Microcalcifications Detected at Screening Mammography: Synthetic Mammography and Digital Breast Tomosynthesis versus Digital Mammography.

Purpose To compare the performance of two-dimensional synthetic mammography (SM) plus digital breast tomosynthesis (DBT) versus conventional full-field digital mammography (FFDM) in the detection of microcalcifications on screening mammograms. Materials and Methods In this retrospective multireader observer study, 72 consecutive screening mammograms recalled for microcalcifications from June 2015 through August 2016 were evaluated with both FFDM and DBT. The data set included 54 mammograms with benign microcalcifications and 18 mammograms with malignant microcalcifications, and 20 additional screening mammograms without microcalcifications used as controls. FFDM alone was compared to synthetic mammography plus DBT. Four readers independently reviewed each data set and microcalcification recalls were tabulated. Sensitivity and specificity for microcalcification detection were calculated for SM plus DBT and for FFDM alone. Interreader agreement was calculated with Fleiss kappa values. Results Reader agreement was kappa value of 0.66 (P < .001) for FFDM and 0.63 (P < .001) for SM plus DBT. For FFDM, the combined reader sensitivity for all microcalcifications was 80% (229 of 288; 95% confidence interval [CI]: 74%, 84%) and for malignant microcalcifications was 92% (66 of 72; 95% CI: 83%, 97%). For SM plus DBT, the combined reader sensitivity for all microcalcifications was 75% (215 of 288; 95% CI: 69%, 80%) and for malignant microcalcifications was 94% (68 of 72; 95% CI: 86%, 98%). For FFDM, the combined reader specificity for all microcalcifications was 98% (78 of 80; 95% CI: 91%, 100%) and for malignant microcalcifications was 98% (78 of 80; 95% CI: 91%, 100%). For SM plus DBT, combined reader specificity for all microcalcifications was 95% (76 of 80; 95% CI: 88%, 99%) and for malignant microcalcifications was 95% (76 of 80; 95% CI: 88%, 99%). Mixed-effects model concluded no differences between modalities (‒0.03; 95% CI: ‒0.08, 0.01; P = .13). Conclusion Relative to full-field digital mammography, synthetic mammography plus digital breast tomosynthesis had similar sensitivity and specificity for the detection of microcalcifications previously identified for recall at screening mammography. © RSNA, 2018 See also the editorial by Bae and Moon in this issue.

Effect of Background Parenchymal Enhancement on Breast MR Imaging Interpretive Performance in Community-based Practices.

Purpose To evaluate the effect of background parenchymal enhancement (BPE) on breast magnetic resonance (MR) imaging interpretive performance in a large multi-institutional cohort with independent analysis of screening and diagnostic MR studies. Materials and Methods Analysis of 3770 breast MR studies was conducted. Examinations were performed in 2958 women at six participating facilities in the San Francisco Bay Area from January 2010 to October 2012. Findings were recorded prospectively in the San Francisco Mammography Registry. Performance measures were compared between studies with low BPE (mild or minimal) and those with high BPE (moderate or marked) by using binomial tests of proportions. Results Of 1726 MR imaging studies in the screening group, 1301 were classified as having low BPE and 425 were classified as having high BPE (75% vs 25%, respectively; P < .001). Of 2044 MR imaging studies in the diagnostic group, 1443 were classified as having low BPE and 601 were classified as having high BPE (71% vs 29%, respectively; P < .001). For low versus high BPE groups at screening, abnormal interpretation rate was 157 of 1301 versus 111 of 424 (12% vs 26%, P < .001); biopsy recommendation rate was 85 of 1301 versus 54 of 424 (7% vs 13%, P < .001); and specificity was 89% (95% confidence interval [CI]: 87, 91) versus 75% (95% CI: 71, 80) (P = .01). For the low versus high BPE groups at diagnostic MR imaging, biopsy recommendation rate was 325 of 1443 versus 195 of 601 (23% vs 32%, P < .001); and specificity was 86% (95% CI: 84, 88) versus 75% (95% CI: 74, 82) (P < .001). There were no significant differences between studies with low versus high BPE in sensitivity for screening (76% [95% CI: 55, 91] vs 83% [95% CI: 52, 98]; P = .94) or diagnostic (93% [95% CI: 87, 97] vs 96% [95% CI: 87, 99]; P = .69) MR imaging, nor were there significant differences in cancer detection rate per 1000 patients between the low BPE versus high BPE groups for screening (15 per 1000 vs 24 per 1000, P = .30) or diagnostic (78 per 1000 vs 85 per 1000, P = .64) MR imaging. Conclusion Relative to MR studies with minimal or mild BPE, those with moderate or marked BPE were associated with higher abnormal interpretation and biopsy rates and lower specificity, with no difference in cancer detection rate. © RSNA, 2017 Online supplemental material is available for this article.

Altered cargo proteins of human plasma endothelial cell-derived exosomes in atherosclerotic cerebrovascular disease.

Plasma endothelial cell-derived exosomes (EDEs) and platelet-derived exosomes (PDEs) were precipitated and enriched separately by immunospecific absorption procedures for analyses of cargo proteins relevant to atherosclerosis. EDEs had usual exosome size and marker protein content, and significantly higher levels than PDEs of the endothelial proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase, whereas PDEs had significantly higher levels of platelet glycoprotein VI. EDE levels of VCAM-1, von Willebrand factor, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, and lysyl oxidase-2 and the cerebrovascular-selective proteins glucose transporter 1, permeability-glycoprotein, and large neutral amino acid transporter 1 were significantly higher for 18 patients with cerebrovascular disease (CeVD) than for 18 age- and gender-matched control subjects. PDE levels of PDGF-AA, platelet glycoprotein VI, integrin-linked kinase-1, high mobility group box-1 protein, chemokine CXCL4, and thrombospondin-1 were significantly higher in patients with CeVD than in control subjects, but differences were less with greater overlaps than for EDE proteins. EDE levels of Yes-associated protein (YAP) were higher and of P(S127)-YAP lower in patients with CeVD than in control subjects, consistent with heightened activity of this mechanical force-sensitive system in atherosclerosis. Elevated EDE and PDE levels of atherosclerosis-promoting proteins in CeVD justify clinical studies of their potential value as biomarkers.-Goetzl, E. J., Schwartz, J. B., Mustapic, M., Lobach, I. V., Daneman, R., Abner, E. L., Jicha, G. A. Altered cargo proteins of human plasma endothelial cell-derived exosomes in atherosclerotic cerebrovascular disease.

Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid ß-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

Clustered Microcysts on Breast Ultrasound: What Is an Appropriate Management Recommendation?

OBJECTIVE: The objective of our study was to determine outcomes of lesions identified as clustered microcysts on breast ultrasound to augment the existing literature and help guide appropriate management recommendations. MATERIALS AND METHODS: We retrospectively identified cases at our institution, from January 2003 through December 2013, of all lesions classified as clustered microcysts at breast ultrasound. Breast ultrasound examinations were performed by the interpreting physician. If ultrasound-guided sampling was performed, results were obtained from the pathology or cytology reports. If sampling was not performed, only lesions with at least 24 months of imaging follow-up or any imaging follow-up with interval resolution or decrease in size were included in the study. Outcomes and frequency of malignancy were determined by reviewing the electronic medical records and our PACS. RESULTS: Of 144 patients with 148 lesions classified as clustered microcysts on ultrasound, 93 patients with 95 lesions had adequate follow-up and were included in our study population. The mean patient age was 50 years (range, 32-72 years). Of the 16 lesions that underwent percutaneous sampling, none (0% [95% CI, 0-21%]) yielded malignancy. Fourteen (88%) sampled lesions were benign, and two (12%) of the sampled lesions revealed atypical ductal hyperplasia at percutaneous sampling but no atypia or upgrade at subsequent surgical excision. In total, 0 of 95 lesions (0% [95% CI, 0-3.8%]) showed malignancy at sampling or imaging follow-up. CONCLUSION: Our results support that lesions sonographically characterized as clustered microcysts carry an extremely low risk of malignancy, and biopsy should be avoided.

Spinal cord gray matter atrophy correlates with multiple sclerosis disability.

OBJECTIVE: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type. METHODS: A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. RESULTS: Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS. INTERPRETATION: SC GM atrophy is detectable in vivo in the absence of WM atrophy in RMS. It is more pronounced in progressive MS than RMS and contributes more to patient disability than SC WM or brain GM atrophy.

Handedness and language learning disability differentially distribute in progressive aphasia variants.

Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ(2) = 15.17, P < 0.001) and (χ(2) = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ(2) = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer's pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.

Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease.

BACKGROUND: There is no angiographically demonstrable obstructive coronary artery disease (CAD) in a significant minority of patients with myocardial infarction, particularly women. We sought to determine the mechanism(s) of myocardial infarction in this setting using multiple imaging techniques. METHODS AND RESULTS: Women with myocardial infarction were enrolled prospectively, before angiography, if possible. Women with ≥50% angiographic stenosis or use of vasospastic agents were excluded. Intravascular ultrasound was performed during angiography; cardiac magnetic resonance imaging was performed within 1 week. Fifty women (age, 57±13 years) had median peak troponin of 1.60 ng/mL; 11 had ST-segment elevation. Median diameter stenosis of the worst lesion was 20% by angiography; 15 patients (30%) had normal angiograms. Plaque disruption was observed in 16 of 42 patients (38%) undergoing intravascular ultrasound. There were abnormal myocardial cardiac magnetic resonance imaging findings in 26 of 44 patients (59%) undergoing cardiac magnetic resonance imaging, late gadolinium enhancement (LGE) in 17 patients, and T2 signal hyperintensity indicating edema in 9 additional patients. The most common LGE pattern was ischemic (transmural/subendocardial). Nonischemic LGE patterns (midmyocardial/subepicardial) were also observed. Although LGE was infrequent with plaque disruption, T2 signal hyperintensity was common with plaque disruption. CONCLUSIONS: Plaque rupture and ulceration are common in women with myocardial infarction without angiographically demonstrable obstructive coronary artery disease. In addition, LGE is common in this cohort of women, with an ischemic pattern of injury most evident. Vasospasm and embolism are possible mechanisms of ischemic LGE without plaque disruption. Intravascular ultrasound and cardiac magnetic resonance imaging provide complementary mechanistic insights into female myocardial infarction patients without obstructive coronary artery disease and may be useful in identifying potential causes and therapies. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00798122.

Post-lumpectomy breast calcifications: Can original tumor features assist in determining need for biopsy?

OBJECTIVE: The objective of our study was to determine whether, in the digital era, imaging features of a primary breast tumor can be used to influence the decision to biopsy ipsilateral breast calcifications that occur following surgery in women treated with breast conservation surgery (BCS). MATERIALS AND METHODS: We retrospectively identified women treated with BCS who subsequently developed suspicious calcifications in the treated breast (BI-RADS 4 or 5) from January 2012 - December 2018. Only cases with histopathological diagnosis by stereotactic or surgical biopsy were included. Pathology reports were reviewed, and biopsy results were considered malignant if invasive carcinoma or ductal carcinoma in situ (DCIS) was found. All other results were considered benign. Fisher's exact test was done comparing frequencies of malignancy between those patients whose original tumor had calcifications versus those whose original tumors were not calcified. RESULTS: Of 90 women with suspicious calcifications on a post-BCS mammogram, 65 (72.2%) were biopsy proven benign and 25 (27.8%) were malignant. The original tumor presented without calcifications in 39 patients (43%), and 51 (57%) had calcifications with or without associated mass, focal asymmetry, or architectural distortion. New calcifications were less likely to be malignant if the original tumor presented without calcifications (5/39; 12.8%) as compared to original tumors with calcifications (20/51; 38.5%) [p-value < 0.05]. CONCLUSION: New calcifications after BCS are significantly less likely to be malignant if the original tumor presented without calcifications. However, with a PPV of 12.8%, even calcifications in a patient with a non-calcified primary tumor require biopsy.

CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.

OBJECTIVE: To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). METHODS: We compared the ability of baseline CSF ß-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. RESULTS: Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). CONCLUSIONS: Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.

Adverse Trends in Ischemic Heart Disease Mortality among Young New Yorkers, Particularly Young Black Women.

BACKGROUND: Ischemic heart disease (IHD) mortality has been on the decline in the United States for decades. However, declines in IHD mortality have been slower in certain groups, including young women and black individuals. HYPOTHESIS: Trends in IHD vary by age, sex, and race in New York City (NYC). Young female minorities are a vulnerable group that may warrant renewed efforts to reduce IHD. METHODS: IHD mortality trends were assessed in NYC 1980-2008. NYC Vital Statistics data were obtained for analysis. Age-specific IHD mortality rates and confidence bounds were estimated. Trends in IHD mortality were compared by age and race/ethnicity using linear regression of log-transformed mortality rates. Rates and trends in IHD mortality rates were compared between subgroups defined by age, sex and race/ethnicity. RESULTS: The decline in IHD mortality rates slowed in 1999 among individuals aged 35-54 years but not ≥55. IHD mortality rates were higher among young men than women age 35-54, but annual declines in IHD mortality were slower for women. Black women age 35-54 had higher IHD mortality rates and slower declines in IHD mortality than women of other race/ethnicity groups. IHD mortality trends were similar in black and white men age 35-54. CONCLUSIONS: The decline in IHD mortality rates has slowed in recent years among younger, but not older, individuals in NYC. There was an association between sex and race/ethnicity on IHD mortality rates and trends. Young black women may benefit from targeted medical and public health interventions to reduce IHD mortality.

Identifying preoperative language tracts and predicting postoperative functional recovery using HARDI q-ball fiber tractography in patients with gliomas.

OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials.

INTRODUCTION: Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials. METHODS: Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS). RESULTS: Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change. CONCLUSION: Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.

Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma.

BACKGROUND: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. METHODS: We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype. RESULTS: Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs. CONCLUSIONS: Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition. FUNDING: This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.

Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.

OBJECTIVE: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. METHODS: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). RESULTS: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. CONCLUSION: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients.

Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration.

IMPORTANCE: Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians' ability to predict disease course and to design targeted management strategies. OBJECTIVE: To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches. DESIGN, SETTING AND PARTICIPANTS: In this retrospective observational study, 90 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD underwent evaluation at the Memory and Aging Center of the Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurologic examination, neuropsychological bedside testing, and socioemotional assessments. All patients underwent structural magnetic resonance imaging at their earliest evaluation at the memory clinic. From each patient's structural imaging scans, the mean volumes of 18 regions of interest (ROI) constituting the functional networks specifically vulnerable in bvFTD, including the salience network (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the semantic appraisal network (SAN), anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Data were collected from from June 19, 2002, to January 13, 2015. MAIN OUTCOMES AND MEASURES: Evaluation of brain morphology and other clinical features, including presenting symptoms, neurologic examination signs, neuropsychological performance, rate of dementia progression, and socioemotional function, in each patient cluster. RESULTS: Ninety patients (54 men [60%]; 36 women [40%]; mean [SD] age at evaluation, 55.1 [9.7] years) were included in the analysis. Four subgroups of patients with bvFTD with distinct anatomic patterns of network degeneration were identified, including 2 salience network-predominant subgroups (frontal/temporal [SN-FT] and frontal [SN-F]), a semantic appraisal network-predominant group (SAN), and a subcortical-predominant group. Subgroups demonstrated distinct patterns of cognitive, socioemotional, and motor symptoms, as well as genetic compositions and estimated rates of disease progression. CONCLUSIONS AND RELEVANCE: Divergent patterns of vulnerability in specific functional network components make an important contribution to the clinical heterogeneity of bvFTD. The data-driven anatomic classification identifies biologically meaningful anatomic phenotypes and provides a replicable approach to disambiguate the bvFTD syndrome.

Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.

We assessed the diagnostic utility of 3 CSF biomarkers-14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)-from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92-1.00) and a diagnostic accuracy of 97% (CI 90%-100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).

Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis.

IMPORTANCE: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques. OBJECTIVES: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels. DESIGN, SETTING, AND PARTICIPANTS: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital. MAIN OUTCOMES AND MEASURES: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates. RESULTS: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume. CONCLUSIONS AND RELEVANCE: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Interleukin-6, age, and corpus callosum integrity.

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

BACKGROUND: In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. METHODS: In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. FINDINGS: 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). INTERPRETATION: Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. FUNDING: Allon Therapeutics.