Robust Quantitative Susceptibility Mapping via Approximate Message Passing

Purpose: It is challenging to recover magnetic susceptibility in the presence of phase errors, which may be caused by noise or strong local-susceptibility shifts in cases of brain hemorrhage and calcification. We propose a Bayesian formulation for quantitative susceptibility mapping (QSM) where a customized Gaussian-mixture distribution is used to model the long-tailed noise distribution. Theory: Complex exponential functions of the phase are used as nonlinear measurements. Wavelet coefficients of the susceptibility map are modeled by the Laplace distribution. Measurement noise is modeled by a two-component Gaussian-mixture distribution, where the second component is reserved to model the noise outliers. The susceptibility map and distribution parameters are jointly recovered using approximate message passing (AMP). Methods: The proposed AMP with built-in parameter estimation (AMP-PE) is compared with the state-of-the-art nonlinear L1-QSM and MEDI approaches that adopt the L1-norm and L2-norm data-fidelity terms respectively. They are tested on the simulated and in vivo datasets. Results: On the simulated Sim2Snr1 dataset, AMP-PE achieved the lowest NRMSE and SSIM, MEDI achieved the lowest HFEN. On the in vivo datasets, AMP-PE is more robust and better at preserving structural details and removing streaking artifacts in the hemorrhage cases than L1-QSM and MEDI. Conclusion: By leveraging a customized Gaussian-mixture noise prior, AMP-PE achieves better performance in challenging cases of brain hemorrhage and calcification. It is equipped with built-in parameter estimation, which avoids subjective bias from the usual visual-tuning step of in vivo reconstruction.Comment: Keywords: Approximate message passing, Compressive sensing, Parameter estimation, QS

Model-based T1, T2* and Proton Density Mapping Using a Bayesian Approach with Parameter Estimation and Complementary Undersampling Patterns

Purpose: To achieve automatic hyperparameter estimation for the joint recovery of quantitative MR images, we propose a Bayesian formulation of the reconstruction problem that incorporates the signal model. Additionally, we investigate the use of complementary undersampling patterns to determine optimal undersampling schemes for quantitative MRI. Theory: We introduce a novel nonlinear approximate message passing framework, referred to as ``AMP-PE'', that enables the simultaneous recovery of distribution parameters and quantitative maps. Methods: We employed the variable flip angle multi-echo (VFA-ME) method to acquire measurements. Both retrospective and prospective undersampling approaches were utilized to obtain Fourier measurements using variable-density and Poisson-disk patterns. Furthermore, we extensively explored various undersampling schemes, incorporating complementary patterns across different flip angles and/or echo times. Results: AMP-PE adopts a model-based joint recovery strategy, it outperforms the $l_1$-norm minimization approach that follows a decoupled recovery strategy. A comparison with an existing joint-recovery approach further demonstrates the advantageous outcomes of AMP-PE. For quantitative $T_1$ mapping using VFA-ME, employing identical k-space sampling patterns across different echo times produced the best performance. Whereas for $T_2^*$ and proton density mappings, using complementary sampling patterns across different flip angles yielded the best performance. Conclusion: AMP-PE is equipped with built-in parameter estimation, and works naturally in clinical settings with varying acquisition protocols and scanners. It also achieves improved performance by combining information from the MR signal model and the sparse prior on images

Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates

BACKGROUND: The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Aβ production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75(NTR )and proNGF. We have investigated and provide evidence for γ-secretase cleavage of this family of proteins. RESULTS: We provide evidence that these receptors are substrates for presenilin dependent γ-secretase cleavage. γ-Secretase cleavage of these sorting receptors is inhibited by γ-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most γ-secretase substrates, we find that ectodomain shedding precedes γ-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an α-secretase like cleavage. CONCLUSION: These data indicate that the α- and γ-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known γ-secretase substrates, and could possibly regulate the biological functions of these proteins

Decision-making in sustainable uban mobility planning: Common practice and future directions

This paper highlights the challenges for cities in selecting sustainable and cost-effective transport and mobility measures. Thereby it shall provoke thought on the implications for decision-making resulting from Sustainable Urban Mobility Plans. Firstly, an understanding of the challenges of determining a transport project’s viability will be conveyed. Secondly, the paper presents five case studies of sustainable urban mobility planning and the role of project appraisal in those policy-making processes.In discussing the challenges of traditional project-appraisal and examining actual local decision-making, the paper finds some crucial challenges in the appraisal of small-scale sustainable transport activities. It concludes by highlighting potential implications of these

Proteomic Analysis of Hippocampal Dentate Granule Cells in Frontotemporal Lobar Degeneration: Application of Laser Capture Technology

Frontotemporal lobar degeneration (FTLD) is the most common cause of dementia with pre-senile onset, accounting for as many as 20% of cases. A common subset of FTLD cases is characterized by the presence of ubiquitinated inclusions in vulnerable neurons (FTLD-U). While the pathophysiological mechanisms underlying neurodegeneration in FTLD-U have not yet been elucidated, the presence of inclusions in this disease indicates enhanced aggregation of one or several proteins. Moreover, these inclusions suggest altered expression, processing, or degradation of proteins during FTLD-U pathogenesis. Thus, one approach to understanding disease mechanisms is to delineate the molecular changes in protein composition in FTLD-U brain. Using a combined approach consisting of laser capture microdissection (LCM) and high-resolution liquid chromatography-tandem mass spectrometry (LC–MS/MS), we identified 1252 proteins in hippocampal dentate granule cells excised from three post-mortem FTLD-U and three unaffected control cases processed in parallel. Additionally, we employed a labeling-free quantification technique to compare the abundance of the identified proteins between FTLD-U and control cases. Quantification revealed 54 proteins with selective enrichment in FTLD-U, including TAR–DNA binding protein 43 (TDP-43), a recently identified component of ubiquitinated inclusions. Moreover, 19 proteins were selectively decreased in FTLD-U. Subsequent immunohistochemical analysis of TDP-43 and three additional protein candidates suggests that our proteomic profiling of FTLD-U dentate granule cells reveals both inclusion-associated proteins and non-aggregated disease-specific proteins. Application of LCM is a valuable tool in the molecular analysis of complex tissues, and its application in the proteomic characterization of neurodegenerative disorders such as FTLD-U may be used to identify proteins altered in disease

Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

Background: Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN) occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD). The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP), events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s) in APP that regulate its sorting to the TGN have not been characterized. Results: Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life. Conclusions: We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to the TGN or lysosomes. Significantly, the data are consistent with known interactions involving the retromer, SorLA and APP. Further, these findings add to our understanding of APP targeting and potentially contribute to our knowledge of sporadic AD pathogenesis representing putative new targets for AD therapeutic strategies

Characterization of the manganese sites in manganese redox enzymes: Catalase and superoxide dismutase.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30701/1/0000346.pd

Development of a Rapid Screening Instrument for Mild Cognitive Impairment and Undiagnosed Dementia

Mild cognitive impairment (MCI) often presages development of Alzheimer’s disease (AD). We recently completed a cross-sectional study to test the hypothesis that a combination of a brief cognitive screening instrument (Mini-Cog) with a functional scale (Functional Activities Questionnaire; FAQ) would accurately identify individuals with MCI and undiagnosed dementia. The Mini-Cog consists of a clock drawing task and 3-item recall, and takes less than 5 minutes to administer. The FAQ is a 30-item questionnaire completed by an informant. In addition to the Mini-Cog and FAQ, a traditional cognitive test battery was administered, and two neurologists and a neuropsychologist determined a consensus diagnosis of Normal, MCI, or Dementia. A classification tree algorithm was used to pick optimal cutpoints, and, using these cutpoints, the combined Mini-Cog and FAQ (MC-FAQ) predicted the consensus diagnosis with an accuracy of 83% and a weighted kappa of 0.81. When the population was divided into Normal and Abnormal, the sensitivity, specificity and positive predictive value were 89%, 90%, and 95%, respectively. The MC-FAQ discriminates individuals with MCI from cognitively normal individuals and those with dementia, and its ease of administration makes it an attractive screening instrument to aid detection of cognitive impairment in the elderly