Comprehensive evaluation of AT(N) imaging biomarkers for predicting cognition.

Background And Objectives: Imaging biomarkers enable quantification of amyloid, tau, and neurogenerative pathologies that develop in Alzheimer's Disease (AD). Interest in imaging biomarkers has led to a wide variety of biomarker definitions, some of which potentially offer less predictive value than others. We aimed to assess how different operationalizations of AD imaging biomarkers affect prediction of cognition.

Evaluation of ComBat Harmonization for Reducing Across-Tracer Differences in Regional Amyloid PET Analyses.

Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [F]-florbetapir (FBP) and [C]-Pittsburgh compound-B (PiB).

Analyzing heterogeneity in Alzheimer Disease using multimodal normative modeling on imaging-based ATN biomarkers.

Introduction: Previous studies have applied normative modeling on a single neuroimaging modality to investigate Alzheimer Disease (AD) heterogeneity. We employed a deep learning-based multimodal normative framework to analyze individual-level variation across ATN (amyloid-tau-neurodegeneration) imaging biomarkers.

Methods: We selected cross-sectional discovery (n = 665) and replication cohorts (n = 430) with available T1-weighted MRI, amyloid and tau PET.

Evaluation of ComBat harmonization for reducing across-tracer differences in regional amyloid PET analyses.

Introduction: Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [F]-florbetapir (FBP) and [C]-Pittsburgh Compound-B (PiB).

Data-driven decomposition and staging of flortaucipir uptake in Alzheimer's disease.

Introduction: Previous approaches pursuing in vivo staging of tau pathology in Alzheimer's disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression.

Methods: We selected discovery (n = 418) and replication (n = 132) cohorts with flortaucipir imaging.

Patterns of Glucose Metabolism in [ F]FDG PET Indicate Regional Variability and Neurodegeneration in the Progression of Alzheimer's Dementia.

Unlabelled: In disorders of cognitive impairment, such as Alzheimer's disease, neurodegeneration is the final common pathway of disease progression. Modulating, reversing, or preventing disease progression is a clinical imperative most likely to succeed following accurate and explanatory understanding of neurodegeneration, requiring enhanced consistency with quantitative measurements and expanded interpretability of complex data. The on-going study of neurodegeneration has robustly demonstrated the advantages of accumulating large amounts of clinical data that include neuroimaging, motiving multi-center studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Analyzing heterogeneity in Alzheimer Disease using multimodal normative modeling on imaging-based ATN biomarkers.

Introduction: Previous studies have applied normative modeling on a single neuroimaging modality to investigate Alzheimer Disease (AD) heterogeneity. We employed a deep learning-based multimodal normative framework to analyze individual-level variation across ATN (amyloid-tau-neurodegeneration) imaging biomarkers.

Methods: We selected cross-sectional discovery (n = 665) and replication cohorts (n = 430) with available T1-weighted MRI, amyloid and tau PET.

The Health & Aging Brain among Latino Elders (HABLE) study methods and participant characteristics.

Introduction: Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature.

Methods: Community-dwelling Mexican Americans and non-Hispanic White adults and elders (age 50 and above) were recruited.

Regional relationships between CSF VEGF levels and Alzheimer's disease brain biomarkers and cognition.

Vascular endothelial growth factor (VEGF) is a complex signaling protein that supports vascular and neuronal function. Alzheimer's disease (AD) -neuropathological hallmarks interfere with VEGF signaling and modify previously detected positive associations between cerebral spinal fluid (CSF) VEGF and cognition and hippocampal volume. However, it remains unknown 1) whether regional relationships between VEGF and glucose metabolism and cortical thinning exist, and 2) whether AD-neuropathological hallmarks (CSF Aβ, t-tau, p-tau) also modify these relationships.

White matter hyperintensities and their relationship to cognition: Effects of segmentation algorithm.

White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer's disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent.

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results.

miR-221/222 compensates for Skp2-mediated p27 degradation and is a primary target of cell cycle regulation by prostacyclin and cAMP.

p27(kip1) (p27) is a cdk-inhibitory protein with an important role in the proliferation of many cell types. SCF(Skp2) is the best studied regulator of p27 levels, but Skp2-mediated p27 degradation is not essential in vivo or in vitro. The molecular pathway that compensates for loss of Skp2-mediated p27 degradation has remained elusive.

Apolipoprotein E-mediated cell cycle arrest linked to p27 and the Cox2-dependent repression of miR221/222.

Objective: In addition to its effects on cholesterol levels, apoE3 has lipid-independent effects that contribute to cardiovascular protection; one of these effects is the ability to inhibit cell cycling in VSMCs. The goal of this study was to identify and characterize cell cycle-regulatory mechanisms responsible for the anti-mitogenic effect of apoE.

Methods And Results: Primary VSMCs were stimulated with serum in the absence or presence of apoE3.

Microsomal prostaglandin e2 synthase-1 modulates the response to vascular injury.

Background: Microsomal (m) prostaglandin (PG) E₂ synthase (S)-1 catalyzes the formation of PGE₂ from PGH₂, a cyclooxygenase product that is derived from arachidonic acid. Previous studies in mice suggest that targeting mPGES-1 may be less likely to cause hypertension or thrombosis than cyclooxygenase-2-selective inhibition or deletion in vivo. Indeed, deletion of mPGES-1 retards atherogenesis and angiotensin II-induced aortic aneurysm formation.

Cell-type- and cell-cycle-specific anti-mitogenesis by cicaprost.

Stents eluting anti-proliferative drugs limit restenosis, but drugs commonly used to date are relatively non-specific cytostatic agents which inhibit proliferation of intimal endothelial cells as well as medial smooth muscle cells and may thereby contribute to the clinical complications associated with angioplasty. In an effort to identify a more specific anti-proliferative agent, we compared the effects of rapamycin to those of cicaprost, a mimetic of the naturally occurring anti-mitogen, PGI(2). Rapamycin and cicaprost were both strongly anti-mitogenic in vascular smooth muscle cells (VSMCs).

Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening.

Background: A number of adhesion-mediated signaling pathways and cell-cycle events have been identified that regulate cell proliferation, yet studies to date have been unable to determine which of these pathways control mitogenesis in response to physiologically relevant changes in tissue elasticity. In this report, we use hydrogel-based substrata matched to biological tissue stiffness to investigate the effects of matrix elasticity on the cell cycle.

Results: We find that physiological tissue stiffness acts as a cell-cycle inhibitor in mammary epithelial cells and vascular smooth muscle cells; subcellular analysis in these cells, mouse embryonic fibroblasts, and osteoblasts shows that cell-cycle control by matrix stiffness is widely conserved.

Differential activation of ERK and Rac mediates the proliferative and anti-proliferative effects of hyaluronan and CD44.

Hyaluronan, a widely distributed component of the extracellular matrix, exists in a high molecular weight (native) form and lower molecular weight form (HMW- and LMW-HA, respectively). These different forms of hyaluronan bind to CD44 but elicit distinct effects on cellular function. A striking example is the opposing effects of HMW- and LMW-HA on the proliferation of vascular smooth muscle cells; the binding of HMW-HA to CD44 inhibits cell cycle progression, whereas the binding of LMW-HA to CD44 stimulates cell cycle progression.

Joint requirement for Rac and ERK activities underlies the mid-G1 phase induction of cyclin D1 and S phase entry in both epithelial and mesenchymal cells.

Cyclin D1 gene induction is a key event in G1 phase progression. Our previous studies indicated that signaling to cyclin D1 is cell type-dependent because the timing of cyclin D1 gene expression in MCF10A mammary epithelial cells and mesenchymal cells such as fibroblasts and vascular smooth muscle cells is very different, with epithelial cells first expressing cyclin D1 in early rather than mid-G1 phase. In this report, we induced a mesenchymal phenotype in MCF10A cells by long-term exposure to TGF-beta and used the control and transitioned cells to examine cell type specificity of the signaling pathways that regulate cyclin D1 gene expression.

Cell adhesion, cellular tension, and cell cycle control.

Cooperative signaling between growth factor receptor tyrosine kinases, integrins, and the actin cytoskeleton is required for activation of the G1-phase cyclin-dependent kinases and progression through G1-phase. Increasing evidence suggests that there is cell type specificity in these cooperative interactions and that the compliance of the underlying substratum can strongly affect adhesion-dependent signaling to the cell cycle. This chapter reviews our current methods for studying how cell type specificity and changes in substratum compliance can contribute to G1-phase cell cycle control.

Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.

High molecular weight (HMW) hyaluronan (HA) is widely distributed in the extracellular matrix, but its biological activities remain incompletely understood. We previously reported that HMW-HA binding to CD44 antagonizes mitogen-induced S-phase entry in vascular smooth muscle cells (SMCs; Cuff, C.A.

Antimitogenic effects of prostacyclin on the G1 phase cyclin-dependent kinases.

The prostanoid prostacyclin (PGI2) inhibits proliferation of cultured vascular SMCs by inhibiting cell cycle progression from G1 to S phase. Progression through G1 phase is regulated by the sequential activation of the G1 phase cyclin-dependent kinases (cdks). Recent studies have shown that PGI2-dependent activation of its receptor, IP, inhibits G1 phase progression by blocking the degradation of p27 and the activation of cyclin E-cdk2.

Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21.

Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCdelta mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 phase impaired progression of lung adenocarcinoma cells into S phase, an effect that was completely abolished by specific depletion of PKCdelta, but not PKCalpha.

Antimitogenesis linked to regulation of Skp2 gene expression.

Prostacyclin has many effects in the vasculature; one of the less well understood is the ability to block cell cycle progression through G(1) phase. We previously reported that the prostacyclin mimetic, cicaprost, selectively inhibits cyclin E-cyclin-dependent kinase-2 (Cdk2), and now we show that it acts by regulating the expression of Skp2, the F-box protein that targets p27(Kip1) for ubiquitin-mediated proteolysis. First, we show that cicaprost prevents the late G(1) phase down-regulation of p27(Kip1) and that the inhibitory effect of cicaprost on cyclin E-Cdk2 activity and S phase entry is eliminated by deleting p27(Kip1).

Antimitogenic effects of HDL and APOE mediated by Cox-2-dependent IP activation.

HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor-binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein-dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP.