Evidence before this study Using PubMed and Google Scholar the authors reviewed prior work on longitudinal neuroimaging markers of Alzheimer pathology with a focus on autosomal dominant Alzheimer disease (ADAD). We searched for all articles prior to October 31 st , 2017 with no language restrictions for the keywords Alzheimer's, Alzheimer, longitudinal, positron emission tomography, PET, MRI, atrophy, FDG, hypometabolism, familial, and autosomal. Theories proposed initially in 2010 by Jack and colleagues and revised in 2013 posited temporal trajectories of Alzheimer biomarkers relative to each other and clinical decline. Work by Bateman and colleagues in 2012, Benzinger and colleagues in 2013, and Fleisher and colleagues in 2015 depict such temporal ordering of biomarkers in ADAD populations derived from cross-sectional analyses. There was also a small subset of longitudinal ADAD studies, but these had one or more limitation such as small populations (n<50), examination of only one biomarker, not accounting for regional differences or correlations in the brain, or had a short duration of longitudinal followup. Added value of this studyOur study presents the first known work examining both the longitudinal temporal trajectories and spatial patterns of Alzheimer pathology in ADAD cohorts using neuroimaging. This work also presents the largest known cohort to date of ADAD individuals studied longitudinally with multiple neuroimaging biomarkers. Longitudinal analyses can provide a more accurate and powerful way to model the temporal emergence of pathology in ADAD. We find that mutation carriers first display Aβ accumulation, followed by hypometabolism, and finally structural atrophy; this is consistent with theoretical models and cross-sectional estimates from ADAD. Most importantly we consider such temporal relationships not in one singular summary measure, but characterize these trajectories throughout the brain. We found that the accrual of pathology varied throughout the brain and by modality in terms of the time of initial emergence and the rates of longitudinal change. These findings suggest region specific vulnerabilities to β-amyloidosis, metabolic decline, and atrophy that change over the course of the disease. Implications of all the available evidenceOur results build upon existing evidence characterizing biomarkers in clinical and preclinical Alzheimer disease. Our findings suggest that imaging biomarkers follow a sequential pattern, with β-amyloidosis, hypometabolism, and structural atrophy emerging more than twenty, fifteen, and ten years respectively before the expected onset of dementia. Although there is a general hierarchical pattern, there was considerable regional heterogeneity. Most commonly, regions demonstrated an increase in β-amyloidosis and structural atrophy, but there was not evidence of metabolic declines. Further, rather than being homogenous, the same biomarker often demonstrates different longitudinal trajectories across brain regions. Characterizing the temporal and regional dynamics...

Pertuzumab is a monoclonal antibody that binds to HER2 and is used in combination with another HER2–specific monoclonal antibody, trastuzumab, for the treatment of HER2+ metastatic breast cancer. Pertuzumab binds to an HER2 binding site distinct from that of trastuzumab, and its affinity is enhanced when trastuzumab is present. We aim to exploit this enhanced affinity of pertuzumab for its HER2 binding epitope and adapt this antibody as a PET imaging agent by radiolabeling with 89Zr to increase the sensitivity of HER2 detection in vivo. Here, we investigate the biodistribution of 89Zr-pertuzumab in HER2–expressing BT-474 and HER2–nonexpressing MDA-MB-231 xenografts to quantitatively assess HER2 expression in vivo. In vitro cell binding studies were performed resulting in retained immunoreactivity and specificity for HER2–expressing cells. In vivo evaluation of 89Zr-pertuzumab was conducted in severely combined immunodeficient mice, subcutaneously inoculated with BT-474 and MDA-MB-231 cells. 89Zr-pertuzumab was systemically administered and imaged at 7 days postinjection (p.i.) followed by terminal biodistribution studies. Higher tumor uptake was observed in BT-474 compared to MDA-MB-231 xenografts with 47.5 ± 32.9 and 9.5 ± 1.7% ID/g, respectively at 7 days p.i (P = 0.0009) and blocking studies with excess unlabeled pertuzumab showed a 5-fold decrease in BT-474 tumor uptake (P = 0.0006), confirming the in vivo specificity of this radiotracer. Importantly, we observed that the tumor accumulation of 89Zr-pertuzumab was increased in the presence of unlabeled trastuzumab, at 173 ± 74.5% ID/g (P = 0.01). Biodistribution studies correlate with PET imaging quantification using max SUV (r = 0.98, P = 0.01). Collectively, these results illustrate that 89Zr-pertuzumab as a PET imaging agent may be beneficial for the quantitative and noninvasive assessment of HER2 expression in vivo especially for patients undergoing trastuzumab therapy.

Highlights Cortical signatures selective to AD could provide an early MRI biomarker. Autosomal dominant Alzheimer disease (ADAD) may model an ideal AD signature. ADAD and late-onset maps overlap in parietal cortex but contain unique features. Signatures predicted increasing amyloid within their own, but not across cohorts. These results indicate atrophy in AD can take multiple spatial patterns.

OBJECTIVECSF shunt placement is the primary therapy for hydrocephalus; however, shunt malfunctions remain common and lead to neurological deficits if missed. There is a lack of literature characterizing the epidemiology of children with possible shunt malfunctions presenting to United States emergency departments (EDs).METHODSA retrospective study was conducted of the 2006–2017 National Emergency Department Sample. The data were queried using an exhaustive list of Current Procedural Terminology and International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes representing children with hydrocephalus diagnoses, diagnostic imaging for shunt malfunctions, and shunt-related surgical revision procedures.RESULTSIn 2017, there were an estimated 16,376 ED visits for suspected shunt malfunction. Children were more commonly male (57.9%), ages 0–4 years (42.2%), and publicly insured (55.8%). Many did not undergo diagnostic imaging (37.2%), and of those who did, most underwent head CT scans (43.7%). Between 2006 and 2017, pediatric ED visits for suspected shunt malfunction increased 18% (95% CI 12.1–23.8). The use of MRI increased substantially (178.0%, 95% CI 176.9–179.2). Visits resulting in discharge home from the ED increased by 76.3% (95% CI 73.1–79.4), and those involving no surgical intervention increased by 32.9% (95% CI 29.2–36.6).CONCLUSIONSBetween 2006 and 2017, ED visits for children to rule out shunt malfunction increased, yet there was a decline in surgical intervention and an increase in discharges home from the ED. Possible contributing factors include improved clinical criteria for shunt evaluation, alternative CSF diversion techniques, changing indications for shunt placement, and increased use of advanced imaging in the ED.

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Options for nonsurgical facial rejuvenation treatment have increased significantly in both availability and popularity over the past two decades. However, there remains a paucity of clinical practice guidelines and evidence-based recommendations for these procedures. The purpose of this article is to assess for the presence of current high-level research for various methods of nonsurgical facial rejuvenation. Botulinum toxin injections remain the best studied method, with several randomized controlled trials guiding recommendations for safety and efficacy. Several studies on injectable fillers document complications and recommendations to avoid these, but sample sizes are small, and many are non-comparative. Deoxycholic acid has been well examined with FDA-approved to address submental fat, but has not been studied in other areas of the face. Although chemical peels, laser skin resurfacing, energy-based facial rejuvenation, microneedling and platelet-rich plasma have a variety of facial rejuvenation applications with minimal side effect profiles, there is significant variability with treatment protocols, outcomes measures, and randomized controlled trials with extended follow-up to develop clinical practice guidelines.

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