Johan Fastbom

Vitamin B12 and folate in relation to the development of Alzheimer’s disease

Objective: To explore the associations of low serum levels of vitamin B12 and folate with AD occurrence. Methods: A population-based longitudinal study in Sweden, the Kungsholmen Project. A random sample of 370 nondemented persons, aged 75 years and older and not treated with B12 and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B12 (≤150 and ≤250 pmol/L) and folate (≤10 and ≤12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria. Results: When using B12 ≤150pmol/L and folate ≤10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B12 or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B12 or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L. Conclusions: This study suggests that vitamin B12 and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B12 and folate concentration in the elderly may be relevant for prevention of AD.

The Association of Inappropriate Drug Use with Hospitalisation and Mortality A Population-Based Study of the Very Old

Background and objectiveInappropriate prescribing is an important and possibly preventable risk factor for adverse drug reactions (ADRs) in the elderly, and hospital-based studies have shown that a large proportion of admissions is a result of ADRs. However, little is known about how inappropriate drug use (IDU) affects the elderly at the population level. The aim of this study was to explore possible associations of IDU with acute hospitalisation and mortality in an elderly population during 3 years of follow-up.Patients and methodsData from a rural, population-based, longitudinal cohort study within the Kungsholmen Project, Sweden, were used. 785 participants, ≥75 years of age, had complete data on drug use and selected covariates collected during baseline investigation from 1995 to 1998, and were included in the study. Hospitalisation and mortality data during 3 years after inclusion were collected. IDU was assessed at baseline using consensus-based criteria applicable to available data (derived from Beers’ criteria, Canadian criteria and clinical indicators of drug-related morbidity in older adults) with the addition of potentially dangerous drug duplication and additional potentially hazardous drug-drug interactions. IDU was defined as presence of at least one inappropriate drug regimen according to the study criteria. Logistic regression and proportional hazard models were used, respectively, to study the association of IDU with hospitalisation and mortality.ResultsDrugs were used on a regular or ‘as needed’ basis by 91.6% of the study population, with a mean of 4.4 drugs per person. IDU was common, with a prevalence of 18.6% and was associated with increased risk of at least one acute hospitalisation in community-living elderly, after adjustment for age, sex, education, comorbidity, dependency in activities of daily living (ADL) and smoking. The odds ratio was 2.72 (95% CI 1.64, 4.51). No association with mortality was found, after adjustment for age, sex, housing, education, comorbidity, ADL-dependency, smoking and body mass index.ConclusionPolypharmacy and IDU are common among the elderly and IDU is associated with acute hospitalisation in community-living elderly. Although causality cannot be established with this study design, the results are consistent with the high prevalence of drug-related hospital admissions found in hospital-based studies. Our results indicate that it is desirable with current knowledge, to reduce IDU through information to physicians and careful prescribing.

Levels of α- and β-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients

Alternative cleavage of the amyloid precursor protein (APP) results in generation and secretion of both soluble APP (sAPP) and β-amyloid (Aβ). Aβ is the main component of the amyloid depositions in the brains of Alzheimers disease (AD) patients. Using Western blotting, we compared the levels of α-secretase cleaved sAPP, β-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid (CSF) from 13 sporadic AD patients and 13 healthy controls. Our findings show significant amounts of β-secretase cleaved sAPP in CSF. There was no statistically significant difference in the levels of β-secretase cleaved sAPP between AD patients and controls. The levels of α-secretase cleaved sAPP and total sAPP were, however, found to be significantly lower in the AD patients than in the controls.

Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus

The role of adenosine in the development of ischemia induced pathological changes has been examined in Mongolian gerbils. A dramatic increase in the concentrations of adenosine, inosine and hypoxanthine was detected by microdialysis in the dorsal part of hippocampus and in the striatum immediately after 5 min bilateral occlusion of the carotid arteries. From a resting value of about 0.5 microM the concentration of adenosine increased to more than 10 microM. The adenosine levels became normalized within 30 min after ischemia. Inosine and hypoxanthine levels were higher and they increased and also returned towards control somewhat later than adenosine. A second occlusion resulted in a similar but somewhat smaller increase in purine levels. Carotid occlusion for up to 12 min had no major, lasting effect on the binding to adenosine A1-receptors in the CA-regions of the hippocampus, as determined by autoradiography. Neuronal and vascular changes (degeneration of neurons, mitochondrial destruction and ribosomal disaggregation, astroglial oedema) due to ischemia (3-12 min, followed by 48 h recirculation) was studied with light and electron microscopy in the selectively vulnerable CA1 area of hippocampus. In one series of experiments the adenosine antagonist theophylline (20 mg/kg i.p.), given 15 min prior to a 5 min occlusion, significantly enhanced the ischemia induced changes. In another experiment the adenosine uptake inhibitor propentofylline (HWA 285, 10 mg/kg), injected 15 min before a 12 min carotid occlusion, reduced the neuronal (90%) and astroglial changes (84%) due to ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug—Drug Interactions in the Elderly

OBJECTIVE: To detect the frequency of potential drug—drug interactions (DDIs) in an outpatient group of elderly people in 6 European countries, as well as to describe differences among countries. DATA SOURCES AND METHODS: Drug use data were collected from 1601 elderly persons living in 6 European countries. The study population participated in a controlled intervention study over 18 months investigating the impact of pharmaceutical care. Potential DDIs were studied using a computerized detection program. RESULTS: The elderly population used on average 7.0 drugs per person; 46% had at least 1 drug combination possibly leading to a DDI. On average, there were 0.83 potential DDIs per person. Almost 10% of the potential DDIs were classified to be avoided according to the Swedish interaction classification system, but nearly one-third of them were to be avoided only for predisposed patients. The risk of subtherapeutic effect as a result of a potential DDI was as common as the risk of adverse reactions. Furthermore, we found differences in the frequency and type of potential DDIs among the countries. CONCLUSIONS: Potential DDIs are common in elderly people using many drugs and are part of a normal drug regimen. Some combinations are likely to have negative effects; more attention must be focused on detecting and monitoring patients using such combinations. As differences in potential DDIs among countries were found, the reasons for this variability need to be explored in further studies.

The Influence of Educational Level on Polypharmacy and Inappropriate Drug Use: A Register-Based Study of More Than 600,000 Older People

OBJECTIVES: To investigate whether low educational attainment is associated with polypharmacy and potential inappropriate drug use (IDU) in older people.

Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 - 2002.

OBJECTIVE This study investigates the changes in drug use, polypharmacy and potential drug-drug interactions (DDIs) between educational groups of Swedish elderly over a 10-year period from 1992 - 2002. METHODS We used data from SWEOLD I (n = 512) from 1992 and SWEOLD II from 2002 (n = 561), which are nationally representative surveys of the elderly population in Sweden aged 77 years and older. Both community-based and institutionalized persons were included. Information on drug use was based on personal interviews and all drugs used in the two weeks prior to the studies were recorded. The three outcomes under study were drug use, polypharmacy (concurrent use of five or more drugs), and potential DDIs. RESULTS In the SWEOLD data from 1992 - 2002, the mean number of drugs used per person increased from 2.5 - 4.4. Overall, 81% of the study participants were drug users in 1992 as compared to 88% in 2002. The prevalence of polypharmacy increased 3-fold (from 18% in 1992 to 42% in 2002) after controlling for age and gender. In both SWEOLD surveys, the less educated reported polypharmacy more often (19% in 1992 and 46% in 2002) than the higher educated (12% in 1992 and 36% in 2002). Potential DDIs also increased, both among the less educated (14% in 1992 to 26% in 2002) and the higher educated (18% in 1992 to 24% in 2002). The most pronounced changes in the consumption of specific drug groups were observed in antithrombotic agents, beta-blocking agents, ACE inhibitors, and vitamin B12 and folic acid. In general, the use of most therapeutic classes increased more among the well educated compared to less educated men between 1992 and 2002, whereas the opposite relationship prevailed among women. CONCLUSION This study indicates that the use of drugs, polypharmacy and potential DDIs have increased during 1992 to 2002 among the elderly. These changes were most prominent among the less educated women. Polypharmacy and potential DDIs represent potential health hazards for the elderly. Therefore, the trends of increasing polypharmacy and drug-drug interactions deserve attention and the mechanisms behind should be investigated further.

Ischaemic damage in gerbil hippocampus is reduced following upregulation of adenosine (A1) receptors by caffeine treatment

We have used the fact that long-term caffeine treatment upregulates the adenosine receptors, to examine the role of adenosine in ischaemia. Four-week oral treatment with caffeine (0.2% in drinking water) caused a significant (10-17%) increase in the binding of the adenosine A1-receptor ligand [3H]cyclohexyl-adenosine (CHA) to several brain regions, including the hippocampal CA1 area, in Mongolian gerbils. Animals subjected to such treatment exhibited significantly less neuronal damage in the CA1 region following 5 min bilateral carotid occlusion than did control animals (50% of the caffeine-treated animals showed no damage at all compared to 11% in the control group). Our findings provide further evidence for a protective role of endogenous adenosine during ischaemia.

Inappropriate Drug Use in the Elderly: A Nationwide Register-Based Study

Background: Potentially inappropriate drug use (IDU) is an important and preventable safety concern in the care of elderly patients and has been associated with adverse drug reactions, hospitalization, and mortality. Objective: To estimate the prevalence of potentially IDU among the elderly in Sweden and investigate whether age. sex, and number of dispensed drugs are associated with IDU. Methods: We analyzed data on age, sex, and dispensed drugs for people aged 75 years and older who were listed in the Swedish Prescribed Drug Register from October–December 2005 (N = 732 226). The main outcome measures of IDU were prescription of anticholinergics, prescription of long-acting benzodiazepines, concurrent use of 3 or more psychotropic drugs, and an indication of potentially serious drug-drug interactions. Results: Prevalence for IDU was 17%; for anticholinergic drugs 6%, long-acting benzodiazepines 5%, 3 or more psychotropic drugs 5%, and potentially serious drug–drug interactions 4%. After adjustment for age and sex, number of dispensed drugs was strongly associated with all 4 measures of IDU. After adjustment for sex and number of dispensed drugs, increasing age was moderately associated with a higher probability of IDU, long-acting benzodiazepines, and 3 or more psychotropic drugs, After adjustment for age and number of dispensed drugs, women had a slightly increased probability of IDU, anticholinergic drugs, long-acting benzodiazepines, and 3 or more psychotropic drugs. Conclusions: IDU was fairly common among the elderly in Sweden in 2005 and was strongly connected to the number of dispensed drugs they were taking. Older age and female sex were related to inappropriate use of psychotropic drugs, whereas the opposite relationship prevailed for potentially serious drug–drug interactions. Future research is needed to determine whether IDU will become more common due to increasing use of drugs among elderly persons. The challenge is to balance the problems related to IDU without denying older people potentially valuable drug therapy.

Pain Treatment in Elderly Persons With and Without Dementia : A population-Based Study of Institutionalized and Home-Dwelling Elderly

AbstractBackground: Several previous studies have reported an undertreatment of pain in elderly persons with dementia. It has also been suggested that persons with dementia may be at risk for inappropriate treatment of pain with psychotropics. Objectives: The objective of this study was to investigate if persons with dementia are as likely as persons without dementia to receive pharmacological pain treatment, after taking into account residential setting and pain-related disorders. We also aimed to investigate whether use of psychotropics is related to pain in persons with and without dementia. Methods: We used baseline data from the SNAC-K (Swedish National Study of Aging and Care — Kungsholmen). We analysed use of analgesics and psychotropics, prevalence of pain-related diagnoses, self-reported pain, dementia status and residential setting in 2610 participants aged >65 years. Results: Of the persons with dementia, 46% used at least one analgesic drug compared with 25% of those without dementia. Although persons with dementia reported pain less frequently than persons without dementia, the prevalence of pain-related diagnoses was similar. After adjustment for individual factors and residential setting (own home/institution), persons with dementia had a higher probability of use of paracetamol (acetaminophen) and psychotropics, whereas there were no significant differences in use of any analgesic, opioids and NSAIDs. Furthermore, having a pain-related diagnosis was associated with use of psychotropics in persons with dementia. Conclusions: Persons with dementia had a higher probability of use of paracetamol and were about as likely as persons without dementia to use any analgesic, opioids and NSAIDs, after adjustment for confounders. This may reflect a recent increased awareness of pain and pain management in persons with dementia, compared with previous studies that have reported an underuse of analgesics in persons with dementia. However, further research is needed to analyse if persons with dementia are appropriately treated for pain with regard to type of analgesic drug, pain intensity, indication, dosage and regimen.