Citations

Background and objectives: We report a comprehensive clinical, radiological, neuropsychometric and pathological evaluation of a woman with a clinical diagnosis of AD dementia (ADem), but whose autopsy demonstrated widespread demyelination, without Alzheimer disease (AD) pathology. Methods and results: Initial neuropsychometric evaluation suggested amnestic mild cognitive impairment (aMCI). Serial magnetic resonance images (MRI) images demonstrated the rate of increase in her ventricular volume was comparable to that of 46 subjects with aMCI who progressed to ADem, without accumulating white matter disease. Myelin immunohistochemistry at autopsy demonstrated extensive cortical subpial demyelination. Subpial lesions involved the upper cortical layers, and often extended through the entire width of the cortex. Conclusions: Multiple sclerosis (MS) can cause severe cortical dysfunction and mimic ADem. Cortical demyelination is not well detected by standard imaging modalities and may not be detected on autopsy without myelin immunohistochemistry.

AbstractIntroductionWe describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1–42), t‐tau, and p‐tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids.MethodsReview publications authored or coauthored by ADNI Biomarker core faculty and selected non‐ADNI studies to deepen the understanding and interpretation of CSF Aβ1–42, t‐tau, and p‐tau181 data.ResultsCSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non‐ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.DiscussionFurther studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease‐modifying therapeutic trials.

BACKGROUNDUmbilical cord blood (UCB) units collected from African Americans (AAs) have lower total nucleated cell (TNC) and CD34+ cell counts and are more likely to disqualify for banking compared to other ethnic groups. Furthermore, AAs have higher prevalence of 25‐hydroxyvitamin D (25(OH)D) deficiency. Given the importance of 25(OH)D in hematopoiesis, we examined the racial differences in UCB unit 25(OH)D content and its correlation with UCB cellular characteristics.STUDY DESIGN AND METHODSA total of 119 UCB units that did not meet the TNC count banking criteria were analyzed. Fifty‐one UCB units were collected from AA mothers and 68 from Caucasian mothers. We analyzed UCB volume, hematocrit (Hct), TNCs, mononuclear cells (MNCs), CD34+ cells, plasma 25(OH)D concentration, and progenitor clonogenic capacity measured by colony‐forming cell (CFC) assay.RESULTSCompared to Caucasians, AAs had significantly lower UCB 25(OH)D levels (p < 0.0001), TNCs (p = 0.002), MNCs (p = 0.026), and CD34+ cells (p = 0.026). Severe deficiency (25(OH)D < 10 ng/mL) was only detected in AAs. No difference in median CFC count/10,000 MNCs was detected between AAs and Caucasians. Independent of race, a significant association was detected between 25(OH)D level and TNCs (r = 0.193 p = 0.035) and Hct (r = 0.196 p = 0.033).CONCLUSIONThese results indicate the importance of 25(OH)D level as a racially independent predictor of UCB cellular characteristics and support further investigation of bioactive vitamin D and other predictors of hematopoiesis on cord blood quality.

Abstract The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. Clin Cancer Res; 21(3); 505–13. ©2015 AACR.