Biomedical subjects

Piet Eikelenboom

Publications and source records attributed to Piet Eikelenboom.

At least 19 recordsLinked to original sources

PubMed2007

Microglia activation in sepsis: a case-control study.

BACKGROUND: Infection induces an acute phase response that is accompanied by non-specific symptoms collectively named sickness behavior. Recent observations suggest that microglial cells play a role in mediating behavioral changes in systemic infections. In animal models for sepsis it has been shown that after inducing lipopolysaccharide, LPS, microglia in the brain were activated. The aim of this study was to investigate whether activation of microglia can be detected in patients who died of sepsis. METHODS: In a case-control study brain tissue of 13 patients who died with sepsis was compared with that of 17 controls. Activated microglia were identified by expression of MHC-class II antigens and CD68. Microglia activation was analyzed by a semiquantitative score combining both the number of the immunoreactive cells and their morphology. RESULTS: In patients who died with sepsis there was a significant increase in activated microglia in the grey matter when stained with CD68 compared to controls. This effect was independent of the effect of age. CONCLUSION: This study shows for the first time in human brain tissue an association between a systemic infection and activation of microglia in the brain. Activated microglia during sepsis could play a role in behavioral changes associated with systemic infection.

Adult↗

PubMed2006

The unfolded protein response affects neuronal cell cycle protein expression: implications for Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is 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). Previously, we have shown that the UPR is activated in AD neurons. In actively dividing cells, activation of the UPR is accompanied by decreased cell cycle protein expression and an arrest in the G1 phase of the cell cycle. Aberrant expression of cell cycle proteins has been observed in post mitotic neurons in AD and is suggested to be involved in neurodegeneration. In this study we show that the protein levels of BiP/GRP78, an ER-stress marker, is increased in Braak stages B and C for amyloid deposits. This is in contrast to the levels of cell cycle markers cyclin D1, cyclin E and phosphorylated retinoblastoma protein (ppRb) which are decreased in Braak stage C compared to Braak stage A for amyloid deposits. In addition, we report a negative correlation between neuronal expression of ppRb and expression levels of BiP/GRP78 in control and AD cases. Activation of the UPR in neuronal cells induces changes in cell cycle protein expression similar to these observed in AD brain. ER stress inducers tunicamycin and thapsigargin down-regulate cell cycle proteins ppRb and cyclin D1 in differentiated neuroblastoma cells. In contrast, protein levels of p27, a cyclin dependent kinase inhibitor, are increased after induction of ER-stress using tunicamycin. These data suggest that activation of the UPR affects cell cycle protein expression in neurons during neurodegeneration in AD.

Alzheimer Disease↗

PubMed2006

Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation.

Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit microglial activation. In Alzheimer's disease brain, a number of proteins, including serum amyloid P component (SAP) and complement factors such as C1q, accumulate in amyloid beta (Abeta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in Abeta plaques. Furthermore, SAP and C1q enhanced Abeta fibril formation and Abeta mediated cytokine release by human microglia in vitro. In the present study, we report that tetracycline and minocycline dose-dependently reduce TNF-alpha and IL-6 release by adult human microglia upon stimulation with a combination of Abeta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of Abeta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with Abeta alone as well as with Abeta in combination with SAP and C1q. Our data suggest that minocycline and tetracycline at tolerable doses can inhibit human microglial activation. This activity in part is exerted by inhibition of (SAP and C1q enhanced) Abeta fibril formation.

Amyloid beta-Peptides↗

PubMed2006

Risk factors and prediction of postoperative delirium in elderly hip-surgery patients: implementation and validation of a medical risk factor model.

OBJECTIVES: To evaluate risk factors for postoperative delirium in a cohort of elderly hip-surgery patients and to validate a medical risk stratification model. DESIGN: Prospective cohort study. SETTING: Medical school-affiliated general hospital in Alkmaar, the Netherlands. PARTICIPANTS: Six hundred three hip-surgery patients aged 70 and older screened for risk factors for postoperative delirium. MEASUREMENTS: Predefined risk factors for delirium were assessed on admission. One point was assigned for each of four risk factors present, resulting in three groups: low, intermediate, and high risk. Baseline screening and assessment included the Mini-Mental State Examination, the standardized Snellen test for visual impairment, chart review to determine Acute Physiological and Chronic Health Evaluation II score, and blood urea nitrogen to creatinine ratio. The primary outcome was postoperative delirium, as defined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Confusion Assessment Method criteria. All patients were screened daily for delirium. RESULTS: Incidence of delirium was 3.8% in the low-risk group (P<.001), 11.1% in the intermediate-risk group (P=.27, relative risk (RR)=3.0), and 37.1% in the high-risk group (P<.001, RR=9.8). Cognitive impairment at admission had the highest predictive value for postoperative delirium (coefficient of determination=0.15). Contrary to previous findings, age was an independent predictive factor for delirium. Moreover, postoperative delirium was four times as frequent in acute patients as in elective hip-replacement patients. CONCLUSION: The medical risk factor model is valid for elderly hip-surgery patients. Cognitive impairment, age, and type of admission are important risk factors for delirium in this surgical population.

Age Factors↗

PubMed2005

Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease.

Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0-II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD.

Journal Article↗

PubMed2005

Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study.

OBJECTIVES: To study the effectiveness of haloperidol prophylaxis on incidence, severity, and duration of postoperative delirium in elderly hip-surgery patients at risk for delirium. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Large medical school-affiliated general hospital in Alkmaar, The Netherlands. PARTICIPANTS: A total of 430 hip-surgery patients aged 70 and older at risk for postoperative delirium. INTERVENTION: Haloperidol 1.5 mg/d or placebo was started preoperatively and continued for up to 3 days postoperatively. Proactive geriatric consultation was provided for all randomized patients. MEASUREMENTS: The primary outcome was the incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Confusion Assessment Method criteria). Secondary outcomes were the severity of delirium (Delirium Rating Scale, revised version-98 (DRS-R-98)), the duration of delirium, and the length of hospital stay. RESULTS: The overall incidence of postoperative delirium was 15.8%. The percentage of patients with postoperative delirium in the haloperidol and placebo treatment condition was 15.1% and 16.5%, respectively (relative risk=0.91, 95% confidence interval (CI)=0.6-1.3); the mean highest DRS-R-98 score+/-standard deviation was 14.4+/-3.4 and 18.4+/-4.3, respectively (mean difference 4.0, 95% CI=2.0-5.8; P<.001); delirium duration was 5.4 versus 11.8 days, respectively (mean difference 6.4 days, 95% CI=4.0-8.0; P<.001); and the mean number of days in the hospital was 17.1+/-11.1 and 22.6+/-16.7, respectively (mean difference 5.5 days, 95% CI=1.4-2.3; P<.001). No haloperidol-related side effects were noted. CONCLUSION: Low-dose haloperidol prophylactic treatment demonstrated no efficacy in reducing the incidence of postoperative delirium. It did have a positive effect on the severity and duration of delirium. Moreover, haloperidol reduced the number of days patients stayed in the hospital, and the therapy was well tolerated.

Aged↗

PubMed2005

The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications.

The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.

Alzheimer Disease↗

PubMed2004

Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process.

Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia in a process that required cell-cell contact. Pre-treating microglia with polyclonal antibodies to the CD14 protein, or treating neurons exposed to amyloid-beta1-42 with a CD14-IgG chimera, prevented the killing of amyloid-beta1-42 damaged neurons by microglia. Moreover, microglia from CD14 null mice failed to kill amyloid-beta1-42 damaged neurons. Increased neuronal survival was accompanied by a significant reduction in the production of interleukin-6 indicative of reduced microglial activation. These results indicate an important role for CD14 in the recognition and subsequent killing of amyloid-beta damaged neurons by microglia.

Amyloid beta-Peptides↗

PubMed2004

Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study.

INTRODUCTION: Short-term randomised clinical trials on valproate in distinct types of disturbed behaviour in dementia showed no effects on aggressive behaviour. OBJECTIVES: To assess the course of disturbed behaviour during medium term treatment with sodium valproate for aggressive behaviour. DESIGN: An open label observational 12-week follow-up study consecutive to a preceding randomised control trial; assessments at 4-week interval. SETTING: A psychogeriatric medium-stay ward at a psychiatric teaching hospital and psychogeriatric nursing home wards. PARTICIPANTS: Patients who completed a preceding randomised placebo controlled clinical trial on sodium valproate in aggressive behaviour in dementia were included. INTERVENTION: The starting dose of sodium valproate was 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg). The patient's regular physicians managed all treatment decisions, including decisions on dosage and plasma level measurements of sodium valproate and decisions regarding discontinuation. Co-medication was allowed and any change in prescription was recorded. MEASUREMENTS: The Social Dysfunction and Aggression Scale-9 (SDAS-9), the Behaviour Observation scales for Intramural Psychogeriatrics (in Dutch: Gedragsobservatieschaal voor Intramurale Psychogeriatrie (GIP) and the Clinical Global Impression of aggressive behaviour (CGI) were performed at the last week of each 4-week interval. RESULTS: Data of 39 patients (F=24 and M=15) were analysed. At week 12 compared to week 0 mean sodium valproate prescriptions were higher; aggressive behaviour as measured by the SDAS-9 improved. Non-social behaviour, apathetic behaviour, disoriented behaviour and distorted memory improved, but rebellious behaviour increased as measured by the GIP. Seven patients died during this study. LIMITATIONS OF THE STUDY: Open label observational design; absence of placebo/reference prescription; no systematic measurements of sodium valproate plasma levels and the allowance of psychotropic co-medication. CONCLUSION: Low dose sodium valproate may be effective reducing a broad range of types of disturbed behaviours in aggressive demented patients. The high death rate underlines the fragility of demented patients with aggressive behaviour.

Aged↗

PubMed2004

Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex.

In Alzheimer's disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In this study, we show that neuronal immunoreactivity for phosphorylated p38 MAPK does not correlate with COX-2 or phosphorylated pRb (ppRb) in control and AD temporal cortex. Immunoreactivity for activated p38 MAPK co-localizes with AT8 immunoreactivity and increases with the occurrence of neurofibrillary tangles and plaques. On the other hand, COX-2 immunoreactivity co-localizes and correlates with ppRb immunoreactivity in pyramidal neurons. COX-2 and ppRb do not co-localize with AT8 and decrease with increasing pathology. These results suggest that p38 MAPK does not mediate COX-2 expression and pRb inactivation, which are involved in cellular changes in pyramidal neurons early in AD pathogenesis.

Aged↗

PubMed2004

How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes.

A huge amount of evidence has implicated amyloid beta (A beta) peptides and other derivatives of the amyloid precursor protein (beta APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-alpha or interleukin-1 beta can then in combination with interferon-gamma be toxic on neurons and affect the metabolism of beta APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of A beta can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

Aging↗

PubMed2003

Neurones treated with cyclo-oxygenase-1 inhibitors are resistant to amyloid-beta1-42.

Epidemiological studies have shown that the risk of developing Alzheimer's disease is reduced by the chronic use of classical non-steroidal anti-inflammatory drugs (NSAIDs), drugs that inhibit the cyclo-oxygenase (COX) enzymes that convert arachidonic acid to prostaglandins. In the present study, human SH-SY5Y neuroblastoma cells or murine primary cortical neurones treated with NSAIDs were protected against the otherwise toxic effects of amyloid-beta1-42. COX-1 selective inhibitors provided greater protection than did COX-2 selective inhibitors or lipoxygenase inhibitors, suggesting that activation of COX-1 is required for amyloid-beta1-42-induced neurotoxicity. Although the production of neuronal prostaglandin E2 in response to amyloid-beta1-42 was reduced by the presence of COX-1 inhibitors, no neurotoxic effects of prostaglandin E2, or any other prostaglandin, were observed.

Alzheimer Disease↗

PubMed2003

Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease.

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.

Alzheimer Disease↗

PubMed2002

Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro.

Pro-inflammatory cytokines released by activated microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Abeta deposits is related to microglial activation. Activated microglia accumulate in SAP- and C1q-immunoreactive fibrillar amyloid beta (Abeta) plaques in AD temporal cortex. No clustered microglia are seen in SAP- and C1q-positive circumscript, non-fibrillar, tau-negative Abeta plaques in AD caudate nucleus and non-demented control temporal cortex. In addition, no clustered microglia were observed in C1q- and SAP-negative, irregular shaped, diffuse plaques in AD caudate nucleus and in non-demented control temporal cortex, which suggests that microglia are attracted and activated in Abeta deposits of certain fibrillarity that, in addition, have fixed SAP and C1q. Therefore, the effects of Abeta(1-42), SAP and C1q on cytokine secretion by human postmortem microglia in vitro were assessed. Abeta(1-42) alone had little to no effect. Abeta(1-42) peptides in combination with C1q or C1q and SAP increased microglial interleukin (IL)-6 secretion four- and eightfold, respectively. Tumor necrosis factor (TNF)-alpha, as well as intracellular IL-1alpha and IL-1beta levels, also increased upon exposure of microglia to Abeta(1-42)-SAP-C1q complexes. Combined with earlier findings, that amyloid and activated microglia accumulate at a relatively early stage of cognitive decline in AD patients, this suggests that clustering of activated, cytokine-secreting microglia in SAP- and C1q-containing Abeta deposits precedes neurodegenerative changes in AD, and thus may provide a "therapeutic window".

Adult↗

PubMed2002

The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease.

Microglial cyclo-oxygenase (COX) expression is considered to be important in the pathogenesis of Alzheimer's disease (AD) and, therefore, constitutes a key target for therapeutic intervention. We investigated the influence of AD plaque associated factors on COX-1 and COX-2 expression and activity in adult human microglial cells in vitro. COX-2 immunoreactivity and mRNA were induced by lipopolysaccharide (LPS), not by AD plaque associated cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, or amyloid (A)beta(1-42). To assess functional COX activity, the release of PGE(2) into the culture medium was determined. LPS and also arachidonic acid (AA) dose-dependently stimulated PGE(2) release. The effects of AA are independent from induction of COX mRNA expression, or of de novo protein synthesis. No effects of either plaque-associated cytokines or Abeta(1-42) on PGE(2) secretion were seen, even when cells were co-stimulated with AA, to provide enough substrate. COX isotype selective inhibitors were used to discern relative contributions of COX-1 and COX-2 activities to microglial PGE(2) secretion. COX-2 and in part COX-1-selective inhibitors inhibited LPS-induced PGE(2) secretion, whereas the AA-induced PGE(2) secretion was reduced by COX-1-selective inhibitors only. Apparently, adult human microglia in vitro (1) constitutively express COX-1, and (2) do not express COX-2 upon exposure to either Abeta or plaque associated cytokines. In the light of microglial COX activity as a potential therapeutical target in AD, the data presented in this study suggest that classical NSAIDs, rather than selective COX-2 inhibitors, are more potent in reducing microglial prostaglandin secretion.

Adult↗

PubMed2002

Adult human microglia secrete cytokines when exposed to neurotoxic prion protein peptide: no intermediary role for prostaglandin E2.

Prion diseases are characterized by accumulation of protease resistant isoforms of prion protein (termed PrP(SC)), glial activation and neurodegeneration. The time course of PrP deposition, appearance of activated microglia, and of neuronal apoptosis in experimentally-induced prion disease suggests that microglial activation precedes the process of neuronal loss. Activated microglia and inflammatory mediators, including cytokines and prostaglandin E2 (PGE2) co-localize with PrP deposits. In vitro, mouse microglia secrete neurotoxic agents and interleukins (IL)-1 and IL-6, when exposed to synthetic peptides representing the neurotoxic fragment of PrP. In this study, adult human microglia were found to secrete IL-6 and TNF-alpha upon exposure to synthetic fibrillar PrP105-132, the putative transmembrane domain of PrP. Little cytokine release occurred following exposure of microglia to C-terminally amidated, nonfibrillar PrP105-132, suggesting that the degree of fibrillarity of PrP peptides affects their biological properties. Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to exert beneficial effects in neurodegenerative disorders through suppressive effects on microglial activation and on cyclooxygenase (COX) activity. Since microglial COX-2 expression and PGE(2) synthesis are increased in human and experimental prion diseases, we investigated the effects of the NSAIDs indomethacin and BF389, an experimental COX-2 selective inhibitor, on the PrP105-132-induced microglial IL-6 and TNF-alpha synthesis in vitro. No inhibitory effects of the NSAIDs were observed. Furthermore, PrP105-132 did not stimulate microglial PGE(2) synthesis. We conclude that, unlike IL-1beta-induced IL-6 synthesis in astrocytes, the PrP-induced IL-6 synthesis in human adult microglia is not PGE2 mediated.

Adult↗

PubMed2002

Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial.

OBJECTIVES: The efficacy and tolerability of sodium valproate 2 x 240 mg compared to placebo were investigated in aggressive behavior in dementia. DESIGN: A randomized, placebo controlled, double-blind cross-over design. The trial included a baseline period (one week); a placebo period (three weeks); a wash-out period with placebo (one week); and a treatment period with sodium valproate (three weeks). SETTING: A psychogeriatric short-stay ward at a psychiatric teaching hospital. PARTICIPANTS: Demented patients who met Patel's criteria for aggressive behavior and had a score of > or =3 on at least one of the items of the Social Dysfunction and Aggression scale-9 (SDAS-9). INTERVENTION: A fixed dose of sodium valproate 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg) was compared to placebo. MEASUREMENTS: Primary outcome variables were changes of the score of SDAS-9 and Clinical Global Impression scale (CGI) performed at the last week of each treatment period. RESULTS: Data of 42 patients (F=25 and M=17; age 80.4+/-6.8 years) were analyzed. Treatment with sodium valproate showed no differences compared to placebo on aggressive behavior. The mean plasma level of sodium valproate was 40.9+/-10.8 microg/ml. Regression analysis showed a trend for improvement between the plasma levels of sodium valproate and the SDAS-9 and the CGI scores. Adverse events were not related to the plasma levels of sodium valproate. Secondary outcome measurements showed significant improvement on restless, melancholic and anxious behavior; a trend for improvement was found on suspicious and dependent behavior. Possible limitations of this study are the low dose of sodium valproate, the relatively short treatment period (three weeks), and the absence of statistical corrections for multiple comparisons. CONCLUSION: This study showed no effect of sodium valproate 2 x 240 mg over placebo on aggressive behavior in dementia.

Aged↗

PubMed2002

Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex.

Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the progression of several diseases, including colon cancer, lung cancer, breast cancer and Alzheimer disease (AD). Several studies have shown that NSAIDs can modulate cell cycle progression, especially in the G0/G1 phase. The main target of most NSAIDs is the enzyme cyclo-oxygenase (COX), which occurs in 2 isoforms, COX-1 and COX-2. In AD and non-demented control brain, COX-2 is expressed in neuronal cells. In this study the expression of COX-2, cyclin D1, and cyclin E was investigated at the immunohistochemical level in AD and non-demented control temporal cortex. COX-2, cyclin D1, and cyclin E expression was detected in pyramidal neurons in both AD and control patients. The number of COX-2-immunoreactive neurons positively correlated with the number of cyclin E- and cyclin D1-immunoreactive neurons. Moreover, immunostaining of sequential tissue sections and double immunofluorescence labeling revealed co-expression of COX-2 and cyclin D1 and E in neuronal cells. In addition, an inverse correlation was observed between the neuronal expression of COX-2 and cyclin E and the Braak score for amyloid beta deposits. Our findings suggest a relationship between the neuronal expression of COX-2 and cell cycle markers, which may be involved early in AD pathology.

Aged↗