Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-ß and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype. METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-ß1-42, total (t-)Tau, and phosphorylated (p-)Tau. RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

The Dutch Parelsnoer Institute--Neurodegenerative diseases; methods, design and baseline results.

BACKGROUND: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. METHODS: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). DISCUSSION: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.

Dementia: Alzheimer pathology and vascular factors: from mutually exclusive to interaction.

Alzheimer's disease (AD) is the most common type of dementia. Both its incidence and prevalence are expected to increase exponentially as populations' age worldwide. Despite impressive efforts of research worldwide, neither cure nor effective preventive strategy is available for this devastating disease. Currently there are several hypotheses on what causes AD, with the amyloid hypothesis being the most investigated and accepted hypothesis over the past 20 years. However the exact role of amyloid-ß in the onset and progression of AD is not yet fully understood, and even the validity of the amyloid hypothesis itself is still being discussed. This debate is fuelled by the vascular hypothesis, as increasing epidemiological, neuroimaging, pathological, pharmacotherapeutic and clinical studies suggest that vascular pathology plays a key role in the onset and progression of AD. We here will discuss arguments in favor and limitations of both hypotheses within the framework of available literature, but also provide arguments for convergence of both hypotheses. Finally we propose approaches that may aid in unraveling the etiology and treatment of AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

A new combined strategy to implement a community occupational therapy intervention: designing a cluster randomized controlled trial.

BACKGROUND: Even effective interventions for people with dementia and their caregivers require specific implementation efforts. A pilot study showed that the highly effective community occupational therapy in dementia (COTiD) program was not implemented optimally due to various barriers. To decrease these barriers and make implementation of the program more effective a combined implementation (CI) strategy was developed. In our study we will compare the effectiveness of this CI strategy with the usual educational (ED) strategy. METHODS: In this cluster randomized, single-blinded, controlled trial, each cluster consists of at least two occupational therapists, a manager, and a physician working at Dutch healthcare organizations that deliver community occupational therapy. Forty-five clusters, stratified by healthcare setting (nursing home, hospital, mental health service), have been allocated randomly to either the intervention group (CI strategy) or the control group (ED strategy). The study population consists of the professionals included in each cluster and community-dwelling people with dementia and their caregivers. The primary outcome measures are the use of community OT, the adherence of OTs to the COTiD program, and the cost effectiveness of implementing the COTiD program in outpatient care. Secondary outcome measures are patient and caregiver outcomes and knowledge of managers, physicians and OTs about the COTiD program. DISCUSSION: Implementation research is fairly new in the field of occupational therapy, making this a unique study. This study does not only evaluate the effects of the CI-strategy on professionals, but also the effects of professionals' degree of implementation on client and caregiver outcomes. CLINICAL TRIALS REGISTRATION: NCT01117285.

Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To investigate the effect of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation on quality of life (QOL). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Independently living individuals from the general older Dutch population. PARTICIPANTS: Three hundred two individuals aged 65 and older without depression or dementia. INTERVENTION: 1,800 mg/d EPA-DHA (n=96), 400 mg/d EPA-DHA (n=100), or placebo capsules (n=106) for 26 weeks. MEASUREMENTS: QOL was assessed using the short version of the World Health Organization QOL questionnaire (WHOQOL-BREF). The WHOQOL-BREF covers four domains: physical health, psychological health, social relationships, and satisfaction with environment. The total score range is 26 to 130, with higher scores indicating a more favorable condition. RESULTS: Mean age of the participants was 70, and 55% were male. Plasma concentrations of EPA-DHA increased 238% in the high-dose and 51% in the low-dose EPA-DHA group, reflecting excellent adherence. Median baseline total WHOQOL scores ranged from 107 to 110 in the three groups and were not significantly different from each other. After 26 weeks, the mean difference from placebo was -1.42 (95% confidence interval (CI)=-3.40-0.57) for the high-dose and 0.02 (95% CI=-1.95-1.99) for the low-dose fish oil group. Treatment with 1,800 mg or 400 mg EPA-DHA did not affect total QOL or any of the separate domains after 13 or 26 weeks of intervention. CONCLUSION: Supplementation with high or low doses of fish oil for 26 weeks did not influence the QOL of healthy older individuals.

Effects of community occupational therapy on quality of life, mood, and health status in dementia patients and their caregivers: a randomized controlled trial.

BACKGROUND: Cure of dementia is not possible, but quality of life of patients and caregivers can be improved. Our aim is to investigate effects of community occupational therapy on dementia patients' and caregivers' quality of life, mood, and health status and caregivers' sense of control over life. METHODS: Community-dwelling patients aged 65 years or older, with mild-to-moderate dementia, and their informal caregivers (n = 135 couples of patients with their caregivers) were randomly assigned to 10 sessions of occupational therapy over 5 weeks or no intervention. Cognitive and behavioral interventions were used to train patients in the use of aids to compensate for cognitive decline and caregivers in coping behaviors and supervision. Outcomes, measured at baseline, 6 weeks, and 12 weeks, were patients' and caregivers' quality of life (Dementia Quality of Life Instrument, Dqol), patients' mood (Cornell Scale for Depression, CSD), caregivers' mood (Center for Epidemiologic Studies Depression Scale, CES-D), patients' and caregivers' health status (General Health Questionnaire, GHQ-12), and caregivers' sense of control over life (Mastery Scale). RESULTS: Improvement on patients' Dqol overall (0.8; 95% confidence interval [CI], 0.6-.1, effect size 1.3) and caregivers' Dqol overall (0.7; 95% CI, 0.5-.9, effect size 1.2) was significantly better in the intervention group as compared to controls. Scores on other outcome measures also improved significantly. This improvement was still significant at 12 weeks. CONCLUSION: Community occupational therapy should be advocated both for dementia patients and their caregivers, because it improves their mood, quality of life, and health status and caregivers' sense of control over life. Effects were still present at follow-up.

Non-cardiovascular co-morbidity in elderly patients with heart failure outnumbers cardiovascular co-morbidity.

BACKGROUND: Patients with heart failure often suffer from multiple co-morbid conditions. However, until now only cardiovascular co-morbidity has been well described. AIMS: To understand heart failure in the context of multi-morbidity, by describing the age and sex specific patterns of non-cardiovascular co-morbidity in elderly patients with heart failure in general practice. METHODS: All patients aged 65 years and over, diagnosed with heart failure in four practices of the Nijmegen Academic Practice-based Research Network (NPBRN) between January 1999 and December 2003 were selected, and the prevalence of 27 cardio- and non-cardiovascular co-morbidities determined. RESULTS: Of the 269 patients identified (mean age 79 years; 57% women), 80.2% had four or more co-morbidities. With increasing age, a significant increase in the prevalence of non-cardiovascular conditions like visual and hearing impairments, osteoarthritis, dementia and urine incontinence; and a decrease in cardiovascular conditions like myocardial infarction and in women, hypertension, was observed. In patients aged 85 years and over, non-cardiovascular disorders predominated over cardiovascular disorders. CONCLUSIONS: In elderly patients with heart failure, the prevalence of non-cardiovascular co-morbidity is very high and exceeds the prevalence of cardiovascular conditions. Diseases such as dementia and osteoarthritis must be taken into account in the management of elderly patients with heart failure.