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Objective: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). Methods: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non‐AD dementia was investigated. Ninety patients underwent clinical evaluation (follow‐up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1‐structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. Results: A progressive increase of whole‐brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A−T−. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A−T− progressing to a mix of AD and non‐AD dementias). Adding whole‐brain AngleR as an N marker, produced good differentiation between stable and converting MCI A−T− patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). Interpretation: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A−T− patients. Further work will investigate other complexities of the real‐world clinical setting, including A−T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision‐making. [ABSTRACT FROM AUTHOR]

Successful epilepsy surgery depends on localizing and resecting cerebral abnormalities and networks that generate seizures. Abnormalities, however, may be widely distributed across multiple discontiguous areas. We propose spatially constrained clusters as candidate areas for further investigation and potential resection. We quantified the spatial overlap between the abnormality cluster and subsequent resection, hypothesizing a greater overlap in seizure‐free patients. Thirty‐four individuals with refractory focal epilepsy underwent pre‐surgical resting‐state interictal magnetoencephalography (MEG) recording. Fourteen individuals were totally seizure‐free (ILAE 1) after surgery and 20 continued to have some seizures post‐operatively (ILAE 2+). Band power abnormality maps were derived using controls as a baseline. Patient abnormalities were spatially clustered using the k‐means algorithm. The tissue within the cluster containing the most abnormal region was compared with the resection volume using the dice score. The proposed abnormality cluster overlapped with the resection in 71% of ILAE 1 patients. Conversely, an overlap only occurred in 15% of ILAE 2+ patients. This effect discriminated outcome groups well (AUC = 0.82). Our novel approach identifies clusters of spatially similar tissue with high abnormality. This is clinically valuable, providing (a) a data‐driven framework to validate current hypotheses of the epileptogenic zone localization or (b) to guide further investigation. [ABSTRACT FROM AUTHOR]

Background: Endomyocardial biopsies are standard of care for transplant surveillance, however the procedural risks are not well established, especially in children. The purpose of the study was therefore to assess procedural risks and outcomes associated with elective (surveillance) biopsies and non‐elective (clinically indicated) biopsies. Methods: We used the NCDR IMPACT registry database for this retrospective analysis. Patients undergoing an endomyocardial biopsy were identified using the procedural code, with a diagnosis of heart transplantation required. Data regarding indication, hemodynamics, adverse events and outcomes was gathered and analyzed. Results: A total of 32 547 endomyocardial biopsies were performed between 2012–2020; 31 298 (96.5%) elective and 1133 (3.5%) were non‐elective biopsies. Non‐elective biopsy was more commonly performed in infants and in those above 18 years of age, in female and in Black race patients and in those with non‐private insurance (all p <.05) and showed hemodynamic derangements. Overall rate of complications was low. Combined major adverse events were more common in non‐elective patients, with sicker patient profile, use of general anesthesia and femoral access with overall decline in these events over time. Conclusions: This large‐scale analysis shows safety of surveillance biopsies and that non‐elective biopsies carry a small but significant risk of major adverse event. Patient profile impacts the safety of the procedure. These data may serve as important comparison point for newer non‐invasive tests and for bench marking, especially in children. [ABSTRACT FROM AUTHOR]

Background: XPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a 12‐week, phase‐1b open‐label dose finding study in patients with AD (NCT03943264). An unbiased screen of imaging outcomes revealed signals for target engagement in gray matter (GM) cortices documented in the literature as regions most frequently affected by accumulation of amyloid‐beta (Aβ) in early and late phases of AD (Mattsson et al. 2019). Post‐hoc analyses were conducted to further investigate these signals. Method: Study results for patients (n = 9; MMSE range: 8‐27) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met inclusion criteria. Correlation matrices (uncorrected Pearson's r) were created to compare key secondary and exploratory imaging outcomes to clinical characteristics and CSF biomarkers of AD specific pathology (Roche Elecsys NeuroToolKit). Imaging outcomes included white matter free‐water (WM‐FW) as a prespecified proxy for neuroinflammation, and GM PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns and serves as an indicator of worsening GM microarchitecture when increased in AD. Due to the small sample size, the threshold for identification of informative values was set at P<0.05. Result: At baseline, PerpPD in GM regions associated with early Aβ accumulation (insula, precuneus, isthmus and posterior cingulate, and lateral‐orbitofrontal cortices), and WM‐FW in the cingulum bundle, showed strong associations with CSF biomarkers of neurodegeneration (pTau and tTau), inflammatory gliosis (YKL‐40, GFAP and sTREM2), cognitive status (MMSE scores) and disease duration (Table1). Week‐12 results showed decreased PerpPD+ and WM‐FW in these regions, with a dose‐dependent signal concentrated in the isthmus cingulate GM and cingulum WM. Isthmus cingulate PerpPD+ ∆ (%) correlated positively with baseline Aβ42/40 and MMSE (Figure1), and negatively with duration of disease and cingulum WM‐FW, whereas cingulum WM‐FW ∆ (%) corelated with baseline pTau and tTau (Table 2). Conclusion: PerpPD+ in isthmus cingulate GM and WM‐FW in cingulum WM represent potential indicators of disease activity sensitive to early treatment effects in small, proof of concept clinical trials for AD. Additional research is warranted to further elucidate these signals. [ABSTRACT FROM AUTHOR]

Background: The use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer's disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered. Method: The study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer's disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited. Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022). Result: Of the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1. Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ > 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone. The Cohen's d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a). Conclusion: The pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy surgery fails to achieve seizure freedom in 30%–40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient‐specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes. Methods: Resting‐state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band‐power spatial maps were computed using source‐localized recordings. Patient and region‐specific band‐power abnormalities were estimated as the maximum absolute z‐score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom. Results: Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC] = 0.80, p =.003; partial resection of epileptogenic zone: AUC = 0.68, p =.053; and insufficient cortical abnormality impact: AUC = 0.64, p =.096). Furthermore, 95% of those patients who were not seizure‐free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure‐free. Significance: The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band‐power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre‐surgical evaluations. [ABSTRACT FROM AUTHOR]

Background: Quantitative imaging studies of the pancreas have often targeted the three main anatomical segments, head, body, and tail, using manual region of interest strategies to assess geographic heterogeneity. Existing automated analyses have implemented whole‐organ segmentation, providing overall quantification but failing to address spatial heterogeneity. Purpose: To develop and validate an automated method for pancreas segmentation into head, body, and tail subregions in abdominal MRI. Study Type: Retrospective. Subjects: One hundred and fifty nominally healthy subjects from UK Biobank (100 subjects for method development and 50 subjects for validation). A separate 390 UK Biobank triples of subjects including type 2 diabetes mellitus (T2DM) subjects and matched nondiabetics. Field strength/Sequence: A 1.5 T, three‐dimensional two‐point Dixon sequence (for segmentation and volume assessment) and a two‐dimensional axial multiecho gradient‐recalled echo sequence. Assessment: Pancreas segments were annotated by four raters on the validation cohort. Intrarater agreement and interrater agreement were reported using Dice overlap (Dice similarity coefficient [DSC]). A segmentation method based on template registration was developed and evaluated against annotations. Results on regional pancreatic fat assessment are also presented, by intersecting the three‐dimensional parts segmentation with one available proton density fat fraction (PDFF) image. Statistical Test: Wilcoxon signed rank test and Mann–Whitney U‐test for comparisons. DSC and volume differences for evaluation. A P value < 0.05 was considered statistically significant. Results: Good intrarater (DSC mean, head: 0.982, body: 0.940, tail: 0.961) agreement and interrater (DSC mean, head: 0.968, body: 0.905, tail: 0.943) agreement were observed. No differences (DSC, head: P = 0.4358, body: P = 0.0992, tail: P = 0.1080) were observed between the manual annotations and our method's segmentations (DSC mean, head: 0.965, body: 0.893, tail: 0.934). Pancreatic body PDFF was different between T2DM and nondiabetics matched by body mass index. Data Conclusion: The developed segmentation's performance was no different from manual annotations. Application on type 2 diabetes subjects showed potential for assessing pancreatic disease heterogeneity. Level of Evidence: 4 Technical Efficacy Stage: 3 [ABSTRACT FROM AUTHOR]

Background: Evidence in support of the amyloid cascade hypothesis for Alzheimer's disease (AD) suggests that pathological amyloid‐beta (Aβ) is initially associated with synaptic hyperactivity and accumulates in an activity dependent fashion. These findings are corroborated by longitudinal data from cohort studies with Aβ‐PET imaging, wherein Aβ accumulates first in gray matter (GM) cortices associated with the default‐mode network (DMN) before spreading in a semi‐hierarchical pattern to different neocortical regions as the disease progresses (Mattsson et al. 2019). Mapping brain regions most frequently affected by Aβ pathology at different stages of disease may provide a framework for investigation of new drug entities targeting other components of Aβ toxicity using less invasive imaging modalities. The hypothesis here is that indicators of disease specific, tissue‐level treatment effects should be first detectable in brain regions most frequently affected by active pathology. Method: XPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a small, open‐label phase‐1b dose finding study (NCT03943264) in patients with AD. Clinical trial results for patients (n = 9) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met criteria for post‐hoc analysis. Exploratory outcomes included the novel cortical diffusivity measurement PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns, indicates microscopic disruption when increased, and has proven more sensitive than standard volumetrics to changes in indicators of synaptic function, neuroinflammation and neurodegeneration across the AD continuum. Result: Mean MMSE scores at baseline were 23.7 (SD = 2.5) and 15.8 (SD = 7.0) in the low‐dose and high‐dose groups, respectively, indicating varying degrees of severity. Week‐12 results showed decreases in bilateral PerPD+ at the whole brain level and in multiple GM cortices documented in the literature with the highest frequency of early (precuneus, isthmus cingulate, posterior cingulate, insula, and lateral and medial orbitofrontal) and late (lingual, pericalcarine, paracentral, precentral, and postcentral) Aβ accumulation (Figures1‐2). Conclusion: Cortical diffusivity measurements related to minicolumnar microstructure may provide an opportunity for noninvasive detection of early, disease specific, tissue‐level target engagement in clinical trials for investigational new drugs in AD. [ABSTRACT FROM AUTHOR]

Background: Previous research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative. Method: Three hundred and thirty‐five cognitively normal (MMSE > 24) participants with baseline CSF Aβ42 and MRI scans were obtained from the European Prevention of Alzheimer's Dementia (EPAD) cohort. Participants were classified as Aβ42‐ (N = 231) or Aβ42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM. Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni's correction (p<0.05/5). Result: The interaction between Aβ42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aβ42‐ HIGH compared to Aβ42‐ LOW and significantly higher PerpPD+ values in Aβ42+ HIGH compared to Aβ42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected. Conclusion: Cortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aβ42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aβ42+ HIGH may indicate the secondary cortical microstructural damage. References: (1) Torso et al. 2022, PMID:36281682 (2) Ingala et al. 2021 PMID:33811742 [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E ε4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer's disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer's disease neuropathological changes (ADNC). Method: Forty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n = 34) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks. Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche & Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682). Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR<0.05). Result: The cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores. Conclusion: Cortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal). Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration. [ABSTRACT FROM AUTHOR]

Roses (Rosa) are one of the most valuable ornamental flowering shrubs around the globe. They are susceptible to numerous pathogens that require management, increasing the cost of cultivation. Rose rosette virus (RRV; genus Emaravirus) is a devastating virus that has been spreading since the 1940s in the United States and Canada. It is an emerging risk to European and worldwide rose cultivation, causing symptoms such as witches' broom, malformations, excessive thorn production, and eventually plant death. RRV is transmitted by the eriophyid mite Phyllocoptes fructiphilus and by grafting. Research is being undertaken to understand RRV and to find control measures and resistant cultivars, as they are not currently available. Early detection of the disease is the key to prevent the establishment and spread of RRV and its vector. Different molecular and serological diagnostic methods have been designed and implemented, including ELISA, RT‐PCR, RT‐qPCR, LAMP, and high‐throughput sequencing. RRV infected plants can remain symptomless for long periods, so these diagnostic assays are necessary in conjunction with visual assessment to facilitate early detection. Significant social, economic, and environmental impacts are expected if RRV and its vector establish and spread in Europe. Rose trade between countries is the most likely pathway of introduction of RRV into Europe. In this review we describe current knowledge about RRV, the molecular and serological methods available for the detection of this virus, pathways to entry, and the possible impact if it establishes and spreads in Europe. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance cholangiopancreatography (MRCP) is an important tool for noninvasive imaging of biliary disease, however, its assessment is currently subjective, resulting in the need for objective biomarkers.Purpose: To investigate the accuracy, scan/rescan repeatability, and cross-scanner reproducibility of a novel quantitative MRCP tool on phantoms and in vivo. Additionally, to report normative ranges derived from the healthy cohort for duct measurements and tree-level summary metrics.Study Type: Prospective.Phantoms/subjects: Phantoms: two bespoke designs, one with varying tube-width, curvature, and orientation, and one exhibiting a complex structure based on a real biliary tree. Subjects Twenty healthy volunteers, 10 patients with biliary disease, and 10 with nonbiliary liver disease.Sequence/field Strength: MRCP data were acquired using heavily T2 -weighted 3D multishot fast/turbo spin echo acquisitions at 1.5T and 3T.Assessment: Digital instances of the phantoms were synthesized with varying resolution and signal-to-noise ratio. Physical 3D-printed phantoms were scanned across six scanners (two field strengths for each of three manufacturers). Human subjects were imaged on four scanners (two fieldstrengths for each of two manufacturers).Statistical Tests: Bland-Altman analysis and repeatability coefficient (RC).Results: Accuracy of the diameter measurement approximated the scanning resolution, with 95% limits of agreement (LoA) from -1.1 to 1.0 mm. Excellent phantom repeatability was observed, with LoA from -0.4 to 0.4 mm. Good reproducibility was observed across the six scanners for both phantoms, with a range of LoA from -1.1 to 0.5 mm. Inter- and intraobserver agreement was high. Quantitative MRCP detected strictures and dilatations in the phantom with 76.6% and 85.9% sensitivity and 100% specificity in both. Patients and healthy volunteers exhibited significant differences in metrics including common bile duct (CBD) maximum diameter (7.6 mm vs. 5.2 mm P = 0.002), and overall biliary tree volume 12.36 mL vs. 4.61 mL, P = 0.0026).Data Conclusion: The results indicate that quantitative MRCP provides accurate, repeatable, and reproducible measurements capable of objectively assessing cholangiopathic change. Evidence Level: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:807-820. [ABSTRACT FROM AUTHOR]

Background: Microstructural changes associated with the progression of Alzheimer's disease (AD) precede macrostructural atrophy. We investigate cortical microstructural changes along the AD continuum in patients with cerebrospinal fluid (CSF) AD biomarkers and plasma neurofilament light chain (NfL). Method: Three hundred fifty‐one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with CSF amyloid‐beta 42 (Aβ42) and Phosphorylated Tau 181 (pTau181) were included. The CSF pTau181‐Aβ42 ratio was used to assess the presence (+/‐) of the pathophysiological hallmarks of AD and classify the participants into four groups: 149 cognitively normal biomarker negative (CN‐), 61 cognitively normal positive (CN+), 73 patients diagnosed with Mild Cognitive Impairment positive (MCI+) and 68 AD positive (AD+). Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, sex and site‐ID, with false discovery rate correction (pFDR<0.05). The association between cortical diffusivity and NfL was investigated in a subset of 111 participants. Result: At whole‐brain level, the AD+ group exhibited significantly higher AngleR, PerpPD+, ParlPD and MD values compared to the other groups. PerpPD+ was the only measure able to differentiate between all subsequent disease stages (CN‐ and CN+ vs MCI+, and MCI+ vs AD+); regional results are presented in the Figure. Along the AD continuum, the results revealed a widespread progressive pattern of higher PerpPD+, involving mainly fronto‐temporal and occipital regions. Correlation analysis showed significant association between cortical diffusivity measures (PerpPD+ and ParlPD) and NfL values. Conclusion: Cortical diffusivity measures can detect progressive microstructural changes along the AD continuum and are significantly associated with NfL. Cortical diffusion MRI offers a microstructural marker of neurodegeneration within the ATN framework (Jack et al. 2018); as an imaging measure, regional patterns can provide disease specificity that is lacking for fluid measures like NfL. [ABSTRACT FROM AUTHOR]

Background: Several lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer's disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer's disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh). Method: Participants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe). Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR<0.05). Result: The more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1). Conclusion: Together, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system. [ABSTRACT FROM AUTHOR]

ABSTRACT This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Aβ42 and total tau were measured ( n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls ( P = 0.002) and MCI subjects ( P = 0.03), and with brain atrophy rate in controls ( P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls ( P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns. Method: A total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer's Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and "sex" and "age" as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1. Result: Differences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p<0.05) as well as age (p<0.001) and sex (p<0.001). Between‐subjects effects revealed that PerpPD (p<0.0001), ParlPD (p<0.0001), and MD (p<0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p<0.005) and cortical thickness (p<0.01) were significantly lower in the mutation carrier group. Conclusion: In autosomal dominant (inherited) Alzheimer's disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD. [ABSTRACT FROM AUTHOR]

Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient’s fungal burden. Despite this apparent improvement, the patient’s pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death. [ABSTRACT FROM AUTHOR]

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template-based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co-localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp 35:4163-4179, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Postoperative (PO) junctional ectopic tachycardia (JET) can be a life-threatening arrhythmia that follows surgical repair of congenital heart disease (CHD) and results in PO morbidity. Methods We reviewed 750 open heart surgeries (OHS) for CHD performed between January 2005 and February 2009. Kaplan-Meier and Cox proportional hazards model analyses were used to estimate the frequency and evaluate risk factors that might predict JET occurrence. Results The patients ranged in age from 1 day to 36.6 years; half were less than 4.8 months at the time of OHS. JET occurred in 115 of 750 (15.3%) OHS. JET was bimodally distributed by age with a peak incidence between 1-2 weeks and 1-3 years. JET occurred more commonly: (1) in specific types of OHS (single ventricle [19.5%] and cono-truncal defects [19.3%]) (P = 0.03); (2) with increased total surgical time (P = 0.001), aortic cross-clamp time (P < 0.001), cardiopulmonary bypass time (P < 0.001); and (3) followed use of inotropic agents (dopamine or milrinone, P < 0.001). JET lengthened intensive care stay by 3 days (P = 0.0001) and increased mortality (+JET [9.6%] vs -JET [4.6%], P = 0.03). In a multiple variable Cox regression model, total surgical time and PO use of milrinone were the best predictors for JET risk. PO administration of nitroprusside decreased risk of JET. Conclusions JET occurred more commonly following OHS associated with prolonged surgical times and PO use of inotropic medications. In contrast to previous reports, our results suggest that mechanical injury to the atrioventricular node area is not strongly associated with JET. [ABSTRACT FROM AUTHOR]

Abstract: Background: Posterior cortical atrophy (PCA) is a neurodegenerative condition predominantly associated with Alzheimer’s disease (AD) pathology. Cross-sectional imaging studies have shown different atrophy patterns in PCA patients compared with typical amnestic Alzheimer’s disease (tAD) patients, with greatest atrophy commonly found in posterior regions in the PCA group, whereas in the tAD group, atrophy is most prominent in medial temporal lobe regions. However, differential longitudinal atrophy patterns are not well understood. Methods: This study assessed longitudinal changes in brain and gray matter volumes in 17 PCA patients, 16 tAD patients, and 18 healthy control subjects. Both patient groups had symptom durations of approximately 5 years. Results: Progressive gray matter losses in both PCA and tAD patients were relatively widespread throughout the cortex, compared with control subjects, and were not confined to areas related to initial symptomatology. A multivariate classification analysis revealed a statistically significant group separation between PCA and tAD patients, with 72.7% accuracy (P < .01). Conclusion: Progression from an initially focal presentation to a more global pattern suggests that these different clinical presentations of AD might converge pathologically over time. [Copyright &y& Elsevier]

Pollen is traded internationally as a source of germplasm and for pollination. Thirty-nine viruses and five viroids are known to be pollen transmitted. We investigated whether reverse transcription-polymerase chain reaction (RT-PCR) could be used to detect viruses reliably in pollen. Four extraction methods yielded nucleic acid in appropriate quantity and quality from Tobacco ringspot virus (TRSV)-infected pollen for RT-PCR amplification. One method, the RNeasy Plant Mini Kit was used subsequently to extract nucleic acid of amplifiable quality from nine plant species, and pollen infected with three ilarvirus and two nepovirus species. A real-time TaqMan™ RT-PCR for the detection of TRSV was reliable and specific using 167 extracts of pollen from plants of Nicotiana glutinosa. The assay was highly sensitive, with extracts testing positive to a 10 dilution, equivalent to a single pollen grain. This demonstrated that RT-PCR methods can detect virus-infected pollen reliably, sensitively and specifically. The possible application of these RT-PCR methods to replace current quarantine procedures without compromising biosecurity is discussed. [ABSTRACT FROM AUTHOR]

Background and purpose: α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4- a]phthalazine) is a triazolophthalazine with subnanomolar affinity for α1-, α2-, α3- and α5-containing GABAA receptors. Here we have evaluated the relationship between plasma α5IA concentrations and benzodiazepine binding site occupancy in rodents and primates (rhesus monkey). Experimental approach: In awake rats, occupancy was measured at various times after oral dosing with α5IA (0.03–30 mg·kg−1) using an in vivo {[3H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} binding assay. In anaesthetized rhesus monkeys, occupancy was measured using {[123I]iomazenil (ethyl 5,6-dihydro-7-iodo-5-methyl-6-oxo-4 H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} γ-scintigraphy and a bolus/infusion paradigm. In both rat and rhesus monkey, the plasma drug concentration corresponding to 50% occupancy (EC50) was calculated. Key results: In rats, α5IA occupancy was dose- and time-dependent with maximum occupancy occurring within the first 2 h. However, rat plasma EC50 was time-independent, ranging from 42 to 67 ng·mL−1 over a 24 h time course with the average being 52 ng·mL−1 (i.e. occupancy decreased as plasma drug concentrations fell). In rhesus monkeys, the EC50 for α5IA displacing steady-state [123I]iomazenil binding was 57 ng·mL−1. Conclusions and implications: Rat plasma EC50 values did not vary as a function of time indicating that α5IA dissociates readily for the GABAA receptor in vivo. These data also suggest that despite the different assays used (terminal assays of [3H]flumazenil in vivo binding in rats and [123I]iomazenil γ-scintigraphy in anaesthetized rhesus monkeys), these techniques produced similar plasma α5IA EC50 values (52 and 57 ng·mL−1 respectively) and that the plasma–occupancy relationship for α5IA translates across these two species. [ABSTRACT FROM AUTHOR]

Purpose: Four cases of silicone intraocular lens (IOL) opacifications presented at a routine cataract service at a UK district general hospital. A systematic investigation was performed to identify and eliminate the causative factor. Methods: An experiment was set up to determine the role of a chemically induced IOL injury. Silicone IOLs were exposed to the various chemical agents used during cataract surgery. One IOL was not exposed to any chemicals and was used as a control. The samples were then photographed with the same camera settings against the same background in a medical photography studio. Results: All samples photographed using this technique were clear as the unexposed control IOL, except the IOLs that had come into contact with povidone iodine (PI). Exposure to higher concentrations of PI appears to give a greater opacification and staining – a graded effect. Conclusion: While the toxic effects of PI on corneal endothelial health is well recognized, as far as the authors are aware no reports exists on the possible harmful effects of PI on IOLs. The results from the current study suggest that exposure of silicone IOLs to even small volumes of 5% PI can lead to IOL opacifying effects. Further studies are needed to determine the toxic effects of PI on all IOL materials. However, based on the results of our study, we strongly recommend extreme caution in the use of PI as prophylaxis against infection at the conclusion of cataract surgery and recommend great care to ensure complete wound closure. [ABSTRACT FROM AUTHOR]

There is increasing interest in imaging cadavers for noninvasive autopsies for research purposes. However, the temperature is well below that of in vivo imaging, and a variety of interesting 'cold brain' effects are observed. At lower temperatures conventional FLAIR sequences no longer produce dark cerebrospinal fluid (CSF); T1 is reduced from about 4.0 sec in vivo to 1.7 sec at 1°C. The diffusion coefficient (DC) of CSF is much reduced (from 3.1 10−9 m2s−1 in vivo to 1.1 at 1°C). DC values therefore provide a noninvasive thermometer to measure brain core temperature to within 1.0°C. In three cadavers DC values were 1.1-1.5 10−9 m2s−1, indicating brain core temperatures of 1-10°C, consistent with external thermocouple measurements. An improved inversion time (TI0) can then be found for FLAIR. At 10°C this Cold FLAIR sequence (TI0 = 1.5 sec) gave black CSF. Expressions for CSF DC and T1 as a function of temperature were produced. A measurement of CSF DC could be converted directly to temperature and the required TI0 found. In vitro values of CSF DC were about 1% lower than that of water. Thus, FLAIR imaging can be optimized for cadaveric brains at low and unknown temperatures, thereby improving value for autopsy purposes and facilitating comparisons with in vivo imaging. Magn Reson Med, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Gram-positive pathogens are increasingly implicated in today's changing epidemiology of hospital-acquired infections. Staphylococci, streptococci, and enterococci are among the most frequently identified causes of surgical site, complicated skin-structure, and bloodstream infections. In accordance, the use of antimicrobial agents with gram-positive activity, especially those with activity against resistant organisms, has also increased. We describe a septic, neutropenic patient with bacteremia due to Enterococcus gallinarum. Therapeutic options were restricted due to resistance factors of the organism, limited guidance in the medical literature, and the patient's history and underlying condition. Despite these challenges, the patient was successfully treated with a combination of daptomycin and gentamicin and replacement of her indwelling central line. As antimicrobial stewards and diagnosticians, we must bear in mind. that selective pressures exerted by the increasing use of agents with gram-positive activity may result in an increased prevalence of organisms such as E. gallinarum. [ABSTRACT FROM AUTHOR]

Background and Purpose: Brain atrophy is a proposed marker of disease progression in multiple sclerosis (MS). Many magnetic resonance imaging-based methods of atrophy quantification exist, but their relative sensitivity and precision is unclear. Our aim was to compare atrophy rates from the brain boundary shift integral (BBSI), structural image evaluation, using normalization of atrophy (SIENA) (both registration-based methods) and segmented brain volume difference, in patients with clinically isolated syndromes (CIS), relapsing remitting MS (RRMS), and controls.Methods: Thirty-seven CIS patients, 30 with early RRMS and 16 controls had T1-weighted volumetric imaging at baseline and 1 year. Brain atrophy rates were determined using segmented brain volume difference, BBSI, and SIENA.Results: BBSI and SIENA were more precise than subtraction of segmented brain volumes and were more sensitive distinguishing RRMS subjects from controls. A strong correlation was observed between BBSI and SIENA. Atrophy rates were greater in CIS and RRMS subjects than controls (RRMS P < .001). With all methods, significantly greater atrophy rates were observed in CIS patients who developed clinically definite MS relative to subjects who did not.Conclusion: Registration-based techniques are more precise and sensitive than segmentation-based methods in measuring brain atrophy, with BBSI and SIENA providing comparable results. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether the upper cervical cord area (UCCA) is influenced by disease effect in early relapsing-remitting multiple sclerosis (MS), using statistical modeling to account for potential covariates.Materials and Methods: A cohort of 39 patients were studied cross-sectionally within three years of first symptom onset (median disease duration = 1.6 years) and compared with 26 healthy controls. The UCCA was measured from axial reconstructions of three-dimensional T1-weighted scans with automated detection of the edge of the cord. Statistical analysis adjusted for factors such as total intracranial volume (TICV) and gender. Clinical correlations, in particular those thought likely to be related to cord pathology, were also investigated.Results: No significant disease effect was noted on UCCA (P = 0.685), although there was borderline evidence of a lower UCCA in patients with symptoms of bowel or bladder disturbance (P = 0.043). A strong association was noted between UCCA and TICV (r = 0.558; P < or = 0.001), and there was a trend for females to have a smaller UCCA (P = 0.062). The latter finding appeared to reflect a gender-related difference in TICV (P < or = 0.001).Conclusion: Atrophy of the upper cervical cord is not readily apparent in most patients early in the course of relapsing-remitting MS. In evaluations of disease-related changes in the UCCA in cross-sectional studies, TICV and gender should be considered as potentially confounding covariates. [ABSTRACT FROM AUTHOR]

Learning and memory are central topics in behavioral neuroscience, and inbred mice strains are widely investigated. However, operant conditioning techniques are not as extensively used in this field as they should be, given the effectiveness of the methodology of the experimental analysis of behavior. In the present study, male C57B1/6 mice, widely used as background for transgenic studies, were trained to lever press on discrete-trial fixed-ratio 5 or fixed-interval (11 s or 31 s) schedules of food reinforcement and then exposed to 15 extinction sessions following vehicle or chlordiazepoxide injections (15 mg/kg i.p., administered either prior to all extinction sessions, or prior to the final 10 extinction sessions). Extinction of operant behavior was facilitated by drug administration following training on either schedule, but this facilitation only occurred once a number of extinction sessions had taken place. The extinction process proceeded more rapidly following fixed-interval training. Resistance to extinction was equally high following training with either schedule type, and was reduced by drug administration in both cases. These phenomena were evident in individual cumulative records and in analyses of group data. Results are interpreted in terms of phenomena of operant extinction identified in Skinner's (1938) Behavior of Organisms, and by behavioral momentum theory. These procedures could be used to extend the contribution of operant conditioning to. contemporary behavioral neuroscience. [ABSTRACT FROM AUTHOR]

a3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABAA receptors containing ana3 rather than ana1,a2 ora5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects ofa3IA are most probably mediated by thea3 subtype.a3IA has good CNS penetration in rats and mice as measured using a[3H]Ro 15-1788 in vivo binding assay.At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e.a1-containing receptors),a3IA (30?mg?kg-1 i.p.), like the nonselective partial inverse agonist N-methyl-ß-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil).Neurochemically,a3IA (30?mg?kg-1 i.p.) as well as FG 7142 (15?mg?kg-1 i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress.Taken together, these data demonstrate that an inverse agonist selective for GABAA receptors containing ana3 subunit is anxiogenic, and suggest that sincea3-containing GABAA receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.British Journal of Pharmacology (2005) 144, 357-366. doi:10.1038/sj.bjp.0706056 [ABSTRACT FROM AUTHOR]