E. van Exel

Neuroinflammation - An Early Event in Both the History and Pathogenesis of Alzheimer's Disease

Background: About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. Objectives: To show that the interest in inflammation in Alzheimer’s disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. Methods: Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. Results: Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. Conclusion: Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau-related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD.

The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer's disease: neuropathological, epidemiological and genetic evidence

The idea that an inflammatory process is involved in Alzheimers disease (AD) was proposed already hundred years ago but only the past twenty years inflammation-related proteins have been identified within plaques. A number of acute-phase proteins colocalize with the extracellular amyloid fibrils, the so called Aβ-associated proteins. Activated microglia and astrocytes surrounding amyloid deposits express receptors of innate immunity and secrete pro-inflammatory cytokines. In this paper we review the evidence for involvement of innate immunity in the early stages of the pathological cascade of AD. Diffuse plaques, the initial neuropathological lesion in the cerebral neocortex, contain next to Aβ also apolipoprotein E, clusterin, α1-antichymotrypsin and activated complement proteins. Interestingly, genetic studies have shown gene-loci to be associated with AD for all these proteins, except α1-antichymotrpsin. Fibrillar Aβ can, through stimulation of toll-like receptors and CD-14 on glial cells, activate pathways for increased production of pro-inflammatory cytokines. This pathway, inducing production of proinflammatory cytokines, is under genetic control. The finding that the responsiveness of the innate immunity is higher in offspring with a parental history of late-onset AD indicates heritable traits for AD that are related to inflammatory processes. Prospective epidemiological studies which report that higher serum levels of certain acute-phase proteins are associated with cognitive decline or dementia provide additional evidence for the early involvement of inflammation in AD pathogenesis. The reviewed neuropathological, epidemiological and genetic findings show evidence for involvement of the innate-immunity in the early stages of pathological cascade as well as for the hypothesis that the innate immunity contributes to the etiology of late-onset AD.

The prognosis of depression in old age: Outcome six to eight years after clinical treatment

Previous studies suggest that the short-term outcome in severely depressed elderly in The Netherlands is worse compared to other studies in the Western world. The present study examines the long-term prognosis of hospitalized elderly patients with major depressive disorder and possible predictors of outcome. One hundred and five elderly inpatients with unipolar major depression, admitted by regional mental health services in a geographically delimited area, were evaluated six to eight years after index episode by trained residents using a structured diagnostic interview (C.I.D.I.) The GP was interviewed using a standard questionnaire. At follow-up 40% of the original sample had died. Of the survivors 33% had fared well, 24% had a relapsing course, 22% had residual symptoms, 11% were continuously ill, and 9% had probable dementia. With respect to prognostic factors, personality disorder predicted a worse outcome. All patients with a major depressive disorder at follow-up received specialised care and used antidepressants. None of the patients received ECT. The mortality rate in clinically treated elderly with major depressive disorder is high. Among survivors the long-term prognosis in The Netherlands is comparable with other studies to date. The presence of a personality disorder predicts worse outcome. Though the accessibility of services seems to be good, more vigorous treatment was not applied.

Depression in systemic lupus erythematosus, dependent on or independent of severity of disease.

Objectives To estimate the prevalence of depression in subjects with systemic lupus erythematosus (SLE) in relation to the general population and to unravel the relation between depression and SLE disease characteristics. Methods One hundred and two subjects with SLE (mean age 44.4 years) were studied using the Beck Depression Inventory (BDI) score to estimate the prevalence of depression. The BDI scores in subjects with SLE were compared with BDI scores from a pan-European population based study (Outcome in Depression International Network (ODIN) study, nu2009=u20097934), i.e. the general population. Results The mean BDI score was higher in SLE subjects (10.1 points) compared with the BDI scores derived from the general population (10.1 versus 5.6 points, respectively, pu2009<u20090.001). This corresponds to a prevalence of depression of 16.6% and 6.7%, respectively. There was no association between disease activity or organ damage and BDI scores in subjects with SLE (pu2009>u20090.1). Only 7% of SLE subjects with high BDI scores used antidepressants. Conclusion The mean BDI score and prevalence of depression are significantly higher in SLE subjects compared with the general population. No association was found between SLE disease characteristics and BDI scores. The number of depressed SLE subjects treated with antidepressants is low, suggesting inadequate recognition and treatment of depression in SLE.

Insulin-like growth factor-1 and risk of late-onset Alzheimer's disease: findings from a family study

Insulin-like growth factor-1 (IGF-1), part of an evolutionary conserved signaling pathway in both mammalian and non-mammalian species, is inferred in neurodegenerative disorders including Alzheimers disease (AD). A murine model for AD shows that reduced IGF-1 signaling prevents AD-like characteristics. However, variation in serum levels of IGF-1 and risk of AD in humans has yet to be determined. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. The offspring under study carry an increased risk of AD but do not yet experience cognitive impairment. A total of 206 offspring from 92 families with a parental history of AD were compared with 200 offspring from 97 families without a parental history of AD. Apolipoprotein-E (APOE) genotypes and serum IGF-1 levels were compared in subjects with and without a parental history of AD using linear regression, adjusted for APOE genotype and other possible demographic and clinical confounders. Offspring with a parental history of AD were more likely to be an APOE ε4 allele carrier (46.5% vs. 21%, p = 0.001) than were offspring without such a parental history. Offspring with a parental history of AD had higher IGF-1 levels than subjects without such a history, in both unadjusted and adjusted analyses (18.3 mmol/L vs. 16.7 mmol/L, p = 0.001). In conclusion, higher serum IGF-1 levels in middle age are associated with risk of AD disease in older age, independent of APOE genotype.

Pulling out all the stops: what motivates 65+ year olds with depressive symptoms to participate in an outreaching preference-led intervention programme?

Objectives: Many older adults have significant depressive symptoms but few people access care for these. This study explores which personal, clinical and need factors facilitate or hinder acceptance of a new outreaching preference-led intervention programme. Methods: From a sample of 9661 community-dwelling 65+ year olds, 244 persons with depressive symptoms according to the Patient Health Questionnaire-9 were included. Data on programme effectiveness in terms of care utilisation were collected. Associations between programme acceptance and personal, clinical and need factors were studied using quantitative (logistic regression analyses) and qualitative methods (semi-structured interviews with 26 subjects, who accepted (n = 20) or declined (n = 6) the programme). Results: Fifty-six per cent (n = 137) took part in the interventions. Quantitative logistic regression analyses showed that participants were more often female, suffered from more severe depressive symptoms and perceived more loneliness. Qualitative analyses revealed that people accepting the intervention programme felt that medical terms as having a depressed mood were applicable to their situation, more often perceived their symptoms as hindering, felt lonely and more often perceived a need for care. They were more often advised by their general practitioner to participate than individuals who refused the interventions. Many participating individuals did not see a match between the intervention programme and their needs, especially with respect to meeting new people. Conclusion: Many older persons with depressive symptoms did not feel the need to take part in the programme. Providing support in alleviating loneliness and further adaptation to older adults’ illness representations and perceptions when discussing depressive symptoms might enhance care utilisation.

The course of apathy in late-life depression treated with electroconvulsive therapy; a prospective cohort study

Apathy, a lack of motivation, is frequently seen in older individuals, with and without depression, with substantial impact on quality of life. This prospective cohort study of patients with severe late‐life depression treated with electroconvulsive therapy (ECT) aims to study the course of apathy and the predictive value of vascular burden and in particular white matter hyperintensities on apathy course.

SAT0229 Depression in systemic lupus erythematosus, dependent or independent of severity of disease?

Background Depression is one of the most commonly reported neuropsychiatric symptoms in systemic lupus erythematosus (SLE) patients. However, the prevalence of depression in relation to the general population and its relationship with SLE disease characteristics are still largely unkown. Objectives To estimate the prevalence of depression in subjects with SLE in relation to the general population and to unravel the relation between depression and SLE disease characteristics. Methods We studied 102 patients with SLE (mean age 44.4 yrs, 88% female, mean disease duration 7.8 yrs), all fulfilling the ACR classification criteria for SLE. Severity of SLE was determined with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics Damage Index (SDI), representing disease activity and organ damage. We used the Beck Depression Inventory score (BDI), a validated screening instrument able to detect major depression and to estimate the prevalence of depression. A BDI score of more than 13 points was considered a high score. As a proxy for treatment of depression we assessed the number of patients using anti-depressants. Results The mean BDI score was higher in SLE patients (n=102) compared to the BDI scores derived from a European population based study (ODIN study, n=7934), (10.1 points in patients with SLE vs 5.6 points in subjects from ODIN, p<0.001). This corresponds with a prevalence of depression of 16.6% in SLE patients vs 6.7% in the general population. Only 7% of the SLE patients with a high BDI score used anti-depressant medication. There was no difference in disease characteristics, disease activity score (SLEDAI) and organ damage index (SDI) between SLE patients with and without depression (all p>0.1). The number of years of education was significantly lower in SLE patients with a depression compared to those without a depression (9.5 yrs. vs 12.2 yrs, p=0.004). Conclusions The mean BDI score, i.e. a proxy for prevalence of depression, is almost doubled in SLE patients compared to the mean BDI score from a large pan European population based study. Surprisingly, we found no association between disease characteristics or severity of SLE and presence of depression, determined with the BDI. Finally, we found that a small part of SLE patients with a high depression score were treated with anti-depressant medication, suggesting that depressed SLE patients might not be adequately recognized and treated for depression. For depressed SLE patients, this study provides clues that screening for depression in SLE patients should be done routinely, and that psychiatric counseling for these patients should be readily available. References Veerman JL, Dowrick C, Ayuso-Mateos JL, et al. Population prevalence of depression and mean Beck Depression Inventory score. Br J Psychiatry. 2009;195:516-9. Disclosure of Interest None Declared