Dag S. Halvorsen

Co-morbidity and drug treatment in Alzheimer's disease. A cross sectional study of participants in the Dementia Study in Northern Norway

BackgroundInappropriate medical treatment of co-morbidities in Alzheimers disease (AD) is an increasing concern in geriatric medicine. The objective of this study was to compare current drug use related to co-morbidity between individuals with a recent diagnosis of AD and a cognitively healthy control group in a population based clinical trial in Northern Norway.MethodsSetting: Nine rural municipalities with 70 000 inhabitants in Northern Norway.Participants: Participants with and without AD recruited in general practice and by population based screening.187 participants with a recent diagnosis of AD were recruited among community dwellers. Of 791 respondents without cognitive symptoms, 500 were randomly selected and invited to further clinical and cognitive testing. The final control group consisted of 200 cognitively healthy individuals from the same municipalities. Demographic characteristics, data on medical history and current medication were included, and a physical and cognitive examination was performed. The statistical analyses were carried out by independent sample t-test, chi-square, ANCOVA and logistic regression.ResultsA co-morbidity score was significantly higher in AD participants compared to controls. The mean number of drugs was higher for AD participants compared to controls (5.1 ± 3.6 and 2.9 ± 2.4 respectively, p < 0.001 age and gender adjusted), also when adjusted for co-morbidity. AD participants used significantly more anticholinergic, sedative and antidepressant drugs. For nursing home residents with AD the mean number of drugs was significantly higher compared to AD participants living at home (6.9 ± 3.9 and 4.5 ± 3.3, respectively, p < 0.001).ConclusionsAD participants were treated with a significantly higher number of drugs as compared to cognitively healthy controls, even after adjustment for co-morbidity. An inappropriate use of anticholinergic and sedative drugs was identified, especially among nursing home residents with AD. The drug burden and the increased risk of adverse reactions among individuals suffering from AD need more attention from prescribing doctors.

Retention of phagocytic functions in cryopreserved human monocytes.

Phagocytosis and respiratory burst activity were measured by flow cytometry in fresh and cryopreserved human monocytes, after ingestion of Escherichia coli and Staphylococcus aureus. Mononuclear leukocytes, isolated from 15 healthy donors, were divided into two portions, of which one was examined immediately and the other was cryopreserved for 3 weeks. Morphological characteristics and expression of receptors involved in phagocytosis were similar in fresh and cryopreserved monocytes. Furthermore, both internalization of bacteria and respiratory burst activity remained unchanged after cryopreservation. Transmission electron microscopy confirmed actual internalization of bacteria and not merely bacterial attachment to monocytes. Monocytes were demonstrated to retain integral cellular functions during cryopreservation. This may imply that the method has potential for use in basal and clinical trials. J. Leukoc. Biol. 57: 235–241; 1995.

The Association between Inflammatory Markers and Carotid Atherosclerosis Is Sex Dependent: the Tromsø Study

Background: The presence of echolucent artery plaques is associated with increased risk of cardiovascular events as compared to echogenic plaques. Whether inflammatory markers are associated with carotid plaque morphology is questioned. Methods: 5,341 individuals were examined with ultrasonography of the right carotid artery. Of these, 3,205 had carotid plaque(s), in whom plaque area (mm2) and plaque echogenicity, expressed as the computer-assisted gray scale median (GSM), were determined. White blood cell count (WBC), fibrinogen and C-reactive protein (CRP) were analyzed, as well as other cardiovascular risk factors. In multiple linear and logistic regression models, we determined the relationship between plaque area and echogenicity, and inflammatory markers. Results: Women and men with carotid plaque(s) had significantly elevated levels of WBC and fibrinogen, but not CRP, as compared to subjects without plaques. All inflammatory markers were significantly associated with plaque area in men. WBC was significantly associated with plaque echogenicity in women, whereas no association was found between fibrinogen and CRP and plaque echogenicity in either gender. Conclusions: This cross-sectional study showed sex-dependent differences in associations between measures of carotid atherosclerosis and inflammatory markers. CRP did not discriminate echolucent from echogenic carotid plaques in either gender. Our data highlight the importance of sex-specific analyses in future studies.

Effects of Insulin-Like Growth Factor 1 on Neutrophil and Monocyte Functions in Normal and Septic States:

BACKGROUND Insulin-like growth factor 1 (IGF-1) mediates anabolic actions in catabolic states and also influences the immune system. Endogenous IGF-1 production is suppressed in sepsis; replacement therapy is therefore a natural approach to obtain the protein anabolic and potentially immune-stimulating effects of IGF-1. METHODS Twenty-two piglets were randomized to three groups: an IGF-1 group (n = 8) receiving a continuous infusion of 1.3 mg/h of IGF-1, a nontreated septic control group (n = 8), and a nonseptic control group (n = 6) receiving saline. Phagocytosis and respiratory burst in porcine neutrophils were evaluated by flow cytometry (FCM); tumor necrosis factor (TNF) levels were measured in serum during the septic period. In addition, human neutrophils and monocytes were primed in vitro with IGF-1 and subsequently were stimulated with phorbol myristate acetate (PMA) or Escherichia coli; phagocytosis and respiratory burst were evaluated by FCM. RESULTS Under nonseptic conditions, pretreatment with IGF-1 suppressed the ability of neutrophils to ingest bacteria (ie, the level of phagocytosis) 43.4% +/- 2.7% (IGF-1-treated) vs 55.8% +/- 3.4% (nontreated septic controls) and 57.3% +/- 3.34% (nonseptic controls) (p = .01). When challenged by live E. coli infusion, phagocytosis increased in the IGF-1 group to the levels of the nontreated group. The respiratory burst showed a convincing priming effect of IGF-1. After 4 hours of sepsis, the mean fluorescence intensity was 63.1 +/- 6.9 in the IGF-1 group and 40.7 +/- 3.0 in nontreated septic controls. The serum levels of TNF-alpha in the nontreated septic control group were twice those in the IGF-1-treated group, ie, 65.7 +/- 13.1 pg/mL in the nontreated septic controls and 31.5 +/- 7.5 pg/mL in the IGF-1 group (p = .03). In vitro priming of human neutrophils and monocytes with IGF-1 and subsequent stimulation with PMA or E. coli demonstrated that IGF-1 enhanced both phagocytosis and respiratory burst. CONCLUSIONS IGF-1 serves as a priming agent for biologic functions of leukocytes.

Chlamydophila pneumoniae diagnostics : importance of methodology in relation to timing of sampling

The diagnostic impact of PCR-based detection was compared to single-serum IgM antibody measurement and IgG antibody seroconversion during an outbreak of Chlamydophila pneumoniae in a military community. Nasopharyngeal swabs for PCR-based detection, and serum, were obtained from 127 conscripts during the outbreak. Serum, drawn many months before the outbreak, provided the baseline antibody status. C. pneumoniae IgM and IgG antibodies were assayed using microimmunofluorescence (MIF), enzyme immunoassay (EIA) and recombinant ELISA (rELISA). Two reference standard tests were applied: (i) C. pneumoniae PCR; and (ii) assay of C. pneumoniae IgM antibodies, defined as positive if >or=2 IgM antibody assays (i.e. rELISA with MIF and/or EIA) were positive. In 33 subjects, of whom two tested negative according to IgM antibody assays and IgG seroconversion, C. pneumoniae DNA was detected by PCR. The sensitivities were 79%, 85%, 88% and 68%, respectively, and the specificities were 86%, 84%, 78% and 93%, respectively, for MIF IgM, EIA IgM, rELISA IgM and PCR. In two subjects, acute infection was diagnosed on the basis of IgG antibody seroconversion alone. The sensitivity of PCR detection was lower than that of any IgM antibody assay. This may be explained by the late sampling, or clearance of the organism following antibiotic treatment. The results of assay evaluation studies are affected not only by the choice of reference standard tests, but also by the timing of sampling for the different test principles used. On the basis of these findings, a combination of nasopharyngeal swabbing for PCR detection and specific single-serum IgM measurement is recommended in cases of acute respiratory C. pneumoniae infection.

Immunodeficiency in alpha-mannosidosis : a matched case-control study on immunoglobulins, complement factors, receptor density, phagocytosis and intracellular killing in leucocytes

Abstract Patients with the autosomal recessive lysosomal storage disease alpha-mannosidosis suffer from recurrent infections. To study the mechanisms of this immunodeficiency, six patients were matched against six healthy controls and their humoral and cellular immunocompetence investigated. No differences in the number of circulating leucocytes including B-cells, levels of immunoglobulin main classes, nor IgG subclasses were observed. However, post-immunisation serum levels of specific antibodies against poliovirus, diphtheria toxin and tetanus toxin were significantly reduced. In patients, the density of the complement-binding receptor CD11b and the Fc-receptor CD16 was significantly enhanced on monocytes and polymorphonuclear neutrophils (PMN) and the number of phagocytosing PMN was significantly increased in the presence of pooled human serum. This was not observed in the presence of autologous serum, indicating altered opsonic properties. Also in normal PMN, phagocytosis was inhibited by a factor in the serum from the patients. Despite maintained oxidative burst, patient PMN demonstrated insufficient intracellular bacterial killing. Conclusion Our data indicate that patients with alpha-mannosidosis have an immunodeficiency at both the humoral and cellular level.

Recruitment methods in Alzheimer's disease research: general practice versus population based screening by mail

BackgroundIn Alzheimers disease (AD) research patients are usually recruited from clinical practice, memory clinics or nursing homes. Lack of standardised inclusion and diagnostic criteria is a major concern in current AD studies. The aim of the study was to explore whether patient characteristics differ between study samples recruited from general practice and from a population based screening by mail within the same geographic areas in rural Northern Norway.MethodsAn interventional study in nine municipalities with 70000 inhabitants was designed. Patients were recruited from general practice or by population based screening of cognitive function by mail. We sent a questionnaire to 11807 individuals ≥ 65 years of age of whom 3767 responded. Among these, 438 individuals whose answers raised a suspicion of cognitive impairment were invited to an extended cognitive and clinical examination. Descriptive statistics, chi-square, independent sample t-test and analyses of covariance adjusted for possible confounders were used.ResultsThe final study samples included 100 patients recruited by screening and 87 from general practice. Screening through mail recruited younger and more self-reliant male patients with a higher MMSE sum score, whereas older women with more severe cognitive impairment were recruited from general practice. Adjustment for age did not alter the statistically significant differences of cognitive function, self-reliance and gender distribution between patients recruited by screening and from general practice.ConclusionsDifferent recruitment procedures of individuals with cognitive impairment provided study samples with different demographic characteristics. Initial cognitive screening by mail, preceding extended cognitive testing and clinical examination may be a suitable recruitment strategy in studies of early stage AD.Clinical RegistrationClinicalTrial.gov Identifier: NCT00443014

Detection of diphtheria antitoxin by four different methods

OBJECTIVE To investigate the reliability of the different methods used in Norway and Russia for detection of diphtheria antitoxin. METHODS One hundred and twenty-two sera were selected among Russian serum samples previously collected for seroepidemiologic studies of diphtheria antitoxin. The sera were selected to cover the total antitoxin range and were analyzed by four different antidiphtheria toxin assays: an in vitro toxin neutralization test using Vero cells (in vitro NT), an in vivo neutralization test using rabbit skin inoculation (in vivo NT), an indirect enzyme immunoassay (EIA) and a passive hemagglutination assay (PHA). The results were expressed according to the international standard as: not protected (<0.01 IU/mL), relatively protected (0.01-0.1 IU/mL) or protected (≥0.1 IU/mL). The sensitivity, specificity and inter-rater agreement (K or Kw) of each method were related to the in vitro NT selected as the reference method. RESULTS The in vivo NT test corresponded very well with the in vitro NT in its ability to differentiate between protection/relative protection and no protection (sensitivity 97%, specificity 87% and K=0.84). The EIA test showed a high sensitivity (96%), but since many sera were categorized as protected rather than not protected, the specificity (30%) and inter-rater agreement (K=0.29) were low. The PHA test had a very high specificity (100%) but a low sensitivity (86%). CONCLUSIONS The agreement between the two neutralization tests was high. If none of the neutralization assays is routinely available, the PHA test can be used to predict the need for vaccination on an individual basis but should not be used for seroepidemiologic studies, since the protection rate for diphtheria would be falsely too low, due to the lower sensitivity. The indirect EIA test used in this study should not be used routinely.

Immunity to diphtheria among children in Northern Norway and North-Western Russia

In 1990, diphtheria re-emerged in Russia and during the following four-year period the resulting epidemic reached all the Newly Independent States (NIS) of the former Soviet Union. Several neighbouring countries of NIS, Norway included, have experienced sporadic imported cases. A sero-epidemiological study among children in Northern Norway and North-Western Russia was performed in order to evaluate protection against diphtheria and how differences in vaccination programmes affect immunity. A total of 664 sera, 400 from Norwegian and 264 from Russian children, were examined for antibodies against diphtheria, using an in vitro toxin neutralisation method. The Russian children studied had satisfactory protection in all age groups examined. The Norwegian children had poor protection against diphtheria from the age of 7 years until they received the booster dose at the age of 11. Therefore, a revision of the Norwegian vaccination programme, including a booster dose at school-entry age, seems warranted.

The effect of stimulation therapy and donepezil on cognitive function in Alzheimer's disease. A community based RCT with a two-by-two factorial design.

BackgroundProgressive neurodegeneration in Alzheimer’s disease (AD) induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD.MethodDesign: A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added.Setting: Nine rural municipalities in Northern Norway.Participants: 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one-year follow-up. INTERVENTIONS: In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period.Main outcome: Changes in MMSE sum score.Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test.ResultsMMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo.ConclusionIn rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results.Trial registrationClinicalTrials.gov (Identifier: NCT00443014). EudraCT database (no 2004-002613-37).