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Biomedical subjects

P Eikelenboom

Publications and source records attributed to P Eikelenboom.

At least 19 recordsLinked to original sources
PubMed2006

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.

Alzheimer Disease↗
PubMed2006

Dementia and mortality in persons with Down's syndrome.

BACKGROUND: Numerous studies have documented that persons with Down's syndrome (DS) are at an increased risk of Alzheimer's disease (AD). However, at present it is still not clear whether or not all persons with DS will develop dementia as they reach old age. METHODS: We studied 506 people with DS, aged 45 years and above. A standardized assessment of cognitive, functional and physical status was repeated annually. If deterioration occurred, the patients were examined and the differential diagnosis of dementia was made according to the revised Dutch consensus protocol and according to the ICD-10 Symptom Checklist for Mental Disorders. We compared our findings with those reported in the literature. RESULTS: The overall prevalence of dementia was 16.8%. Up to the age of 60, the prevalence of dementia doubled with each 5-year interval. Up to the age of 49, the prevalence is 8.9%, from 50 to 54, it is 17.7%, and from 55 to 59, it is 32.1%. In the age category of 60 and above, there is a small decrease in prevalence of dementia to 25.6%. The lack of increase after the age of 60 may be explained by the increased mortality among elderly demented DS patients (44.4%) in comparison with non-demented patients (10.7%) who we observed during a 3.3-year follow-up. There was no decrease in incidence of dementia in the age group of 60 and above. Our findings are very similar to those published in the literature. Patients with dementia were more frequently treated with antiepileptic, antipsychotic and antidepressant drugs. The history of depression was strongly associated with dementia. CONCLUSIONS: Our study is one of the largest population-based studies to date. We found that despite the exponential increase in prevalence with age, the prevalence of dementia in the oldest persons with DS was not higher than 25.6%.

Aged↗
PubMed2006

Always around, never the same: pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease.

There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid beta (Abeta) in the pathogenic cascade of Alzheimer's disease (AD). Different Abeta assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Abeta oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Abeta on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Abeta in AD pathology. In later stages of AD pathology, the fibrillarity of Abeta increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Abeta peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Abeta species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies.

Alzheimer Disease↗
PubMed2006

[Late-onset schizophrenia: is it a dementia nonpraecox? Review article with advice on differential diagnosis].

BACKGROUND: For many years now researchers have been discussing whether late-onset schizophrenia (LOS) is in fact a separate subgroup of schizophrenia. They also want to find out whether LOS has a neurodegenerative aetiology and is a progressive illness. AIM: To obtain insight into the clinical aspects, aetiological factors and the course of late-onset schizophrenia. In addition, advice is given about better ways of diagnosing LOS in clinical practice and about differentiating LOS from dementia. METHOD: The literature was searched via Medline and the Cochrane Library on the basis of the key words '(very) late-onset schizophrenia' and 'paraphrenia' combined with 'course', 'outcome', 'cognition', 'decline', 'white matter hyperintensities', 'MRI', and 'neuropsychological', 'postmortem' and cerebrospinal fluid'. The period studied was from 1960 to November 2004. RESULTS: Clinical parameters andfunctional and structural brain research point to differences from and similarities to the early form of schizophrenia (EOS). In cases of 'very-late-onset schizophrenia-like psychosis' (VLOS) the clinical differences vis-à-vis EOS are even more marked. It is not known to what extent neurodegenerative factors play a role. There is no clear consensus about the course of (V)LOS either. CONCLUSION: In view of the aetiologial and physiopathological factors it is still not clear whether (V)LOS can be differentiated from EOS on a neurobiological basis. There is insufficient proof about the extent to which (V)LOS is a dementia nonpraecox with neurodegenerative aetiology. To achieve clear differentiation between the various forms of dementia it is essential that the clinical diagnosis of LOS is supported as strongly as possible and is evaluated continually.

Age of Onset↗
PubMed2006

[The development of psychotic symptoms in later life: late-onset schizophrenia or frontotemporal dementia? A case study].

The diagnosis of psychotic disorders that develop later in life is complicated, as can be seen from the case of a 65-year-old woman. Initially she was admitted to hospital for psychotic depression, but after some time doubts arose regarding the diagnosis. The most striking symptoms were bizarre delusions with acoustic, haptic and gustatory hallucinations. In addition, she showed behavioral and personality changes. It is difficult to establish whether a patient has late-onset schizophrenia or frontotemporal dementia. The similarities and differences between the symptoms of these two disorders are discussed and advice is given to assist with clinicians with diagnosis in the future.

Aged↗
PubMed2005

Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology.

The initial stages of Alzheimer's disease pathology in the neocortex show upregulation of cell cycle proteins, adhesion and inflammation related factors, indicating the early involvement of inflammatory and regenerating pathways in Alzheimer's disease pathogenesis. These brain changes precede the neurofibrillary pathology and the extensive process of neurodestruction and (astro)gliosis. Amyloid beta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mouse models harbouring the pathological Alzheimer's disease mutations, while neurodegenerative characteristics are not seen in these models. This review will discuss the relationship between neuroinflammation and neuroregeneration in the early stages of Alzheimer's disease pathogenesis.

Alzheimer Disease↗
PubMed2005

The unfolded protein response is activated in Alzheimer's disease.

Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

Adult↗
PubMed2005

Serum inflammatory proteins and cognitive decline in older persons.

OBJECTIVE: To assess whether serum levels of the inflammatory proteins alpha(1)-antichymotrypsin (ACT), C-reactive protein (CRP), interleukin-6 (IL-6), and albumin are associated with cognitive decline in older persons. METHODS: The study sample consisted of 1,284 participants in the Longitudinal Aging Study Amsterdam, aged 62 to 85 years. Cognition was assessed on general cognition (Mini-Mental State Examination [MMSE]), memory (Auditory Verbal Learning Test), fluid intelligence (Raven's Colored Progressive Matrices), and information-processing speed (Coding Task) at baseline and at 3-year follow-up. RESULTS: The highest tertile of ACT was associated with an increased risk of decline on the MMSE (age-, sex-, education-adjusted odds ratio [OR] 1.60; 95% CI: 1.05 to 2.43) but not on any other cognitive test score. CRP, IL-6, and albumin were not associated with cognitive decline on any cognitive test in our study. CONCLUSIONS: This population-based study showed that the serum inflammatory protein alpha1-antichymotrypsin is associated with cognitive decline in older persons, whereas C-reactive protein, interleukin-6, and albumin are not.

Aged↗
PubMed2003

Neuroinflammatory perspectives on the two faces of Alzheimer's disease.

The amyloid plaques in Alzheimer's disease (AD) brains are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that Abeta deposits in AD brains are closely associated with a locally induced, non-immune mediated, chronic inflammatory response. Clinicopathological and neuroradiological studies show that activation of microglia is a relatively early pathogenic event that precedes the process of neuropil destruction in AD. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins that are colocalized with Abeta plaques, are genetic risk factors of AD. Epidemiological studies have also shown that the use of classical nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent the risk of AD but clinical trials with anti-inflammatory drugs in AD patients were negative. These findings indicate that anti-inflammatory agents can be helpful in the prevention but not in the treatment of AD. So, pathological, genetic and therapeutic studies suggest that inflammatory mechanisms are most likely involved in the early steps of the pathological cascade. In the autosomal dominant inherited forms of AD the primary factor is the increased production of Abeta1-42 resulting into fibrillar Abeta deposition that elicits a brain inflammatory response. The etiology of the sporadic forms is yet unknown but this subtype is considered to be heterogeneous and multifactorial in its pathogenesis. Here we review the evidence that inflammation related events could be a critical etiological factor in certain forms of the sporadic AD.

Acute-Phase Reaction↗
PubMed2003

[Cholinergic deficiency syndrome as an indicator for the cholinesterase inhibitors].

Cholinesterase inhibitors are licensed for the treatment of dementia in Alzheimer's disease. In clinical practice, these drugs have little effect on the cognitive symptoms of dementia. Several studies report a beneficial effect of cholinesterase inhibitors on neuropsychiatric symptoms. We hypothesise that symptoms such as the impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome. It is postulated that this syndrome crosses boundaries of nosological entities and occurs in various neurodegenerative diseases. Symptoms resulting from cholinergic deficiency might be a much better target for treatment than cognitive deficits.

Acetylcholinesterase↗
PubMed2003

[Memantine for the treatment of dementia].

Problems in the Netherlands with respect to the reimbursement of memantine have led the patient organization 'Alzheimer Nederland' to establish an emergency fund. Several trials have documented the limited, but consistent beneficial effects of memantine in severely demented patients. It is not clear which subgroup of patients might benefit the most. The drug seems to have dopamimetic and antidepressant effects which might explain its overall effect. The publicity surrounding memantine contributes to an atmosphere in which patients and care providers have to explain why they are not yet using 'anti-dementia drugs'. This should be avoided. Patients can expect to gain more benefit from ongoing, thorough and independent investigations than from hastily established emergency funds to finance the use of a drug with a limited and poorly defined efficacy.

Dementia↗
PubMed2003

Anti-inflammatory therapy in Alzheimer's disease: is hope still alive?

Based on observations from neuropathology, epidemiology, and in vitro and animal experiments, the inflammatory component of Alzheimer's disease (AD) has been considered a compelling target for therapeutic intervention. However, a summary of all published trial reports to date suggests that AD patients do not benefit from treatment with anti-inflammatory drugs. In this brief review, we try to reconcile these sobering trial results with recent observations from basic research and epidemiology that continue to strengthen the idea that inflammatory mechanisms play an important role in the pathogenesis of AD. We review the possibilities that (1) not all components of the inflammatory response in AD are detrimental, (2) beneficial effects of anti-inflammatory drugs may not be mediated by inflammatory pathways, and (3) the timing of the intervention should be in the earliest stages of the pathogenesis of AD, perhaps even before the first symptoms emerge. We conclude that studies on primary prevention of AD are the logical next step in testing the inflammatory hypothesis of AD.

Alzheimer Disease↗
PubMed2002

[Novel therapeutic approach to amyloidosis: no implications as yet for patients with Alzheimer's disease].

Many disorders, such as Alzheimer's disease and diabetes, are characterised by the misfolding and aggregation of proteins. Pepys et al. described a new approach of destabilizing these aggregates by removing an associated protein, serum amyloid P. This offers opportunities for treating amyloidosis and possibly other protein folding diseases. Understanding the mechanism of this unique disease process and the different elements involved is necessary for future drug development.

Alzheimer Disease↗
PubMed2002

Neuroinflammation in Alzheimer's disease and prion disease.

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.

Acute-Phase Proteins↗
PubMed2002

CSF markers related to pathogenetic mechanisms in Alzheimer's disease.

Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity. Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Aged↗
PubMed2001

Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain.

Epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) lower the risk of developing Alzheimer's disease (AD). Most NSAIDs act upon local inflammatory events by inhibiting the expression or activation of cylooxygenase (COX). In the present study the expression of COX-1 and COX-2 in AD and non-demented control temporal and frontal cortex was investigated using immunohistochemistry. COX-1 expression was detected in microglial cells, while COX-2 expression was found in neuronal cells. In AD brains, COX-1-positive microglial cells were primarily associated with amyloid beta plaques, while the number of COX-2-positive neurons was increased compared to that in control brains. No COX expression was detected in astrocytes. In vitro, primary human microglial and astrocyte cultures, and human neuroblastoma cells (SK-N-SH) were found to secrete prostaglandin E2 (PGE2), especially when stimulated. PGE2 synthesis by astrocytes and SK-N-SH cells was stimulated by interleukin-1beta. Microglial cell PGE2 synthesis was stimulated by lipopolysaccharide only. Although astrocytes are used in studies in vitro to investigate the role of COX in AD, there are no indications that these cells express COX-1 or COX-2 in vivo. The different distribution patterns of COX-1 and COX-2 in AD could implicate that these enzymes are involved in different cellular processes in the pathogenesis of AD.

Aged↗
PubMed2001

Interleukin-1beta induced cyclooxygenase 2 expression and prostaglandin E2 secretion by human neuroblastoma cells: implications for Alzheimer's disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of developing Alzheimer's disease (AD). Cyclooxygenase 2 (COX-2), one of the targets of NSAIDs, is increasingly expressed in neuronal cells in AD brain. In this study, of the cytokines that are found at increased levels in AD brain (interleukin (IL)-1alpha, IL-1beta, IL-6 and tumour necrosis factor (TNF)alpha), IL-1beta was found to induce COX-2 immunoreactivity and prostaglandin (PG) E2 secretion by human neuroblastoma cell line SK-N-SH. COX inhibitors indomethacin and BF389, as well as the glucocorticoid dexamethasone (DEX) and pyrrolidinedithiocarbamate, which is an inhibitor of nuclear factor kappaB as well as a potent antioxidant, inhibited IL-1beta induced PGE2 secretion. In addition, DEX reduced the IL-1beta induced COX-2 immunoreactivity in the same concentration as wherein it inhibited PGE2 secretion. Palmitoyl trifluormethyl ketone, an inhibitor of Ca(2+) independent phospholipase A2 (iPLA2) and a less potent inhibitor of cytosolic PLA2, dose-dependently reduced the IL-1beta induced PGE2 secretion. This suggests that the IL-1beta induced PGE2 secretion may depend on the availability of arachidonic acid. Although the physiological role of neuronal COX-2 still remains unclear, we suggest an interplay between glial derived IL-1 and neuronal upregulation of COX-2 expression in chronic neurodegenerative diseases, such as AD.

Alzheimer Disease↗