Neurofilament light protein levels in cerebrospinal fluid predict long-term disability of Guillain-Barré syndrome: A pilot study.

OBJECTIVES: Although the recovery from Guillain-Barré syndrome (GBS) is good in most patients, some develop permanent severe disability or even die. Early predictors would increase the likelihood to identify patients at risk for poor outcome at the acute stage, allowing them intensified therapeutic intervention. MATERIALS AND METHOD: Eighteen patients with a history of GBS 9-17 years ago were reassessed with scoring of neurological disability and quality of life assessment (QoL). Their previous diagnostic work-up included clinical examination with scoring of disability, neurophysiological investigation, a battery of serology tests for infections, and cerebrospinal fluid (CSF) examination. Aliquots of CSF were frozen, stored for 20-28 years, and analyzed by ELISA for determination of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP). RESULTS: Patients with poor outcome (n = 3) had significantly higher NFL and GFAP levels at GBS nadir than those with good outcome (n = 15, P < .01 and P < .05, respectively). High NFL correlated with more prominent disability and worse QoL at long-term follow-up (r = .694, P < .001, and SF 36 dimension physical component summary (PCS) (r =-.65, P < .05), respectively, whereas GFAP did not correlate with clinical outcome or QoL. CONCLUSION: High NFL in CSF at the acute stage of GBS seems to predict long-term outcome and might, together with neurophysiological and clinical measures, be useful in treatment decisions and clinical care of GBS.

Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.

BACKGROUND: Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer. OBJECTIVES: To test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 cluster, is associated with a change in risk of smoking-related mortality and morbidity in the Malmö Diet and Cancer study, a population-based prospective cohort study. METHODS: At baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox-proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco-related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow-up. RESULTS: Amongst current smokers there were 480 first incident COPD events, 852 tobacco-related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco-related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers. CONCLUSION: Our data suggest that gene variance in the CHRNA5-CHRNA3-CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco-related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study.

OBJECTIVES: Inflammatory diseases and inflammatory markers secreted by the liver, including C-reactive protein (CRP) and ceruloplasmin, have been associated with incident atrial fibrillation (AF). Genetic studies have not supported a causal relationship between CRP and AF, but the relationship between ceruloplasmin and AF has not been studied. The purpose of this Mendelian randomization study was to explore whether genetic polymorphisms in the gene encoding ceruloplasmin are associated with elevated ceruloplasmin levels, and whether such genetic polymorphisms are also associated with the incidence of AF. DESIGN: Genetic polymorphisms in the ceruloplasmin gene (CP) were genotyped in a population-based cohort study of men from southern Sweden (Malmö Preventive Project; n = 3900). Genetic polymorphisms associated with plasma ceruloplasmin concentration were also investigated for association with incident AF (n = 520) during a mean follow-up of 29 years in the same cohort. Findings were replicated in an independent case-control sample (The Malmö AF cohort; n = 2247 cases, 2208 controls). RESULTS: A single nucleotide polymorphism (rs11708215, minor allele frequency 0.12) located in the CP gene promoter was strongly associated with increased levels of plasma ceruloplasmin (P = 9 × 10(-10) ) and with AF in both the discovery cohort [hazard ratio 1.24 per risk allele, 95% confidence interval (CI) 1.06-1.44, P = 0.006] and the replication cohort (odds ratio 1.13, 95% CI 1.02-1.26, P = 0.02). CONCLUSIONS: Our findings indicate a causal role of ceruloplasmin in AF pathophysiology and suggest that ceruloplasmin might be a mediator in a specific inflammatory pathway that causally links inflammatory diseases and incidence of AF.

Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?

BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.

Chromosome 9p21 genetic variation explains 13% of cardiovascular disease incidence but does not improve risk prediction.

OBJECTIVES: To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors. DESIGN, SETTING AND PARTICIPANTS: rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models. RESULTS: In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11-1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy. CONCLUSION: The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes.

BACKGROUND AND AIMS: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. METHODS AND RESULTS: The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events.

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis.

OBJECTIVE: To assess whether or not a genetic risk score that was previously shown to be associated with myocardial infarction (MI) and coronary artery disease (CAD) is also associated with markers of carotid atherosclerosis. DESIGN: A total of 4022 middle-aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single-nucleotide polymorphisms (SNPs), previously associated with MI and CAD. The genetic score (Score-MI) was then related to carotid bulb intima-media thickness (IMT), common carotid artery (CCA) IMT and to the occurrence of carotid plaques in the study population. RESULTS: Score-MI was associated with IMT of the bulb (P < 0.001) and the CCA (P < 0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P = 0.003). The effect size of Score-MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score-MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score-MI = 1.11; 95% confidence interval 1.04-1.18; P = 0.001). In addition to SNPs with known effects on LDL levels, Score-MI showed nominal associations with increasing systolic blood pressure and decreasing C-reactive protein levels. CONCLUSIONS: This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic MI risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether or not assessing the genetic score could be valuable for early treatment decisions in these subjects.

Secular changes in cognitive predictors of dementia and mortality in 70-year-olds.

BACKGROUND: Successive elderly birth cohorts improved in cognitive performance during the 20th century. It is not clear whether this influences cognitive predictors of dementia and mortality. OBJECTIVE: In 2 longitudinal population studies, representing 2 cohorts of 70-year-olds examined 30 years apart, we investigated the relation between baseline cognitive function and 5-year occurrence of dementia and mortality. METHODS: Two representative cohorts of 70-year-olds initially free from dementia born in 1901-1902 (cohort 1901-1902: n = 381) and 1930 (cohort 1930: n = 551) from Gothenburg, Sweden, were examined in 1971-1972 and 2000-2001 and after 5 years for the outcome of dementia and death. Recent memory was evaluated during psychiatric examinations, and nonmemory domains using psychometric tests. RESULTS: At age 70, cohort 1930 performed better on psychometric tests, and had fewer recent memory problems compared to cohort 1901-1902. During 5-year follow-up, 5.0% in cohort 1901-1902 and 4.4% in cohort 1930 (p = 0.742) developed dementia, and 15.7% in cohort 1901-1902 and 4.4% in cohort 1930 died (p < 0.001). Recent memory was associated with incident dementia in both cohorts. Low scores in nonmemory tests were associated with incident dementia in cohort 1901-1902, but not in cohort 1930. Recent memory problems and lower scores in nonmemory tests were associated with 5-year mortality in cohort 1901-1902, but not in cohort 1930. CONCLUSIONS: Secular changes in cognitive performance may influence cognitive predictors of dementia and mortality, despite similar incidence of dementia. The findings should be taken cautiously due to differences between cohorts in refusal rates, quality of education, and dementia recognition in medical records.

Apathy is a prominent neuropsychiatric feature of radiological white-matter changes in patients with dementia.

OBJECTIVE: Cerebral white-matter changes (WMCs) are frequently found in dementia and have been proposed to be related to vascular factors and a certain symptomatological profile. However, few studies have included both vascular factors and a broad spectrum of cognitive, neurological and psychiatric symptoms, easily detectable by the physician in the everyday clinical work. The objective was to study the relationships between WMCs on MRI/CT and neuropsychiatric symptoms and vascular factors in patients with cognitive impairment. METHODS: One hundred and seventy-six patients with Alzheimer's disease, vascular dementia, mixed dementia, and mild cognitive impairment were included. All patients underwent a standardized examination including medical history, clinical examinations, laboratory tests and brain imaging (CT or MRI). The identification and severity degree of WMCs was assessed blindly to clinical findings, using a semi-quantitative scale. For statistical analyses, patients were grouped based on absence or presence of WMCs. Significant variables in bivariate analyses were included as predictors in stepwise multiple logistic regression analyses. RESULTS: Bivariate analyses showed significant associations between WMCs and age, gender, blood pressure, hypertension, ischaemic heart disease and TIA/RIND. Furthermore, there were significant associations between WMCs and apathy, mental slowness, disinhibition, gait disturbance and focal neurologic symptoms. The multivariate logistic model revealed apathy, mental slowness and age as the most consistent predicting factors for WMCs, together with MRI as a radiological method for the detection of WMCs. CONCLUSIONS: The findings indicate that WMCs in patients with dementia are associated with a dysexecutive-related behavioural symptom profile, vascular factors related to small and large vessel diseases and age.

The search for putative unifying genetic factors for components of the metabolic syndrome.

AIMS/HYPOTHESIS: The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. METHODS: Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI >or= 30 kg/m(2)), dyslipidaemia (triacylglycerol >or= 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure >or= 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose >or= 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. RESULTS: Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity (p = 0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09-1.22, p < 0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p < 0.00001) and the development of hyperglycaemia (OR 1.06, p < 0.00001). Carriers of >or=19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of

A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment.

Dose reductions of pegylated interferon alpha and ribavirin may be avoided by using growth factors. This phase II clinical trial assesses the dose, efficacy and safety of darbepoetin alpha and filgrastim for treatment of anaemia and neutropenia associated with combination therapy for hepatitis C virus (HCV). Chronic hepatitis C patients (n = 101) received pegylated interferon alpha-2b (1.5 mug/kg once weekly) and ribavirin (800-1400 mg once daily). Patients with anaemia [haemoglobin (Hb) /= 0.75 x 10(9)/L and <10 x 10(9)/L. During antiviral therapy, 52% of patients required darbepoetin alpha, filgrastim or both. Hb at the time of darbepoetin alpha initiation was 10.2 +/- 0.4 g/dL. After 81 days of darbepoetin alpha, Hb increased by 1.9 +/- 1.0 g/dL to 12.1 +/- 1.1 g/dL (P < 0.0001). Filgrastim resulted in a significant increase in ANC [0.75 +/- 0.16 x 109/L to 8.28 +/- 5.67 x 10(9)/L (P < 0.0001)]. In treatment-naïve patients, 48% achieved sustained virological response (SVR), whereas 27% of patients previously treated with a course of pegylated interferon alpha achieved SVR. Low viral load, nongenotype 1 and treatment with growth factors were independently associated with SVR. Mild and severe anaemia were associated with quality of life impairments. Darbepoetin alpha resulted in an improvement in the Vitality domain of Short Form-36. No significant adverse events were related to growth factors. During anti-HCV therapy, filgrastim improved neutropenia and darbepoetin alpha improved both anaemia and quality of life. Future randomized clinical trials are needed to establish the impact of growth factors in improving sustained virological response.

Hepatitis C virus E2 envelope protein induces dendritic cell maturation.

Maturation is a critical process for dendritic cells (DC) to gain or enhance their functions in antigen presentation and T-cell activation. In this study, we investigated the effect of hepatitis C virus (HCV) envelope protein E2 on DC maturation and related functions. We show that binding of E2 protein to DC leads to a change from immature to mature phenotype as detected by an increased expression of cell surface molecules including CD83, CD80, CD86, CD11c and MHC class II. The E2-matured DC showed higher capacity to stimulate T-cell proliferation and interferon-gamma production and displayed higher levels of interleukin-12 production when compared with immature DC. The induction of DC maturation by E2 is both time- and dose-dependent and can be inhibited by anti-E2 antibodies. In addition, DC matured by E2 showed decreased uptake of bovine serum albumin and latex beads, indicating their decreased activities of endocytosis and phagocytosis upon maturation. Taken together, our results demonstrated that E2 protein is able to induce dendritic cell maturation and suggested that E2 protein may play an important role in regulation of immune responses during HCV infection.

Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes.

AIMS/HYPOTHESIS: Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. SUBJECTS AND METHODS: We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. RESULTS: In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. CONCLUSIONS/INTERPRETATION: Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.

The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients.

AIMS/HYPOTHESIS: The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. METHODS: The AGER -374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. RESULTS: AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE -374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p<0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA(1c) values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). CONCLUSIONS/INTERPRETATION: Our results show an association between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA(1c)-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.

Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.

In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.

Prodromal cognitive signs of dementia in 85-year-olds using four sources of information.

OBJECTIVE: To evaluate the utility of assessing four cognitive domains obtained from four information sources to identify individuals at risk for developing dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A representative population sample of nondemented 85-year-olds (n = 313) from Gothenburg, Sweden, was examined regarding memory, language, and visuospatial and executive functions, using self- and key informant reports and neuropsychiatric and psychometric examinations. The sample was followed 3 years for incident dementia, AD, or possible VaD. RESULTS: All cases of dementia, AD, and VaD were preceded by low performance in most domains irrespective of information source. Isolated low memory performance or low cognitive performance with unimpaired memory did not predict dementia. Positive predictive values increased with number of domains affected. Self- and key informant reports were less useful for predicting dementia than neuropsychiatric and psychometric examinations. The best positive predictive value (88%) was for low cognitive performance in all domains using neuropsychiatric and psychometric examinations; however, sensitivity was only 18%. CONCLUSIONS: Although memory impairment was necessary to predict dementia, it was not sufficient. Other cognitive domains needed to be affected. Relying on self-reports or key informants for early detection of dementia excluded a large group at risk. In addition, vascular dementia appeared to have a prodromal stage.

The Goteborg MCI study: mild cognitive impairment is a heterogeneous condition.

BACKGROUND: Mild cognitive impairment (MCI) has been considered a transitional state between normal aging and dementia, characterised by memory impairment but normal general cognitive functioning. Recently other cognitive deficits have been reported. This has led to a modification of MCI criteria. OBJECTIVE: To examine which neuropsychological tests most clearly distinguish MCI subjects from normal controls. METHODS: 112 consecutive MCI subjects and 35 controls were included in the study. The diagnosis of MCI was based on an objective history of cognitive decline and a neuropsychiatric examination, comprising instruments STEP, I-Flex, MMSE, and CDR. Participants were examined with 21 neuropsychological tests in the cognitive domains speed/attention, memory and learning, visuospatial function, language, and executive function. RESULTS: Controls were significantly older. No differences were found in education or general intellectual capacity. Controls performed significantly better than MCI on tests within all five cognitive domains. The clearest differences were seen on language tests, followed by executive function, and learning and memory. Only two subjects (1.8%) were purely amnestic; 17% showed no impairment compared with controls, with a cut off of 1.5 SD below age mean. These subjects were better educated and performed significantly better on measures of general cognitive capacity. CONCLUSIONS: The results illustrate the heterogeneity of MCI, with a significant degree of impairment in all five cognitive domains. When examined with a comprehensive neuropsychological battery, very few subjects had an isolated memory impairment.

High total cholesterol levels in late life associated with a reduced risk of dementia.

OBJECTIVE: To examine the longitudinal association between plasma total cholesterol and triglyceride levels and incident dementia. METHODS: Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88. RESULTS: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia. CONCLUSIONS: High cholesterol in late life was associated with decreased dementia risk, which is in contrast to previous studies suggesting high cholesterol in mid-life is a risk factor for later dementia. The conflicting results may be explained by the timing of the cholesterol measurements in relationship to age and the clinical onset of dementia.

The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease.

During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.