High-risk mammographic parenchymal patterns and anthropometric measures: a case–control study

Mammographic parenchymal patterns are related to breast cancer risk and are also affected by anthropometric measure. We carried out a case–control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of body size and shape and breast size on mammographic patterns. Women in the highest quartile of body mass index (BMI) distribution were significantly less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.08–0.52, P-value for trend = 0.001) compared to those in the lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than 0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80 was 0.30 (95% CI 0.14–0.63). Breast size as measured by cup size was significantly and negatively related to high-risk pattern. Our study indicates that both BMI and WHR are negatively associated with high-risk patterns. However, both phenomena are associated with increased risk of breast cancer in post-menopausal women. This negative confounding of two positive risk factors means that the effect of parenchymal patterns on risk will tend to be underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have underestimated the importance of BMI and mammographic parenchymal patterns in the past. Further studies are needed to determine a measure of parenchymal density that is independent of anthropometric measures and breast size. © 1999 Cancer Research Campaig

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Cerebrospinal fluid levels of glial marker YKL-40 strongly associated with axonal injury in HIV infection

Background: HIV-1 infects the central nervous system (CNS) shortly after transmission. This leads to a chronic intrathecal immune activation. YKL-40, a biomarker that mainly reflects activation of astroglial cells, has not been thoroughly investigated in relation to HIV. The objective of our study was to characterize cerebrospinal fluid (CSF) YKL-40 in chronic HIV infection, with and without antiretroviral treatment (ART). Methods: YKL-40, neopterin, and the axonal marker neurofilament light protein (NFL) were analyzed with ELISA in archived CSF samples from 120 HIV-infected individuals (85 untreated neuroasymptomatic patients, 7 with HIVassociated dementia, and 28 on effective ART) and 39 HIV-negative controls. Results: CSF YKL-40 was significantly higher in patients with HIV-associated dementia compared to all other groups. It was also higher in untreated neuroasymptomatic individuals with CD4 cell count < 350 compared to controls. Significant correlations were found between CSF YKL-40 and age (r = 0.38, p < 0.001), CD4 (r = − 0.36, p < 0. 001), plasma HIV RNA (r = 0.35, p < 0.001), CSF HIV RNA (r = 0.35, p < 0.001), CSF neopterin (r = 0.40, p < 0.001), albumin ratio (r = 0.44, p < 0.001), and CSF NFL (r = 0.71, p < 0.001). Age, CD4 cell count, albumin ratio, and CSF HIV RNA were found as independent predictors of CSF YKL-40 concentrations in multivariable analysis. In addition, CSF YKL-40 was revealed as a strong independent predictor of CSF NFL together with age, CSF neopterin, and CD4 cell count. Conclusions: CSF YKL-40 is a promising biomarker candidate for understanding the pathogenesis of HIV in the CNS. The strong correlation between CSF YKL-40 and NFL suggests a pathogenic association between astroglial activation and axonal injury, and implies its utility in assessing the prognostic value of YKL-40