Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis.

The S100B protein is associated with brain damage and a breached blood-brain barrier. A previous pilot study showed that high serum levels of S100B are associated with shorter survival in glioma patients. The aim of our study was to assess the prognostic value in terms of survival and longitudinal dynamics of serum S100B for patients with newly diagnosed and recurrent glioma. We obtained blood samples from patients with newly diagnosed and recurrent glioma before the start (baseline) and at fixed time-points during temozolomide chemotherapy. S100B-data were dichotomized according to the upper limit of the reference value of 0.1 µg/L. Overall survival (OS) was estimated with Kaplan-Meier curves and groups were compared with the log rank analysis. To correct for potential confounders a Cox regression analysis was used. We included 86 patients with newly-diagnosed and 27 patients with recurrent glioma. Most patients in both groups had baseline serum levels within normal limits. In the newly diagnosed patients we found no significant difference in OS between the group of patients with S100B levels >0.1 µg/L at baseline compared to those with <0.1 µg/L. In the patients with recurrent glioma we found a significantly shorter OS for patients with raised levels. In both groups, S100B values did not change significantly throughout the course of the disease. Serum S100B levels do not seem to have prognostic value in newly diagnosed glioma patients. In recurrent glioma patients S100B might be of value in terms of prognostication of survival.

The inflammatory marker GDF-15 is not independently associated with late-life depression.

OBJECTIVES: Growth differentiation factor-15 (GDF-15) is an inflammatory molecule that reacts to cell stress. Since major depression is associated with inflammation, we examined whether GDF-15 levels are elevated in patients with late-life depression. METHODS: Plasma GDF-15 levels were analyzed in 350 patients diagnosed with major depressive disorder in the last six months and 128 non-depressed controls from the Netherlands Study of Depression in Older persons (age ≥ 60 years). Major depressive disorder and age of onset were assessed with the Composite International Diagnostic Interview. Severity of depressive symptoms was measured with the Inventory of Depressive Symptoms (IDS-30). Multiple linear regression models were applied to study depression (diagnosis, onset age, severity, antidepressant drug use) as determinant of GDF-15 level, adjusted for demographic and clinical variables. RESULTS: Plasma GDF-15 levels were 22% higher in patients with major depression compared to controls. Within the depressed group, levels were higher in patients with older age of onset. GDF-15 levels showed a small, positive correlation to the levels of the inflammatory mediators IL-6 and C-reactive protein (r=0.23, and 0.24, p<0.05). This increase was independent from comorbidities, such as cardiovascular disease, rheumatism and diabetes, and anti-inflammatory drugs. However, this increase was dependent on lifestyle factors as smoking, physical activity and alcohol use. Within the depressed subgroup, neither depression severity or antidepressant drug use was associated with GDF-15 levels in the fully adjusted models. CONCLUSION: The inflammatory factor GDF-15 does not seem to be an independent inflammatory marker for late-life major depressive disorder.

Testosterone, free testosterone, and free androgen index in women: Reference intervals, biological variation, and diagnostic value in polycystic ovary syndrome.

OBJECTIVE: The objective of our study was to determine reference intervals and biologic variation for testosterone (T), free testosterone (fT), and free androgen index (FAI) in women with accurate methods and to test the discriminative value of these parameters in a polycystic ovary syndrome (PCOS)-population. METHODS: Serum was obtained daily during a normal menstrual cycle from 25 healthy women (677 data-points). A single serum sample was obtained from 44 PCOS-patients. T was measured by LC­MS/MS and by Architect® 2nd generation T Immunoassay. Sex hormone-binding globulin was measured to calculate fT and FAI. Results: Reference intervals which were established in healthy women with an ovulatory menstrual cycle were T = 0.3-1.6 nmol/L and 0.5-2.0 nmol/L, fT = 5.2-26 pmol/L and 7.2-33 pmol/L, and FAI = 0.4-2.9 and 0.6-4.4, by LC-MS/MS and immunoassay, respectively. T, fT and FAI were higher in PCOS patients than in controls (p b 0.0001). The areas under the curve of receiver operator characteristic (ROC) plots were not different for T, fT, or FAI when T was measured by LC­MS/MS versus immunoassay based on prediction of PCOS. FAI and fT were the strongest predictors of PCOS. CONCLUSIONS: When based upon the appropriate reference intervals and ROC analysis, LC-MS/MS and second generation immunoassay have equivalent clinical utility for the diagnosis of PCOS.

The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis.

UNLABELLED: BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T. METHODS: A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T. RESULTS: A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18-40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) -0.49 nmol/l (-0.55, -0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20-25 µg EE had similar effects on total and free T compared with COCs with 30-35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20-25 µg EE) were found to have less impact on SHBG concentrations. CONCLUSIONS: The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.

Prevalence of vitamin D deficiency and consequences for PTH reference values.

Reference values of PTH depend on vitamin D status of the reference population. This is often not described in package inserts. The aim of the present study was therefore to calculate assay specific PTH reference levels in EDTA plasma for the Architect (Abbott) in relation to 25-hydroxyvitamin D (25OHD) levels. The relation between PTH levels, 25OHD, BMI, age, gender and kidney function was determined in a cohort of older individuals from the Longitudinal Aging Study Amsterdam (LASA, n = 738, age 55-65 years) and in a cohort of healthy individuals from the Netherlands Study of Depression and Anxiety (NESDA, n = 633, 18-65 years). The LASA cohort is a representative sample of the Dutch older population. As expected, PTH reference values were significantly lower in 25OHD sufficient subjects (25OHD>50 nmol/L) than in 25OHD deficient and insufficient subjects. The 97.5th percentile of PTH in 25OHD sufficient subjects was 10 pmol/L (94.3 pg/mL), which was higher than the upper limit stated by the manufacturer (7.2 pmol/L or 68.3 pg/mL). The relation between vitamin D and PTH was independent of age, gender, BMI and kidney function. In conclusion, we have shown that it is important to establish PTH reference values in a local reference population taking 25OHD status into account.

Age independent first trimester screening for Down syndrome: improvement in test performance.

OBJECTIVE: The aim of this study was to compare screening performance for Down syndrome of the absolute risk (AR) method to the first trimester combined test (FCT) at different maternal ages. METHODS: There was a retrospective analysis of 32,448 FCT. AR was defined as final risk divided by maternal age risk. RESULTS: The likelihood of receiving a true prediction was comparable between both methods in all age groups. With the AR method, two extra Down syndrome cases were detected in women <30 years, three cases were missed in women ≥36 years, and the likelihood of receiving a false prediction decreased overall (OR 0.82, CI 0.77-0.87; P < 0.0001), in women aged 36-40 years (0.45, CI 0.41-0.51; P < 0.0001), in women aged 41-45 years (0.18, CI 0.13-0.26; P < 0.0001) and increased in women aged ≤25 years (2.12, CI 1.52-2.96; P < 0.004). CONCLUSIONS: The AR method results in a significant decreased likelihood of receiving a false prediction with a comparable likelihood of receiving a true prediction. Thus, fewer invasive diagnostic tests will be performed. It will take away the misunderstanding about differences in screening performance for women of different ages. This might lead to a higher uptake of first trimester screening resulting in a more efficient screening policy.

CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome.

BACKGROUND: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest. OBJECTIVE: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS). METHODS: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them. RESULTS: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients' NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load. CONCLUSION: Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage.

Increased plasma 8,12-iso-iPF2alpha- VI levels in relapsing multiple sclerosis patients are not predictive of disease progression.

BACKGROUND: Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression. OBJECTIVE: To study whether plasma isoprostane levels were related to disease progression in MS. METHODS: Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing-remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters. RESULTS: Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7-77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9-82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1-49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS). CONCLUSION: These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.

No effects of n-3 fatty acid supplementation on serum total testosterone levels in older men: the Alpha Omega Trial.

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60-80 years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400 mg/day of EPA-DHA (n = 453), 2 mg/day of ALA (n = 467), EPA-DHA plus ALA (n = 458), or placebo (n = 472). Serum testosterone levels were assessed at baseline and after 41 months using whole day blood samples obtained at the subjects' home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6) nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA-DHA, and EPA-DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n = 76 with total testosterone <8.0 nmol/L). We conclude that n-3 fatty acids supplementation did not affect serum total testosterone in men who had had a MI.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.

OBJECTIVE: To determine how amyloid ß 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. METHODS: Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aß42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients. RESULTS: A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aß42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%. CONCLUSION: CSF Aß42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

First trimester screening for intra-uterine growth restriction and early-onset pre-eclampsia.

OBJECTIVE: To assess first trimester placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) as screening markers for early-onset pre-eclampsia (PE) and intra-uterine growth restriction (IUGR). METHODS: PlGF concentration was retrospectively measured in first trimester serum specimens of 23 cases of early-onset PE (<34 weeks), 26 cases of IUGR (birth weight < 5th centile) and 5 controls per case. Levels were adjusted for gestational age (GA), ethnicity and smoking to obtain multiples of the expected median (MoM). Logistic regression was used to assess PlGF, PAPP-A and maternal characteristics as potential predictors of early-onset PE and IUGR. RESULTS: PlGF MoM levels were significantly lower in the early-onset PE group (P < 0.0001) compared with controls, but not in the IUGR group. PAPP-A MoM levels were significantly lower in the IUGR group (P < 0.01) compared with controls but not in the early-onset PE group. PlGF significantly improved the ability of systolic blood pressure at the first prenatal visit to predict early-onset PE [achieving a receiver-operating characteristics curve with area under the curve (AUC) of 0.8]. Combining systolic blood pressure at the first prenatal visit and PlGF did not significantly improve the predictive ability compared with PlGF alone (AUC = 0.83). CONCLUSION: Serum PlGF is an acceptable marker in first trimester screening for early-onset PE, but a poor marker in screening for IUGR. Screening performance of serum PAPP-A is poor for both early-onset PE and IUGR.

Frequency distribution of polymorphisms in the FSH receptor gene in infertility patients of different ethnicity.

Studies on the frequency distribution of follicle-stimulating hormone receptor (FSHR) polymorphisms report conflicting results. It has been suggested that ethnicity might influence these outcomes. Therefore, the aim of this study was to determine the frequency distribution of FSHR polymorphisms at position 680 of exon 10 within a large group of women with fertility problems from different ethnic backgrounds. A total of 1771 women of different ethnic origin (Caucasian, Asian, Hindustani, Creole and Mediterranean) were studied. FSHR single-nucleotide polymorphisms at codon 680 of exon 10 were determined by restriction fragment length polymorphism of amplicons generated by polymerase chain reaction. Genotypes were compared with serum FSH concentrations and between different ethnic groups. A significantly lower number of Asians (10.5%) were found to have the Ser680Ser receptor variant compared with Caucasians (21.5%) and Mediterraneans (22.3%) (P = 0.010). FSH concentrations did not differ between the various ethnic groups, or the different FSHR polymorphisms. In conclusion, the Ser680Ser receptor variant is less common in the Asian subgroup compared with Caucasians and Mediterraneans. This indicates that, when comparing allelic frequency distributions of the FSHR polymorphism variants, ethnic background should be accounted for. FSH concentrations did not differ between FSHR polymorphisms or between ethnic groups.

Batch prepared protein standards for cerebrospinal fluid (CSF) biomarkers for neurodegeneration.

Immuno-assays are increasingly used for quantification of protein biomarkers for neurodegeneration. It has been proposed to use such cerebrospinal fluid (CSF) protein biomarkers as diagnostic tests for Alzheimer's disease. In two recent world-wide validation studies we found the analytical accuracy to be poor (inter-laboratory coefficient of variation, CV>10%) for CSF tau protein, CSF phospho-tau protein, CSF amyloid beta protein and the CSF neurofilament light chain protein. Retrospectively we suspected that the lack of preparation of accurate and consistent protein standards may have been one reason for the poor inter-laboratory CV. Here we confirm this hypothesis prospectively under standardised and optimised conditions. The CVs for CSF tau, CSF phospho-tau and CSF amyloid beta of individually prepared standards are 8%, 12% and 12% compared to significantly lower CVs for batch prepared standards (5%, 8%, 7%, respectively, p<0.05). This issue will need to be solved in order to ensure that the attempts to include these CSF protein biomarkers either as a diagnostic tool or a secondary outcome measure for treatment trials will be successful.

Differences in total human chorionic gonadotropin immunoassay analytical specificity and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors.

OBJECTIVE: To determine the ability of several radioimmunoassays and commercial two-site immunoassays to detect the first World Health Organization International Reference Reagents (IRRs) for 6 defined human chorionic gonadotropin (hCG) variants and to compare their performance in measuring hCG in sera from patients with gestational trophoblastic disease (GTD) and germ cell tumors (GCTs) of the testis or ovary. STUDY DESIGN: The reactivity of the different assays with the 6 IRRs together with the current fourth International Standard (IS, 75/589) was tested using 5 commercial two-site assays as well as 2 competitive polyclonal radioimmunoassays (RIAs) and a competitive monoclonal immunoassay. Individual samples from 41 patients (19 GCT and 22 GTD) with high circulating levels of hCG (range, 718-6,055,000 IU/L) were diluted and measured using the various immunoassays. RESULTS: The results of 4 GCT patient samples varied markedly among the assays, including 1 sample that was grossly underestimated by 3 of the commercial assays. CONCLUSION: Comparison of each assay's reactivity to the variant isoforms revealed that recognition of the isoforms was highly variable, particularly for hCGbeta and hCGbeta core fragment (hCGbetacf).

New research criteria for the diagnosis of Alzheimer's disease applied in a memory clinic population.

BACKGROUND: In the newly proposed research criteria for Alzheimer's disease (AD), patients are defined as having memory dysfunction in addition to either hippocampal atrophy or an abnormal cerebrospinal fluid (CSF) profile. This study applies the criteria in a memory clinic population, using clinical criteria as the reference criterion. METHODS: 138 AD patients, 145 nondemented subjects, 78 patients with other dementias and 91 patients with mild cognitive impairment (MCI) were included. Dichotomized medial temporal lobe atrophy (MTA) score on MRI and dichotomized CSF profiles (based on beta-amyloid1-42, tau and phosphorylated tau at threonine 181 levels) were used in combination with an episodic memory test to assess sensitivity, specificity and likelihood ratios (LR) of the newly proposed criteria and their components separately. RESULTS: We found specificities of 95 and 49% for comparison with nondemented subjects and other demented patients, respectively, with a sensitivity of 86% for AD. Specificity was highest (100 and 77%, respectively, LR+ = 48) when both MTA score and CSF profile were abnormal in addition to the episodic memory test, at the cost of a low sensitivity (48%). CONCLUSION: The newly proposed research criteria for AD yield a good specificity for comparison with nondemented subjects. When the type of dementia is clinically doubted, however, at least two supportive features should be considered (i.e. abnormal MTA score and CSF profile) in addition to memory impairment as core diagnostic criterion.

Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population.

BACKGROUND: Cerebral microbleeds (MBs) are commonly observed in memory clinic patients. Little is known about occurrence of and risk factors for developing new MBs in this population. OBJECTIVE: To investigate incidence of lobar and nonlobar MBs in a memory clinic population. Furthermore, to assess risk factors for the development of new MBs and their associations with other MRI changes. METHODS: A total of 254 patients visiting our memory clinic, with repeat gradient-recalled echo T2*-weighted MRI, were included (scan interval 1.9 +/- 0.9 years). Baseline and incident MBs were regionally counted. White matter hyperintensities (WMH) and progression of WMH were assessed using visual rating scales. Baseline brain volume and whole-brain atrophy rate were estimated automatically. In a subset, APOE was determined. RESULTS: Thirty-one (12%) patients developed new MBs (range 1-19). Both multiple strictly lobar and nonlobar MBs at baseline predicted incident MBs (odds ratio [OR] 8.4; 95% confidence interval [CI] 2.2-33.2, and OR 33.8; 95% CI 8.1-140.8). Furthermore, baseline WMH grade (OR 1.2; 1.1-1.3), lacunar infarcts (OR 2.8; 1.3-6.0), and APOE epsilon2 carriership (OR 4.2; 1.4-12.5) predicted MB incidence. Incident MB patients had more progression of WMH (p < 0.01) and incident lacunar infarcts (p < 0.05). These relations were most prominent for incident nonlobar MBs. Incident strictly lobar MBs were associated with smoking. CONCLUSION: In addition to APOE genotype, presence and progression of small-vessel disease and vascular risk factors were predictors of new MBs. The latter are potentially modifiable, suggesting the possibility of preventing incident MBs, hopefully resulting in slower clinical decline.

First-trimester serum marker distribution in singleton pregnancies conceived with assisted reproduction.

OBJECTIVE: To evaluate marker distribution of free beta-human chorionic gonadotrophin (fbeta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in singleton pregnancies conceived by assisted reproduction techniques (ART). METHODS: In vitro fertilization (IVF) (n = 203) and intracytoplasmic sperm injection (ICSI) (n = 192) cases from a database of 14 645 first-trimester combined tests (overall study group) were selected and matched to 1164 controls for gestational age at sample date and maternal age. RESULTS: In the IVF group and ICSI group, lnPAPP-A was lower (IVF 6.74 vs 7.08; P = 0.0001; ICSI 6.59 vs 7.07; P = 0.0001) compared with the matched controls. Lnfbeta-hCG was lower in the IVF group (3.75 vs 3.90; P = 0.005) but not significantly different in the ICSI group (3.87 vs 3.93; P = 0.27). The computed correction factors for PAPP-A and fbeta-hCG were 1.42 and 1.17 for the IVF group and 1.56 and 1.05 for the ICSI group.The false-positive rate (FPR) in the IVF and ICSI group compared with the matched controls was higher (IVF 10.3% vs 8.6% and ICSI 10.9% vs 7.5%). In the overall age-biased [maternal age significantly lower compared with all ART and control groups] study group the FPR was 6.8%. CONCLUSION: The increase in FPR in the ART groups can be explained by decreased PAPP-A values. Therefore, an adjustment in risk analysis for Down syndrome is suggested.