Mykol Larvie

Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens

The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system.

Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimers disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-β status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-β positive patients with mild cognitive impairment are more likely on a path towards Alzheimers disease dementia than amyloid-β negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-β induced excitoxicity.

The Massachusetts General Hospital acute stroke imaging algorithm: an experience and evidence based approach

The Massachusetts General Hospital Neuroradiology Division employed an experience and evidence based approach to develop a neuroimaging algorithm to best select patients with severe ischemic strokes caused by anterior circulation occlusions (ACOs) for intravenous tissue plasminogen activator and endovascular treatment. Methods found to be of value included the National Institutes of Health Stroke Scale (NIHSS), non-contrast CT, CT angiography (CTA) and diffusion MRI. Perfusion imaging by CT and MRI were found to be unnecessary for safe and effective triage of patients with severe ACOs. An algorithm was adopted that includes: non-contrast CT to identify hemorrhage and large hypodensity followed by CTA to identify the ACO; diffusion MRI to estimate the core infarct; and NIHSS in conjunction with diffusion data to estimate the clinical penumbra.

Early post-bevacizumab progression on contrast-enhanced MRI as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 Central Reader Study

BACKGROUND RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS). METHODS Of 123 enrolled patients, 107 had baseline and at least 1 posttreatment MRI. Two central neuroradiologists serially measured bidimensional (2D) and volumetric (3D) enhancement on postcontrast T1-weighted images and volume of FLAIR hyperintensity. Progression status on all posttreatment MRIs was determined using Macdonald and RANO imaging threshold criteria, with a third neuroradiologist adjudicating discrepancies of both progression occurrence and timing. For each MRI pulse sequence, Kaplan-Meier survival estimates and log-rank test were used to compare OS between cases with or without radiologic progression. RESULTS Radiologic progression occurred after 2 chemotherapy cycles (8 weeks) in 9 of 97 (9%), 9 of 73 (12%), and 11 of 98 (11%) 2D-T1, 3D-T1, and FLAIR cases, respectively, and 34 of 80 (43%), 21 of 58 (36%), and 37 of 79 (47%) corresponding cases after 4 cycles (16 weeks). Median OS among patients progressing at 8 or 16 weeks was significantly less than that among nonprogressors, as determined on 2D-T1 (114 vs 278 days and 214 vs 426 days, respectively; P < .0001 for both) and 3D-T1 (117 vs 306 days [P < .0001] and 223 vs 448 days [P = .0003], respectively) but not on FLAIR (201 vs 276 days [P = .38] and 303 vs 321 days [P = .13], respectively). CONCLUSION Early progression on 2D-T1 and 3D-T1, but not FLAIR MRI, after 8 and 16 weeks of anti-vascular endothelial growth factor therapy has highly significant prognostic value for OS in recurrent GBM.

Safety and Effectiveness of Sacroplasty: A Large Single-Center Experience

The safety and effectiveness of minimally invasive sacroplasty was assessed in 53 patients treated for cancer-related, osteoporotic insufficiency and traumatic fractures. The procedure was judged to be safe and resulted in significant short-term gains in pain relief, increased mobility, and decreased dependence on pain medication. BACKGROUND AND PURPOSE: Sacral insufficiency fractures are a common cause of severe low back pain and immobilization in patients with osteoporosis or cancer. Current practice guideline recommendations range from analgesia and physical therapy to resection with surgical fixation. We sought to assess the safety and effectiveness of sacroplasty, an emerging minimally invasive treatment. MATERIALS AND METHODS: We performed a retrospective review of institutional databases for percutaneous sacroplasty performed between January 2004 and September 2013. Demographic and procedural data and pre- and posttreatment Visual Analog Scale, Functional Mobility Scale, and Analgesic Scale scores were reviewed. Overall response was rated by using a 4-point scale (1, complete resolution of pain; 2, improvement of pain; 3, no change; 4, worsened pain) assessed at short-term follow-up. RESULTS: Fifty-three patients were included; most (83%) were female. Fracture etiology was cancer-related (55%), osteoporotic insufficiency (30%), and minor trauma (15%). No major complication or procedure-related morbidity occurred. There were statistically significant decreases in the Visual Analog Scale (P < .001), Functional Mobility Scale (P < .001), and Analgesic Scale scores (P < .01) in 27 patients with recorded data: pretreatment Visual Analog Scale (median [interquartile range], 9.0 [8.0–10.0]); Functional Mobility Scale, 3.0 (2.0–3.0); and Analgesic Scale scores, 3.0 (3.0–4.0) were reduced to 3.0 (0.0–5.8), 1.0 (0.25–2.8), and 3.0 (2.0–3.8) posttreatment. When we used the overall 4-point score at a mean of 27 days, 93% (n = 45) reported complete resolution or improvement in overall pain. CONCLUSIONS: In this single-center cohort, sacroplasty was a safe and effective procedure. There were significant short-term gains in pain relief, increased mobility, and decreased dependence on pain medication.

Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice

Loss of plasma membrane integrity is a feature of acute cellular injury/death in vitro and in vivo. Plasmalemma-resealing agents are protective in acute central nervous system injury models, but their ability to reseal cell membranes in vivo has not been reported. Using a mouse controlled cortical impact (CCI) model, we found that propidium iodide-positive (PI+) cells pulse labeled at 6, 24, or 48 hours maintained a degenerative phenotype and disappeared from the injured brain by 7 days, suggesting that plasmalemma permeability is a biomarker of fatal cellular injury after CCI. Intravenous or intracerebroventricular administration of Kollidon VA64, poloxamer P188, or polyethylene glycol 8000 resealed injured cell membranes in vivo (P<0.05 versus vehicle or poloxamer P407). Kollidon VA64 (1 mmol/L, 500 μL) administered intravenously to mice 1 hour after CCI significantly reduced acute cellular degeneration, chronic brain tissue damage, brain edema, blood—brain barrier damage, and postinjury motor deficits (all P<0.05 versus vehicle). However, VA64 did not rescue pulse-labeled PI+ cells from eventual demise. We conclude that PI permeability within 48 hours of CCI is a biomarker of eventual cell death/loss. Kollidon VA64 reduces secondary damage after CCI by mechanisms other than or in addition to resealing permeable cells.

Clinical Approach to the Differential Diagnosis Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders

A middle-aged woman with obsessive-compulsive symptoms with atypical features is seen for a diagnostic neuropsychiatric assessment. “Ms. A,” a 46-year-old woman, was referred for inpatient treatment atthe Obsessive-Compulsive DisorderInstitute (OCDI) ofMcLean Hospital (Belmont, Mass.). She had no priorhistoryofpsychiatricdisorders.Twoyearsearliershe haddevelopedcleaningandcheckingritualsthatgradually becamesevereandintrusivetothepointoflosingherlongtermemployment.Shehadbeendiagnosedwithobsessivecompulsive disorder (OCD) by a community psychiatrist. Sertraline was prescribed, but she soon stopped taking it because of side effects. After a few days at the OCDI, a diagnostic neuropsychiatric assessment was requested

Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes

OBJECT World Health Organization (WHO) Grade I (benign) meningiomas with atypical features may behave more aggressively than similarly graded tumors without atypical features. Here, the prognostic significance of atypical features in benign meningiomas was determined. METHODS Data from patients diagnosed with WHO Grade I benign meningiomas per the 2007 WHO criteria and who underwent surgery between 2002 and 2012 were retrospectively reviewed. Patients were stratified by the absence or presence of 1 to 2 atypical features with review of the clinical and histological factors. RESULTS A total of 148 patients met the inclusion criteria (n = 77 with atypia; n = 71 without atypia). The median follow-up duration after pathological diagnosis was 37.5 months. Thirty patients had progression/recurrence (P/R) after initial treatment, and 22 (73%) of 30 patients with P/R had 1-2 atypical features. The presence of atypical features was significantly associated with P/R (p = 0.03) and independent of the MIB-1 labeling index. The 1-year and 5-year actuarial rates of P/R were 9.6% versus 1.4% and 30.8% versus 13.8% fortumors with and without atypical features, respectively. Higher Simpson grade resection (II-IV vs I) was associated with the increased risk of P/R (p < 0.001). Stratification of patients into low-risk (Simpson Grade I), intermediate-risk (Simpson Grade II-IV with no atypical features), and high-risk groups (Simpson Grade II-IV with atypical features) was significantly correlated with increased risk of P/R (p < 0.001). CONCLUSIONS Patients with benign meningiomas with atypical features and those undergoing Simpson Grade II-IV resection are at significantly increased risk of P/R. Patients with these features may benefit from the consideration of additional surgery and/or radiation therapy.

Brain Metabolic Abnormalities Associated with Developmental Venous Anomalies

The authors reviewed 25 developmental venous anomalies imaged with MRI and FDG-PET. Metabolic abnormalities were found in 76%, most commonly adjacent brain hypometabolism. These findings were predominantly seen in older individuals. BACKGROUND AND PURPOSE: Developmental venous anomalies are the most common intracranial vascular malformation and are typically regarded as inconsequential, especially when small. While there are data regarding the prevalence of MR imaging findings associated with developmental venous anomalies, FDG-PET findings have not been well-characterized. MATERIALS AND METHODS: Clinical information systems were used to retrospectively identify patients with developmental venous anomalies depicted on MR imaging examinations who had also undergone FDG-PET. Both the MR imaging and FDG-PET scans were analyzed to characterize the developmental venous anomalies and associated findings on the structural and functional scans. Qualitative and quantitative assessments were performed, including evaluation of the size of the developmental venous anomaly, associated MR imaging findings, and characterization of the FDG uptake in the region of the developmental venous anomaly. RESULTS: Twenty-five developmental venous anomalies in 22 patients were identified that had been characterized with both MR imaging and FDG-PET, of which 76% (19/25) were associated with significant metabolic abnormality in the adjacent brain parenchyma, most commonly hypometabolism. Patients with moderate and severe hypometabolism were significantly older (moderate: mean age, 65 ± 7.4 years, P = .001; severe: mean age, 61 ± 8.9 years, P = .008) than patients with developmental venous aberrancies that did not have abnormal metabolic activity (none: mean age, 29 ± 14 years). CONCLUSIONS: Most (more than three-quarters) developmental venous anomalies in our series of 25 cases were associated with metabolic abnormality in the adjacent brain parenchyma, often in the absence of any other structural abnormality. Consequently, we suggest that developmental venous anomalies may be better regarded as developmental venous aberrancies.

Case 9-2015: A 31-Year-Old Man with Personality Changes and Progressive Neurologic Decline

Dr. Bradford C. Dickerson: A 31-year-old right-handed man was seen in an outpatient neurology clinic of this hospital because of personality changes and progressive neurologic decline. The patient had been well until 3 years before this presentation, when his wife noticed that he was unwilling to share a portable media player that had been given to them, whereas he had previously been very generous and caring. He began to listen obsessively to audio books, insisting that he and his wife listen while cooking or driving. He impulsively purchased items they could not afford. Formerly very social, he began spending time alone; he made mistakes at work and failed advanced-degree examinations. When his wife became pregnant, he repeatedly voiced fears about losing his job if he took paternity leave. He began drinking alcohol and smoking obsessively until he vomited. After the baby was born, he seemed to be disinterested in spending time with his wife and newborn. The patient left his job as a high-school teacher because he planned to run a small home business and care for the infant so his wife could return to work. His clients soon complained about the poor quality of his work. He mixed the infant’s formula incorrectly and forgot to finish dressing the infant before leaving the house. His wife became concerned and began taking the baby to work, which did not bother the patient. The patient was seen by his physician at another facility for a routine evaluation. His wife reported his withdrawn, compulsive behaviors. He had had a serious head injury with loss of consciousness in a car accident at 12 years of age and was otherwise healthy. A presumptive diagnosis of depression was made. Eleven months after symptom onset, the patient was stopped by police for reckless driving while intoxicated, and he was taken to the emergency department of another hospital. Computed tomography of the head reportedly revealed encephalomalacia in the temporal lobes, a finding that was attributed to the head trauma that had occurred during childhood. He was admitted to a psychiatric hospital for 1 week. A diagnosis of severe depression was made, and he was released to the care From the Department of Neurology, Uni‐ versity of California, San Francisco, San Francisco (B.L.M.); and the Departments of Neurology (B.C.D., M.P.F.), Radiology (M.L.), and Pathology (M.P.F.) and the Center for Human Genetics Research (D.E.L.), Massachusetts General Hospi‐ tal, and the Departments of Neurology (B.C.D.), Radiology (M.L.), and Pathology (M.P.F.), Harvard Medical School — both in Boston.