A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease

Background: Alzheimer’s disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. Methods: We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). Results: The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer’s related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype. Conclusions: This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis

Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.Medical Research CouncilThis is the final version of the article. It first appeared from the British Medical Journal via https://doi.org/10.1136/thoraxjnl-2015-20740

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHK alpha). due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [F-18]fluoromethyl-[1,2-H-2(4)]choline ([F-18]D4-FCH). [F-18]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a H-1/D-2 isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [F-18]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [F-18]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [F-18]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. the sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12–16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk

Neurobiology and phenotypic expression in early onset schizophrenia

AIM: Early-onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult-onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early-onset schizophrenia. METHODS: A synthetic and integrative approach is applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia. RESULTS: Childhood and adolescent-onset schizophrenia is associated with severe clinical course, greater rates of premorbid abnormalities, poor psychosocial functioning and increased severity of brain abnormalities. Early-onset cases show similar neurobiological correlates and phenotypic deficits to adult-onset schizophrenia, but show worse long-term psychopathological outcome. Emerging technological advances have provided important insights into the genomic architecture of early-onset schizophrenia, suggesting that some genetic variations may occur more frequently and at a higher rate in young-onset than adult-onset cases. CONCLUSIONS: Clinical, cognitive, genetic and imaging data suggest increased severity in early-onset schizophrenia. Studying younger-onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene-environment interactions leading to the emergence of this debilitating disorder

Visual atrophy rating scales and amyloid PET status in an Alzheimer's disease clinical cohort

Abstract Objectives Visual rating scales (VRS) are the quantification method closest to the approach used in routine clinical practice to assess brain atrophy. Previous studies have suggested that the medial temporal atrophy (MTA) rating scale is a reliable diagnostic marker for AD, equivalent to volumetric quantification, while others propose a higher diagnostic utility for the Posterior Atrophy (PA) scale in early‐onset AD. Methods Here, we reviewed 14 studies that assessed the diagnostic accuracy of PA and MTA, we explored the issue of cut‐off heterogeneity, and assessed 9 rating scales in a group of patients with biomarker‐confirmed diagnosis. A neuroradiologist blinded to all clinical information rated the MR images of 39 amyloid‐positive and 38 amyloid‐negative patients using 9 validated VRS assessing multiple brain regions. Automated volumetric analyses were performed on a subset of patients (n = 48) and on a group of cognitively normal individuals (n = 28). Results No single VRS could differentiate amyloid‐positive from amyloid‐negative patients with other neurodegenerative conditions. 44% of amyloid‐positive patients were deemed to have age‐appropriate levels of MTA. In the amyloid‐positive group, 18% had no abnormal MTA or PA scores. These findings were substantially affected by cut‐off selection. Amyloid‐positive and amyloid‐negative patients had comparable hippocampal and parietal volumes, and MTA but not PA scores correlated with the respective volumetric measures. Interpretation Consensus guidelines are needed before VRS can be recommended for use in the diagnostic workup of AD. Our data are suggestive of high intragroup variability and non‐superiority of volumetric quantification of atrophy over visual assessment