Alzheimer's disease pathology:pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD

Elevated activity of the sympathetic nervous system is related to diminished practice effects in memory:A pilot study

BACKGROUND: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load. OBJECTIVE: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects. METHODS: Thirty cognitively healthy individuals aged 40–70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance. RESULTS: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners. CONCLUSION: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline

Reducing dementia risk by targeting modifiable risk factors in mid-life: study protocol for the Innovative midlife intervention for dementia deterrence (In-MINDD) randomised controlled feasibility trial

Background Dementia prevalence is increasing as populations live longer, with no cure and the costs of caring exceeding many other conditions. There is increasing evidence for modifiable risk factors which, if addressed in mid-life, can reduce the risk of developing dementia in later life. These include physical inactivity, low cognitive activity, mid-life obesity, high blood pressure, and high cholesterol. This study aims to assess the acceptability and feasibility and impact of giving those in mid-life, aged between 40 and 60 years, an individualised dementia risk modification score and profile and access to personalised on-line health information and goal setting in order to support the behaviour change required to reduce such dementia risk. A secondary aim is to understand participants’ and practitioners’ views of dementia prevention and explore the acceptability and integration of the Innovative Midlife Intervention for Dementia Deterrence (In-MINDD) intervention into daily life and routine practice. Methods/design In-MINDD is a multi-centre, primary care-based, single-blinded randomised controlled feasibility trial currently being conducted in four European countries (France, Ireland, the Netherlands and the UK). Participants are being recruited from participating general practices. Inclusion criteria will include age between 40 and 60 years; at least one modifiable risk factor for dementia risk (including diabetes, hypertension, obesity, renal dysfunction, current smoker, raised cholesterol, coronary heart disease, current or previous history of depression, self-reported sedentary lifestyle, and self-reported low cognitive activity) access to the Internet. Primary outcome measure will be a change in dementia risk modification score over the timescale of the trial (6 months). A qualitative process evaluation will interview a sample of participants and practitioners about their views on the acceptability and feasibility of the trial and the links between modifiable risk factors and dementia prevention. This work will be underpinned by Normalisation Process Theory. Discussion This study will explore the feasibility and acceptability of a risk profiler and on-line support environment to help individuals in mid-life assess their risk of developing dementia in later life and to take steps to alleviate that risk by tackling health-related behaviour change. Testing the intervention in a robust and theoretically informed manner will inform the development of a future, full-scale randomised controlled trial

Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia

Background: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI. Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon. Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416. Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization

Calendar 2015

Item does not contain fulltextBACKGROUND: Children of patients with young onset dementia (YOD) who are confronted with a parent who has a progressive disease, often assist in caregiving tasks, which may have a great impact on their lives. The objective of the present study is to explore the experiences of children living with a young parent with dementia with a specific focus on the children's needs. METHODS: Semi-structured interviews with 14 adolescent children between the ages of 15 and 27 years of patients with YOD were analyzed using inductive content analysis. Themes were identified based on the established codes. RESULTS: The emerging categories were divided into three themes that demonstrated the impact of dementia on daily life, different ways of coping with the disease, and children's need for care and support. The children had difficulties managing all of the responsibilities and showed concerns about their future. To deal with these problems, they demonstrated various coping styles, such as avoidant or adaptive coping. Although most children were initially reluctant to seek professional care, several of them expressed the need for practical guidance to address the changing behavior of their parent. The children felt more comfortable talking to someone who was familiar with their situation and who had specific knowledge of YOD and the available services. CONCLUSION: In addition to practical information, more accessible and specific information about the diagnosis and the course of YOD is needed to provide a better understanding of the disease for the children. These findings underline the need for a personal, family-centered approach

The Course of Quality of Life and Its Predictors in Nursing Home Residents With Young-Onset Dementia

OBJECTIVE: To explore the course of quality of life (QoL) and possible resident-related predictors associated with this course in institutionalized people with young-onset dementia (YOD). DESIGN: An observational longitudinal study. SETTING AND PARTICIPANTS: A total of 278 residents with YOD were recruited from 13 YOD special care units in the Netherlands. METHODS: Secondary analyses were conducted with longitudinal data from the Behavior and Evolution in Young-ONset Dementia (BEYOND)-II study. QoL was assessed with proxy ratings, using the Quality of Life in Dementia (QUALIDEM) questionnaire at 4 assessment points over 18 months. Predictors included age, gender, dementia subtype, length of stay, dementia severity, neuropsychiatric symptoms, and psychotropic drug use at baseline. Multilevel modeling was used to adjust for the correlation of measurements within residents and clustering of residents within nursing homes. RESULTS: The total QUALIDEM score (range: 0-111) decreased over 18 months with a small change of 0.65 (95% confidence interval -1.27, -0.04) points per 6 months. An increase in several domains of QoL regarding care relationship, positive self-image, and feeling at home was seen over time, whereas a decline was observed in the subscales positive affect, social relations, and having something to do. Residents with higher levels of QoL and more advanced dementia at baseline showed a more progressive decline in QoL over time. Sensitivity analyses indicated a more progressive decline in QoL for residents who died during the follow-up. CONCLUSION AND IMPLICATIONS: This study shows that although overall QoL in nursing home residents with YOD was relatively stable over 18 months, there were multidirectional changes in the QoL subscales that could be clinically relevant. Higher levels of QoL and more advanced stages of dementia at baseline predicted a more progressive decline in QoL over time. More longitudinal studies are needed to verify factors influencing QoL in YOD

Association Between Cognition, Health Related Quality of Life, and Costs in a Population at Risk for Cognitive Decline

Background: The association between health-related quality of life (HRQoL) and care costs in people at risk for cognitive decline is not well understood. Studying this association could reveal the potential benefits of increasing HRQoL and reducing care costs by improving cognition. Objective: In this exploratory data analysis we investigated the association between cognition, HRQoL utilities and costs in a well-functioning population at risk for cognitive decline. Methods: An exploratory data analysis was conducted using longitudinal 2-year data from the FINGER study (n= 1,120). A change score analysis was applied using HRQoL utilities and total medical care costs as outcome. HRQoL utilities were derived from the Short Form Health Survey-36 (SF-36). Total care costs comprised visits to a general practitioner, medical specialist, nurse, and days at hospital. Analyses were adjusted for activities of daily living (ADL) and depressive symptoms. Results: Although univariable analysis showed an association between cognition and HRQoL utilities, multivariable analysis showed no association between cognition, HRQoL utilities and total care costs. A one-unit increase in ADL limitations was associated with a -0.006 (p Conclusion: The level of cognition in people at-risk for cognitive decline does not seem to be associated with HRQoL utilities. Future research should examine the level at which cognitive decline starts to affect HRQoL and care costs. Ideally, this would be done by means of cross-validation in populations with various stages of cognitive functioning and decline.Peer reviewe

Greater Blood Pressure Variability Is Associated With Lower Cognitive Performance:The Maastricht Study

An increasing number of individuals will face age-related cognitive difficulties because life expectancy has increased. It is, therefore, important to identify modifiable risk factors for cognitive impairment. Very short-term to mid-term blood pressure variability (BPV) may be such a factor because it may cause cerebral ischemia. To this end, we investigated whether greater systolic and diastolic BPV are cross-sectionally associated with memory function (n=1804), information processing speed (n=1793), and executive function (n=1780) in 40- to 75-year-old individuals from The Maastricht Study. A composite BPV-index was derived by standardizing within-visit, 24-hour, and 7-day BPV. We performed linear regression with adjustments for age, sex, educational level, 24-hour systolic or diastolic pressure, and cardiovascular risk factors. We found that a 1-SD greater systolic BPV was not associated with information processing speed (β [SD difference], -0.10; 95% CI, -0.14 to 0.06), or executive function (-0.09; 95% CI, -0.20 to 0.02) but was marginally associated with lower memory function (-0.11; 95% CI, -0.21 to 0.00). A 1-SD greater diastolic BPV was associated with lower information processing speed (-0.10; 95% CI, -0.20 to -0.00) and executive function (-0.12; 95% CI, -0.22 to -0.01) and marginally associated with lower memory function (-0.09; 95% CI, -0.20 to 0.01). These effects on cognitive performance are equivalent to ≈3 additional years of aging. In conclusion, greater very short-term to mid-term diastolic and, to a lesser extent, systolic BPV may be a modifiable risk factor for cognitive deterioration in 40- to 75-year-old, community-dwelling individuals