Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

Cell-Surface Marker Signatures for the Isolation of Neural Stem Cells, Glia and Neurons Derived from Human Pluripotent Stem Cells

Neural induction of human pluripotent stem cells often yields heterogeneous cell populations that can hamper quantitative and comparative analyses. There is a need for improved differentiation and enrichment procedures that generate highly pure populations of neural stem cells (NSC), glia and neurons. One way to address this problem is to identify cell-surface signatures that enable the isolation of these cell types from heterogeneous cell populations by fluorescence activated cell sorting (FACS).We performed an unbiased FACS- and image-based immunophenotyping analysis using 190 antibodies to cell surface markers on naïve human embryonic stem cells (hESC) and cell derivatives from neural differentiation cultures. From this analysis we identified prospective cell surface signatures for the isolation of NSC, glia and neurons. We isolated a population of NSC that was CD184(+)/CD271(-)/CD44(-)/CD24(+) from neural induction cultures of hESC and human induced pluripotent stem cells (hiPSC). Sorted NSC could be propagated for many passages and could differentiate to mixed cultures of neurons and glia in vitro and in vivo. A population of neurons that was CD184(-)/CD44(-)/CD15(LOW)/CD24(+) and a population of glia that was CD184(+)/CD44(+) were subsequently purified from cultures of differentiating NSC. Purified neurons were viable, expressed mature and subtype-specific neuronal markers, and could fire action potentials. Purified glia were mitotic and could mature to GFAP-expressing astrocytes in vitro and in vivo.These findings illustrate the utility of immunophenotyping screens for the identification of cell surface signatures of neural cells derived from human pluripotent stem cells. These signatures can be used for isolating highly pure populations of viable NSC, glia and neurons by FACS. The methods described here will enable downstream studies that require consistent and defined neural cell populations

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Alzheimer’s Dementia due to Suspected CTE from Subconcussive Head Impact

Chronic traumatic encephalopathy (CTE) has been receiving increasing attention due to press coverage of professional football players. The devastating sequelae of CTE compel us to aim for early diagnosis and treatment. However, by current standards, CTE is challenging to diagnose. Clear clinical diagnostic criteria for CTE have not been established. Only recently, pathological diagnostic criteria have been recognized, but postmortem diagnosis is too late. Reliable biomarkers are not available. By imaging criteria, cavum septum pellucidum has been the only consistent identifiable MRI finding. Because of the imprecise nature of diagnosis based on clinical suspicion, physicians must become cognizant of the broad spectrum of presentations of CTE. With this awareness, appropriate workup can be initiated. CTE can present with early symptoms of emotional changes or late symptoms with memory decline and dementia. Here we present an unusual case of a patient with Alzheimer’s disease secondary to suspected CTE that stems from subconcussive head impacts presenting with severe memory and MRI changes. Clinicians should be aware of this presentation and consider CTE in their differential diagnoses while undergoing workup of memory disorders

Emotional Lability as a Unique Presenting Sign of Suspected Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by head trauma. Diagnosis of this disease is difficult as reliable biomarkers have not been established and often this clinical entity is underappreciated with poor recognition of its clinical presentations (Lenihan and Jordan, 2015). The definitive diagnosis of CTE is determined by identification of neurofibrillary tangles in the perivascular space around the sulci in postmortem tissue (McKee et al., 2015). However, performing brain biopsies searching for neurofibrillary tangles is not a feasible option for early diagnosis. Thus, diagnosis of suspected CTE in the living has been based on clinical suspicion using proposed research criteria of clinical presentations. In addition, neuroimaging techniques have shown some promise in assisting diagnosis. Clinically, CTE is more commonly known to be associated with memory impairment and executive function disorder (Stern et al., 2013). However, here, we present two unique cases of prior professional football players where behavioral changes were the first identifying factors in clinical presentation and discuss possible neuroimaging options to help with CTE diagnosis. Because behavioral changes can be mistaken for other neuropsychological diseases, recognizing differing clinical constellations is critical to early diagnosis, early intervention, and improving patient care in suspected CTE

Emotional Lability as a Unique Presenting Sign of Suspected Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by head trauma. Diagnosis of this disease is difficult as reliable biomarkers have not been established and often this clinical entity is underappreciated with poor recognition of its clinical presentations (Lenihan and Jordan, 2015). The definitive diagnosis of CTE is determined by identification of neurofibrillary tangles in the perivascular space around the sulci in postmortem tissue (McKee et al., 2015). However, performing brain biopsies searching for neurofibrillary tangles is not a feasible option for early diagnosis. Thus, diagnosis of suspected CTE in the living has been based on clinical suspicion using proposed research criteria of clinical presentations. In addition, neuroimaging techniques have shown some promise in assisting diagnosis. Clinically, CTE is more commonly known to be associated with memory impairment and executive function disorder (Stern et al., 2013). However, here, we present two unique cases of prior professional football players where behavioral changes were the first identifying factors in clinical presentation and discuss possible neuroimaging options to help with CTE diagnosis. Because behavioral changes can be mistaken for other neuropsychological diseases, recognizing differing clinical constellations is critical to early diagnosis, early intervention, and improving patient care in suspected CTE