cox regression was used to assess individual associations of APOE ε4 and physical activity with risk for dementia and AD, controlling for covariates. We tested for gene-environment interaction by calculating three indices of additive interaction. RESULTS: Among the randomly selected sample of 6619 patients, 3327 (50.3%) individuals participated in the study at baseline and 2810 (42.5%) at follow-up I. Of the 2492 patients without dementia included at follow-up I, 278 developed dementia (184 AD) over the subsequent follow-up interval of 4.5 years. The presence of the APOE ε4 allele significantly increased and higher physical activity significantly decreased risk for dementia and AD. The co-presence of APOE ε4 with low physical activity was associated with higher risk for dementia and AD and shorter dementia- and AD-free survival time than the presence of APOE ε4 or low physical activity alone. Indices of interaction indicated no significant interaction between low physical activity and the APOE ε4 allele for general dementia risk, but a possible additive interaction for AD risk. CONCLUSIONS: Physical activity even in late life may be effective in reducing conversion to dementia and AD or in delaying the onset of clinical manifestations. APOE ε4 carriers may particularly benefit from increasing physical activity with regard to their risk for AD.

A hierarchy of predictors for dementia-free survival in old-age: results of the AgeCoDe study.

OBJECTIVE: Progression from cognitive impairment (CI) to dementia is predicted by several factors, but their relative importance and interaction are unclear. METHOD: We investigated numerous such factors in the AgeCoDe study, a longitudinal study of general practice patients aged 75+. We used recursive partitioning analysis (RPA) to identify hierarchical patterns of baseline covariates that predicted dementia-free survival. RESULTS: Among 784 non-demented patients with CI, 157 (20.0%) developed dementia over a follow-up interval of 4.5 years. RPA showed that more severe cognitive compromise, revealed by a Mini-Mental State Examination (MMSE) score < 27.47, was the strongest predictor of imminent dementia. Dementia-free survival time was shortest (mean 2.4 years) in such low-scoring patients who also had impaired instrumental activities of daily living (iADL) and subjective memory impairment with related worry (SMI-w). Patients with identical characteristics but without SMI-w had an estimated mean dementia-free survival time of 3.8 years, which was still shorter than in patients who had subthreshold MMSE scores but intact iADL (4.2-5.2 years). CONCLUSION: Hierarchical patterns of readily available covariates can predict dementia-free survival in older general practice patients with CI. Although less widely appreciated than other variables, iADL impairment appears to be an especially noteworthy predictor of progression to dementia.

Impact of impairment in instrumental activities of daily living and mild cognitive impairment on time to incident dementia: results of the Leipzig Longitudinal Study of the Aged.

BACKGROUND: Early diagnosis of dementia requires knowledge about associated predictors. The aim of this study was to determine the impact of mild cognitive impairment (MCI) and impairment in instrumental activities of daily living (IADL) on the time to an incident dementia diagnosis. METHOD: Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+), a population-based study of individuals aged ≥75 years. Kaplan-Meier survival analysis was used to determine time to incident dementia. Cox proportional hazards models were applied to determine the impact of MCI and IADL impairment on the time to incident dementia. RESULTS: In total, 180 (22.0%) of 819 initially dementia-free subjects developed dementia by the end of the study. Mean time to incident dementia was 6.7 years [95% confidence interval (CI) 6.5-6.9]. MCI combined with IADL impairment was associated with a higher conversion rate to dementia, a shorter time to clinically manifest diagnosis and a lower chance of reversibility to cognitive normal. The highest risk for a shorter time to incident dementia was found for amnestic MCI combined with IADL impairment. The mean time to incident dementia was 3.7 years (95% CI 2.9-4.4) and thus half as long as in subjects without MCI and IADL impairment. CONCLUSIONS: Subjects with MCI and IADL impairment constitute a high-risk population for future dementia. The consideration of both--MCI and IADL impairment-- might help to improve the prediction of dementia.

Risk factors for incident mild cognitive impairment--results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

OBJECTIVES: To provide age- and gender-specific incidence rates of MCI among elderly general practitioner (GP) patients (75+ years) and to identify risk factors for incident MCI. METHOD: Data were derived from the longitudinal German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Incidence was calculated according to the 'person-years-at-risk' method. Risk factors were analysed using multivariate logistic regression models. RESULTS: During the 3-year follow-up period, 350 (15.0%) of the 2331 patients whose data were included in the calculation of incidence developed MCI [person-years (PY) = 6198.20]. The overall incidence of MCI was 56.5 (95% confidence interval = 50.7-62.7) per 1000 PY. Older age, vascular diseases, the apoE epsilon4 allele and subjective memory complaints were identified as significant risk factors for future MCI. CONCLUSION: Mild cognitive impairment is frequent in older GP patients. Subjective memory complaints predict incident MCI. Especially vascular risk factors provide the opportunity of preventive approaches.

[CERAD-NP battery: Age-, gender- and education-specific reference values for selected subtests. Results of the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe)]. / CERAD-NP-Testbatterie: Alters-, geschlechts- und bildungsspezifische Normen ausgewählter Subtests. Ergebnisse der German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

The CERAD-NP battery represents well-established tests for the neuropsychological diagnosis of characteristic cognitive deficits in Alzheimer's dementia. However, the use of neuropsychological tests requires reliable standard values for the population under consideration, taking sociodemographic characteristics like age, education and gender into account. This report presents age-, education- and gender-specific reference values for the subtests verbal fluency, word list memory, word list recall and word list recognition as well as the word list savings score of the CERAD-NP battery. The study sample consists of 2891 general practitioners' patients from Germany aged 75 years and older. The study participants had a mean age of 80.2 years (SD=3.6); thus, this report provides reliable reference values for the neuropsychological diagnosis of dementia in older age groups.

Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice. We found that Cntnap2 KO mice displayed decreased glutamate receptor expression and transmission. Contrarily, VPA mice exhibited increased glutamate receptor expression and transmission. Next, we investigated whether AMPAR modulators (positive-allosteric-modulator for Cntnap2 KO mice and antagonist for VPA mice) can improve autistic symptoms by normalizing the aberrant excitatory transmission in the respective animal models. Interestingly, the AMPAR modulation specifically ameliorated social deficits in both animal models. These results indicated that AMPAR-derived excitatory neural transmission changes can affect normal social behavior. To validate this, we injected an AMPAR agonist or antagonist in control ICR mice and, interestingly, these treatments impaired only the social behavior, without affecting the repetitive and hyperactive behaviors. Collectively, these results provide insight into the role of AMPARs in the underlying pathophysiological mechanisms of ASD, and demonstrate that modulation of AMPAR can be a potential target for the treatment of social behavior deficits associated with ASD.

Longitudinal Analysis of Outpatient Physician Visits in the Oldest Old: Results of the AgeQualiDe Prospective Cohort Study.

OBJECTIVES: The aim of this study was to identify determinants of outpatient health care utilization among the oldest old in Germany longitudinally. DESIGN: Multicenter prospective cohort "Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe). SETTING: Individuals in very old age were recruited via GP offices at six study centers in Germany. The course of outpatient health care was observed over 10 months (two waves). PARTICIPANTS: Primary care patients aged 85 years and over (at baseline: n=861, with mean age of 89.0 years±2.9 years; 85-100 years). MEASUREMENTS: Self-reported numbers of outpatient visits to general practitioners (GP) and specialists in the past three months were used as dependent variables. Widely used scales were used to quantify explanatory variables (e.g., Geriatric Depression Scale, Instrumental Activities of Daily Living Scale, or Global Deterioration Scale). RESULTS: Fixed effects regressions showed that increases in GP visits were associated with increases in cognitive impairment, whereas they were not associated with changes in marital status, functional decline, increasing number of chronic conditions, increasing age, and changes in social network. Increases in specialist visits were not associated with changes in the explanatory variables. CONCLUSION: Our findings underline the importance of cognitive impairment for GP visits. Creating strategies to postpone cognitive decline might be beneficial for the health care system.

Effects of Several Cosmetic Preservatives on ROS-Dependent Apoptosis of Rat Neural Progenitor Cells.

Benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea are commonly used preservatives in cosmetics. Recent reports suggested that these compounds may have cellular and systemic toxicity in high concentration. In addition, diazolidinyl urea and imidazolidinyl urea are known formaldehyde (FA) releasers, raising concerns for these cosmetic preservatives. In this study, we investigated the effects of benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea on ROS-dependent apoptosis of rat neural progenitor cells (NPCs) in vitro. Cells were isolated and cultured from embryonic day 14 rat cortices. Cultured cells were treated with 1-1,000 nM benzalkonium chloride, and 1-50 µM diazolidinyl urea or imidazolidinyl urea at various time points to measure the reactive oxygen species (ROS). PI staining, MTT assay, and live-cell imaging were used for cell viability measurements. Western blot was carried out for cleaved caspase-3 and cleaved caspase-8 as apoptotic protein markers. In rat NPCs, ROS production and cleaved caspase-8 expression were increased while the cell viability was decreased in high concentrations of these substances. These results suggest that several cosmetic preservatives at high concentrations can induce neural toxicity in rat brains through ROS induction and apoptosis.

T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells.

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3ß-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.

Factors Affecting Functional Impairment among Elderly Germans - Results of a Longitudinal Study.

OBJECTIVE: To investigate causal factors of functional impairment in old age in a longitudinal approach. DESIGN: A population-based prospective cohort study. SETTING: Elderly individuals were recruited via GP offices at six study centers in Germany. They were observed every 1.5 years over six waves. PARTICIPANTS: Three thousand two hundred fifty-six people aged 75 years and older at baseline. MEASUREMENTS: Functional impairment was quantified by the Lawton and Brody Instrumental Activities of Daily Living scale (IADL) and the Barthel-Index (BI). RESULTS: Fixed effects regressions revealed that functional impairment (IADL; BI) increased significantly with ageing (ß=-.2; ß=-1.1), loss of a spouse (ß= .5; ß=-3.1), not living alone in private household (ß=-1.2; ß=-5.5), depression (solely significant for IADL: ß= .6) and dementia (ß=-2.3; ß=-18.2). The comorbidity score did not affect functional impairment. CONCLUSION: Our findings underline the relevance of changes in sociodemographic variables as well as the occurrence of depression or dementia for functional impairment. While several of these causal factors for functional decline in the oldest old are inevitable, some may not be, such as depression. Therefore, developing interventional strategies to prevent depression might be a fruitful approach in order to delay functional impairment in old age.

Does Visual Impairment Affect Social Ties in Late Life? Findings of a Multicenter Prospective Cohort Study in Germany.

OBJECTIVE: To investigate how visual impairment affects social ties in late life longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Individuals in old age were recruited via general practitioners' offices (at six study centers) in Germany. They were interviewed every 18 months. PARTICIPANTS: Individuals aged 75 years and above at baseline. Follow-up wave 2 (36 months after baseline, n=2,443) and wave 4 (72 months after baseline, n=1,618) were used for the analyses presented here. MEASUREMENTS: Social ties were assessed using the 14-item form of the questionnaire for social support (F-SozU K-14). Visual impairment was self-rated on a three level Likert scale (no impairment, mild visual impairment, or severe/profound visual impairment). RESULTS: Adjusting for sociodemographic factors, hearing impairment and comorbidity, fixed effects regressions revealed that the onset of mild visual impairment decreased the social support score, in particular the emotional support score. Additionally, the onset of mild hearing impairment decreased the social support score in men. Moreover, increasing age decreased the social support score in the total sample and in both sexes. Loss of spouse and increasing comorbidity did not affect the social support score. CONCLUSION: Our results highlight the importance of visual impairment for social ties in late life. Consequently, appropriate strategies in order to delay visual impairment might help to maintain social ties in old age.

Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.

Erratum: Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

[This corrects the article on p. 252 in vol. 26, PMID: 29093634.].

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD.