Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporal cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients

Preoperative neutrophil-lymphocyte ratio and outcome from coronary artery bypass grafting

Background: An elevated preoperative white blood cell count has been associated with a worse outcome after coronary artery bypass grafting (CABG). Leukocyte subtypes, and particularly the neutrophil-lymphocyte (N/L) ratio, may however, convey superior prognostic information. We hypothesized that the N/L ratio would predict the outcome of patients undergoing surgical revascularization. Methods: Baseline clinical details were obtained prospectively in 1938 patients undergoing CABG. The differential leukocyte was measured before surgery, and patients were followed-up 3.6 years later. The primary end point was all-cause mortality. Results: The preoperative N/L ratio was a powerful univariable predictor of mortality (hazard ratio [HR] 1.13 per unit, P 3.36). Conclusion: An elevated N/L ratio is associated with a poorer survival after CABG. This prognostic utility is independent of other recognized risk factors.Peer reviewedAuthor versio

Automated VOI Analysis in FDDNP PET Using Structural Warping: Validation through Classification of Alzheimer's Disease Patients

We evaluate an automated approach to the cortical surface mapping (CSM) method of VOI analysis in PET. Although CSM has been previously shown to be successful, the process can be long and tedious. Here, we present an approach that removes these difficulties through the use of 3D image warping to a common space. We test this automated method using studies of FDDNP PET in Alzheimer's disease and mild cognitive impairment. For each subject, VOIs were created, through CSM, to extract regional PET data. After warping to the common space, a single set of CSM-generated VOIs was used to extract PET data from all subjects. The data extracted using a single set of VOIs outperformed the manual approach in classifying AD patients from MCIs and controls. This suggests that this automated method can remove variance in measurements of PET data and can facilitate accurate, high-throughput image analysis

An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

Acknowledgements The authors would like to acknowledge the NHS Grampian Biorepository for their support and assistance with all immunohistochemistry. Sources of funding This work was generously funded by the British Heart Foundation, UK (FS/17/28/32807) and Grampian NHS Endowments.Peer reviewedPublisher PD

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE

Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition. METHODS: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort. RESULTS: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events. CONCLUSION: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP

Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding

Objectives Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations. Design We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity. Results Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. Conclusions The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut–brain axis in the control of reward-based eating behaviour

Decoding of Superimposed Traces Produced by Direct Sequencing of Heterozygous Indels

Direct Sanger sequencing of a diploid template containing a heterozygous insertion or deletion results in a difficult-to-interpret mixed trace formed by two allelic traces superimposed onto each other. Existing computational methods for deconvolution of such traces require knowledge of a reference sequence or the availability of both direct and reverse mixed sequences of the same template. We describe a simple yet accurate method, which uses dynamic programming optimization to predict superimposed allelic sequences solely from a string of letters representing peaks within an individual mixed trace. We used the method to decode 104 human traces (mean length 294 bp) containing heterozygous indels 5 to 30 bp with a mean of 99.1% bases per allelic sequence reconstructed correctly and unambiguously. Simulations with artificial sequences have demonstrated that the method yields accurate reconstructions when (1) the allelic sequences forming the mixed trace are sufficiently similar, (2) the analyzed fragment is significantly longer than the indel, and (3) multiple indels, if present, are well-spaced. Because these conditions occur in most encountered DNA sequences, the method is widely applicable. It is available as a free Web application Indelligent at http://ctap.inhs.uiuc.edu/dmitriev/indel.asp

Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors

BACKGROUND:HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration. METHODS: Prospective cohort study of 292 adults who initiated antituberculosis treatment during a 3-month period. We evaluated those with clinical deterioration over the following 24 weeks of treatment. RESULTS: Seventy-one percent (209/292) of patients were HIV-1 infected (median CD4+: 129 cells/muL [IQR:62-277]). At tuberculosis diagnosis, 23% (34/145) of HIV-1 infected patients qualifying for antiretroviral treatment (ART) were receiving ART; 6 months later, 75% (109/145) had received ART. Within 24 weeks of initiating antituberculosis treatment, 40% (117/292) of patients experienced clinical deterioration due to co-morbid illness (n = 70), tuberculosis related illness (n = 47), non AIDS-defining HIV-1 related infection (n = 25) and AIDS-defining illness (n = 21). Using HIV-1 uninfected patients as the referent group, HIV-1 infected patients had an increasing risk of clinical deterioration as CD4+ counts decreased [CD4+>350 cells/muL: RR = 1.4, 95% CI = 0.7-2.9; CD4+:200-350 cells/muL: RR = 2.0, 95% CI = 1.1-3.6; CD4+<200 cells/muL: RR = 3.0, 95% CI = 1.9-4.7]. During follow-up, 26% (30/117) of patients with clinical deterioration required hospital admission and 15% (17/117) died. Fifteen deaths were in HIV-1 infected patients with a CD4+<200 cells/muL. CONCLUSIONS: In multivariate analysis, HIV-1 infection and a low CD4+ count at tuberculosis diagnosis were significant risk factors for clinical deterioration and death. The initiation of ART at a CD4+ count of <350 cells/muL will likely reduce the high burden of clinical deterioration