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.
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.
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.
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.
To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia.
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). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.
A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 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%.
CSF Aβ42, 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.
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.
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.
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.
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.
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.
To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD).
We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object ...naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (Abeta(1-42)), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates.
Cluster 1 consisted of 88 patients (49%) with relatively high levels of Abeta(1-42) and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of Abeta(1-42) and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of Abeta(1-42) and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency.
Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.
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.
In Alzheimer disease (AD), longitudinal changes of beta-amyloid(1-42) (Abeta(1-42)), tau, and phosphorylated tau at threonine 181 (ptau-181) in CSF have been reported in small studies only. We ...evaluated the natural course of CSF biomarkers in patients with AD, subjective complaints, and mild cognitive impairment (MCI).
One hundred five patients (50 AD, 38 MCI, 17 subjective complaints) underwent two lumbar punctures, with a mean interval of 21 +/- 9 months. CSF levels of Abeta(1-42), tau, and ptau-181 were measured.
CSF Abeta(1-42) and tau levels showed main effects for both diagnosis and time (all p < 0.05), with average increases of 47 +/- 72 and 49 +/- 143 pg/mL. The interaction terms were not significant, which implies a similar time effect for all diagnostic groups. CSF ptau-181 levels showed a main effect for diagnosis (p = 0.01) but not for time (p = 0.27, increase of 1.0 +/- 12 pg/mL).
Levels of CSF beta-amyloid(1-42) and tau but not phosphorylated tau at threonine 181 increased over time in this memory clinic patient cohort with comparable change in all diagnostic groups. The cross-sectional difference between diagnostic groups, however, exceeded by far the longitudinal changes within individuals, suggesting that these biomarkers are not sensitive as markers of disease progression.
CSF biomarkers amyloid beta 1-42 (Abeta(42)), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these ...biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration.
A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age.
The patients with AD (45% women, age 66 +/- 9 years, baseline MMSE 22 +/- 4) had a follow-up period of 2.0 (1.0-5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Abeta(42), high tau, and high tau/Abeta(42)-ratio were associated with rapid cognitive decline (p < 0.05).
At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.
Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(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.
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.
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.
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.
Abstract Objective To study CSF biomarkers, beta-amyloid1-42 (Aβ1-42 ) and tau, and medial temporal lobe atrophy (MTA) on MRI in their ability to predict dementia in patients with mild cognitive ...impairment (MCI). Methods Fifty-nine MCI patients (49% male, mean age 69 ± 8), follow-up 19 months, were included. Baseline CSF levels of Aβ1-42 , tau and MTA-score were dichotomized. Results Thirty-three (56%) of the MCI patients progressed to dementia, 30 of which had Alzheimer's disease. Lower CSF Aβ1-42 level, higher CSF-tau and higher MTA-scores at baseline were found in progressed patients. Cox proportional hazards models revealed that abnormal CSF Aβ1-42 , CSF tau and MTA were significantly associated with dementia at follow-up (hazard ratio (95% confidence interval): 4.0 (1.3–12.1), 5.9 (1.6–21.7) and 2.1 (1.0–4.6)). A fourfold higher risk was found for patients with both abnormal CSF biomarkers and MTA compared to patients with either test abnormal. Ninety-four percent of patients with both abnormalities converted to dementia. Conclusions These findings suggest an added value of CSF to MRI in the diagnostic work up of patients presenting at a memory clinic.
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