Inflammation in older subjects with early- and late-onset depression in the NESDO study: a cross-sectional and longitudinal case-only design.

OBJECTIVE: Different biological mechanisms may underlie depression beginning in early life (early-onset) and depression beginning later in life (late-onset). Although the relation between inflammation and depression has been studied extensively, the distinct role of inflammation in early and late-onset depression in older patients has not been addressed before. In the cross-sectional part of this study, we explored differences in levels of circulating inflammatory markers and cytokine levels in lipopolysaccharide (LPS) stimulated whole blood between older subjects with a late-life onset depression (≥60 years) and older subjects with an early-onset depression (<60 years). Secondly, in a 2-year follow-up study, we examined if circulating and stimulated inflammatory markers influenced the change in Inventory of Depressive Symptomatology (IDS) scores, and if this relation was different for early- and late-onset depression. METHODS: The study was part of the Netherlands Study of Depression in Older Persons (NESDO). We included 350 patients, all aged 60 and older, with a depressive episode in the previous 6 months: 119 with a late-onset depression and 231 with an early-onset depression. Blood samples were collected and CRP, IL-6, NGAL, GDF15, and, LPS plasma levels were determined and whole blood was LPS stimulated and cytokine levels IL-1ß, IL-6, TNFα, IFNγ, IL-10, and IL-1 receptor antagonist (IL-1ra) were determined. RESULTS: After adjustment for demographics, health indicators, and medication use, increased plasma CRP levels were more strongly associated with late-onset depression than early-onset depression (OR [95% CI]: 1.43 [1.05-1.94]). In the longitudinal analyses, higher circulating IL-6 levels were associated with a significantly slower decline in IDS scores in the crude and the adjusted models (p ≤ 0.027). This relation was not different between late- and early-onset depression. Other circulating and stimulated inflammatory markers were not associated with late- and/or early-onset depression. CONCLUSIONS: This study provides preliminary evidence that low-grade inflammation is more strongly associated with late-onset than early-onset depression in older adults, suggesting a distinct inflammatory etiology for late-onset depression. Cytokine production capacity did not distinguish between early- and late-onset depression.

[ResPECT - a decade of Flemish-Dutch ECT research]. / ResPECT ­ een decennium Vlaams-Nederlands onderzoek naar elektroconvulsietherapie.

BACKGROUND: There is increasing clinical and scientific interest in electroconvulsive therapy (ECT). AIM: To provide an overview of the main research findings of the Flemish-Dutch research consortium ResPECT. METHOD: We report on our review of the relevant literature. RESULTS: Our studies confirm that ECT is one of the most efficient treatments for depression in later life and for depression with psychotic features. Older people with age-related brain pathology can respond well to ECT. It is still preferable to apply a standard pulse-width because this increases the efficacy of the treatment and minimises the cognitive impact. Even vulnerable older people can react favourably to ECT. CONCLUSION: Recent findings of the ResPECT consortium are providing new insights that are applicable in daily clinical practice. Research into mechanisms of action can also increase our understanding of the pathophysiology of severe depression.

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 Alzheimer's 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.

Theory of Mind differences in older patients with early-onset and late-onset paranoid schizophrenia.

OBJECTIVE: Theory of Mind (ToM) is considered an essential element of social cognition. In younger schizophrenia patients, ToM impairments have extensively been demonstrated. It is not clear whether similar impairments can be found in older schizophrenia patients and if these impairments differ between older patients with early-onset and late-onset schizophrenia. METHODS: Theory of Mind abilities were assessed using the Hinting Task in 15 older patients (age 60 years and older) with early-onset paranoid schizophrenia, 15 older patients with late-onset paranoid schizophrenia and 30 healthy controls. ANCOVA was performed to test differences between groups. Analyses were adjusted for level of education. Effect sizes, partial eta squared (ε(2) ), were computed as an indication of the clinical relevance of the findings. RESULTS: Patients with early-onset schizophrenia scored significantly lower on the Hinting Task (mean 16.1; SD 4.3) compared with patients with late-onset schizophrenia (mean 18.6; SD 1.5) and with healthy controls (mean 19.0; SD 1.4). The effect size of this difference was large (ε(2) = 0.2). CONCLUSIONS: These results suggest that ToM functioning may be a protective factor modulating the age at onset of psychosis. Further studies into the relationship between social cognition and onset age of psychosis are warranted.

Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer's disease in non-depressed subjects.

BACKGROUND: Apathy is a common symptom in various neuropsychiatric diseases including mild cognitive impairment (MCI) and dementia. Apathy may be associated with an increased risk of cognitive decline. The objective of this study was to investigate if apathy predicts the progression from MCI to Alzheimer's disease (AD). METHODS: The Alzheimer's Disease Neuroimaging Initiative is a prospective multicentre cohort study. At baseline, 397 patients with MCI without major depression were included. Clinical data and the Geriatric Depression Scale at baseline were used. Apathy was defined based on the 3 apathy items of the 15-item Geriatric Depression Scale. The main outcome measure was the association of apathy with progression from MCI to AD. RESULTS: During an average follow-up of 2.7 years (SD 1.0), 166 (41.8%) patients progressed to AD. The presence of symptoms of apathy without symptoms of depressive affect increased the risk of progression from MCI to AD (hazard ratio = 1.85, 95% CI = 1.09-3.15). Apathy in the context of symptoms of depressive affect or symptoms of depressive affect alone, without apathy, did not increase the risk of progression to AD. CONCLUSIONS: Symptoms of apathy, but not symptoms of depressive affect, increase the risk of progression from MCI to AD. Apathy in the context of symptoms of depressive affect does not increase this risk. Symptoms of apathy and depression have differential effects on cognitive decline.

[The immune system and Alzheimer's disease]. / Het immuunsysteem en de ziekte van Alzheimer.

BACKGROUND: It has still not been established unequivocally whether vascular risk factors and inflammatory reactions, determined by heredity, are a cause or a result of Alzheimer's disease AIM: If the offspring of parents with AD have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without AD , this argues strongly in favor of a causal relationship between vascular risk factors, a pro-inflammatory cytokine response and AD. AIM: To determine whether the offspring of parents with ad have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without ad. method Vascular risk-factors, pro-inflammatory cytokines and the apoe genotype were determined in 206 offspring of parents with ad and in 200 offspring of parents without AD. RESULTS: Offspring of parents with ad carried more apoe epsilon4 than offspring of parents without ad (47% vs 21%). Middle-aged offspring of parents with a history of ad also had higher blood pressure and a greater atherosclerotic burden than the offspring of parents without AD. Also their response to the pro-inflammatory cytokine was significantly higher. CONCLUSION: Hypertension and an inherited pro-inflammatory cytokine profile in middle age are early risk factors that contribute to the development of ad in old age. Offspring with a parental history of AD should therefore be offered screening and treatment for hypertension and have their blood pressure checked so that the development of AD in old age can be prevented.

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 Alzheimer's 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 Aß-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 Aß 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 Aß 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.

Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology.

Epidemiological studies suggest that systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard the development of Alzheimer's disease (AD). However, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results. The aim of this review is to distinguish the role of inflammation and the molecular targets of NSAIDs in the different stages of AD pathology. AD brains are characterized by extracellular deposits of ß-amyloid protein and intraneuronal accumulation of hyperphosphorylated tau protein. Already in the early stages of AD pathology ß-amyloid protein deposits are associated with inflammatory proteins and microglia, the brain resident macrophages. Recently, two genome-wide association studies identified new genes that are associated with an increased risk of developing AD. These genes include CLU and CR1 which encode for clusterin and complement receptor 1 respectively. Both genes are involved in the regulation of inflammation. This strongly indicates that inflammation plays a central role in the aetiology of AD. In this review we will show that the primary targets of NSAIDs are involved in a pathological stage that precedes the clinical appearance of AD. The early, preclinical involvement of inflammation in AD explains why patients with clinical signs of AD do not benefit from anti-inflammatory treatment and suggests that NSAIDs, rather than having a direct therapeutic effect, may have preventive effects.

[Melancholia, psychomotor disturbance or depressed mood?]. / Melancholie; verstoorde beweging of ontstemd gemoed?

Melancholia is a historical concept according to which the clinical condition is characterised by gloom, apprehension and psychomotor disturbance, vital symptoms and psychotic phenomena. The condition needs to be accurately diagnosed if treatment is to be appropriate. If a patient shows no clear signs of depression, psychomotor disturbance is often not recognised as a feature of severe depression and as a result treatment is delayed. On the basis of two case studies we show that psychomotor symptoms can be extremely important for an accurate clinical evaluation.

Dyshoric capillary cerebral amyloid angiopathy mimicking Creutzfeldt-Jakob disease.

BACKGROUND: Subjects fulfilling the World Health Organisation clinical diagnostic criteria for Creutzfeldt-Jakob disease (CJD) often have a different diagnosis at autopsy, including Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common finding in Alzheimer's disease, and in rare cases this is particularly capillary CAA with dyshoric changes. METHODS: Six subjects with extensive capillary CAA with dyshoric changes, in addition to neurofibrillary tangles and in the absence of CJD pathology were found in a consecutive series of 225 clinically suspected CJD cases fulfilling criteria for possible or probable CJD clinical data and results of neuroimaging, electroencephalography and cerebrospinal fluid analysis were collected to assess what has led to the erroneous clinical diagnosis of CJD. RESULTS: All six patients had rapidly progressive dementia (mean 8.2 months, range 3-24). Four fulfilled criteria for 'probable' and one for 'possible CJD'. 14-3-3 Protein in CSF and/or EEG-findings supported the suspicion of CJD in five patients. DISCUSSION: Patients with a clinical suspicion of CJD, supported by EEG and/or CSF abnormalities can have severe capillary CAA with dyshoric changes in addition to the presence of neurofibrillary tangles. Possibly dyshoric capillary CAA can contribute to rapid clinical progression in dementia.

[Vaccinations in psychiatry]. / Vaccinaties in de psychiatrie.

BACKGROUND: Vaccination is a well-known strategy for preventing and treating infections. The purpose of vaccinations is to render antigens harmless by the production of antibodies. In psychiatry there are also situations where antigens that have been introduced from outside or that have developed during an illness constitute a threat to the patient's health. AIM: To explore the possible applications of vaccination in psychiatry. METHOD: In this article we discuss the applications of vaccination in psychiatry on the basis of two examples. RESULTS: In addiction research, trials are being conducted with antibodies against substances such as cocaine and nicotine in order to prevent such addictive substances from crossing the blood-brain barrier and thereby initiating their rewarding effect. The first clinical results are very promising, but vaccines have not yet been applied clinically. With regard to Alzheimer's disease it has been shown by means of animal models that specific antibodies can prevent AlphaBeta aggregation and dissolve existing aggregates. On the basis of these findings various large-scale clinical trials have begun in order to study immunotherapy for Alzheimer's disease. The first clinical results showed little neurocognitive effects. A wellknown study had to be terminated because of side-effects of the therapy, in the form of neuro-encephalitis. CONCLUSION: Our tentative conclusion is that the clinical application of immunotherapy in psychiatry still has its limitations, but is indeed promising.

Parental history of Alzheimer disease associated with lower plasma apolipoprotein E levels.

BACKGROUND: Variation in APOE genotype is a determinant of Alzheimer disease (AD), but the risk associated with variation in plasma apoE levels has yet to be determined. Here, we studied offspring with and without a parental history of AD to identify the effect of plasma apoE levels at middle age on the risk of late-onset AD. METHODS: Some 203 offspring from 92 families with a parental history of AD were compared with 197 offspring from 97 families without a parental history of AD. APOE genotypes and plasma apoE levels were assessed in all offspring. Difference in plasma apoE level between subjects with and without a parental history of AD was calculated using robust linear regression, both stratified and adjusted for APOE genotype. RESULTS: Offspring with a parental history of AD were more likely to be an APOE epsilon4 allele carrier (46% vs 21%, p < 0.001) than offspring without such a parental history. Mean plasma apoE levels strongly decreased from epsilon2 to epsilon3epsilon3 to epsilon4 carriers (p < 0.001). Offspring with a parental history of AD had lower plasma apoE levels than subjects without such a history, both in analyses adjusted for APOE genotype (difference: -0.21 mg/dL, p = 0.02) and when using standardized Z scores, when stratified for APOE genotype (difference: -0.22, p = 0.009). CONCLUSIONS: Our findings suggest that lower plasma apoE levels in middle age could be a risk factor for Alzheimer disease in old age, independent of APOE genotype.

[Old age psychiatry in the Netherlands]. / Ouderenpsychiatrie in Nederland.

In recent years there have been significant developments in psychiatry for the elderly in the Netherlands. Epidemiological research has widened its scope, collaborating with other disciplines and thereby creating a range of new perspectives. Patient care is shifting gradually to the general hospital and psychiatry for the elderly has a definite place in the curriculum for trainee psychiatrists. Increasingly, integrated care arrangements are becoming available for elderly psychiatric patients with handicaps. Psychiatry for the elderly has obtained a firm foothold in the Netherlands and should be able to participate in and benefit from the developments that are expected in the years to come.

Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.

The impact of apolipoprotein E on dementia in persons with Down's syndrome.

Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE epsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE epsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.

Rab6 is increased in Alzheimer's disease brain and correlates with endoplasmic reticulum stress.

Alzheimer's disease (AD) is characterized by deposits of aggregated proteins. Accumulation of aggregation-prone proteins activates protein quality control mechanisms, such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER). We previously reported upregulation of the UPR marker BiP in AD brain. In this study, we investigated the small GTPase Rab6, which is involved in retrograde Golgi-ER trafficking and may function as a post-ER quality control system. Using immunohistochemistry and semiquantitative Western blotting, the expression of Rab6 was analysed in hippocampus, entorhinal and temporal cortex of 10 AD patients and six nondemented control subjects. Rab6 is upregulated in AD temporal cortex from Braak stage 3/4, the same stage that UPR activation is found. We observe increased neuronal Rab6 immunoreactivity in all brain areas examined. Although some neurones show colocalization of immunoreactivity for Rab6 and hyperphosphorylated tau, strong Rab6 staining does not colocalize with tangles. We find a highly significant correlation between the Rab6 and BiP levels. In vitro data show that Rab6 is not upregulated as a result of UPR activation or proteasome inhibition indicating an independent regulatory mechanism. Our data suggest that ER and post-ER protein quality control mechanisms are activated early in the pathology of AD.

Activation of the unfolded protein response in Parkinson's disease.

Parkinson's disease (PD) is, at the neuropathological level, characterized by the accumulation of misfolded proteins. The presence of misfolded proteins can trigger a cellular stress response in the endoplasmic reticulum (ER) called the Unfolded Protein Response (UPR). The UPR has been shown to be involved in cellular models for PD. In this study, we investigated UPR activation in the substantia nigra of control and PD patients. Immunoreactivity for the UPR activation markers phosphorylated pancreatic ER kinase (pPERK) and phosphorylated eukaryotic initiation factor 2alpha (peIF2alpha) is detected in neuromelanin containing dopaminergic neurons in the substantia nigra of PD cases but not in control cases. In addition, pPERK immunoreactivity is colocalized with increased alpha-synuclein immunoreactivity in dopaminergic neurons. These data show that the UPR is activated in PD and that UPR activation is closely associated with the accumulation and aggregation of alpha-synuclein.

The significance of neuroinflammation in understanding Alzheimer's disease.

The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.