Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight-based intravenous ravulizumab dosing. Primary end points were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary end points assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) eculizumab-experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 µg/mL in the PEP and EP except in 1 patient. At the end of the study, pre- and post-infusion mean ± standard deviation serum ravulizumab concentrations were 610.50 ± 201.53 µg/mL and 518.29 ± 109.67 µg/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 µg/mL in both cohorts until the end of the study (0.061 ± 0.021 µg/mL and 0.061 ± 0.018 µg/mL for eculizumab-naive and eculizumab-experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH. This trial was registered at www.ClinicalTrials.gov as #NCT03406507.

Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up.

INTRODUCTION: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (Ctrough). Secondary endpoints were ravulizumab Ctrough and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff. RESULTS: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab Ctrough values were > 175 µg/mL (PK threshold) and free C5 < 0.5 µg/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had ≥ 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts. CONCLUSIONS: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy. TRIAL REGISTRATION: NCT03748823.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by the destruction of red blood cells (hemolysis) within blood vessels. In addition to hemolysis, patients with PNH are susceptible to life-threatening blood clots (thromboses). Eculizumab and ravulizumab are types of treatments for PNH, called C5 inhibitors. In the blood, these treatments bind to C5 protein and prevent the destruction of red blood cells, reducing the symptoms and complications of PNH. Both treatments are approved for use via intravenous (through the vein) administration. Ravulizumab is also approved in the USA for use via subcutaneous (under the skin) administration. This study compared subcutaneous ravulizumab with intravenous ravulizumab in patients with PNH who had previously been treated with eculizumab. During the initial treatment period of 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous ravulizumab. Following this period, all patients received subcutaneous ravulizumab. At day 71, the amount of ravulizumab in the blood of patients taking subcutaneous ravulizumab was no less than in patients taking intravenous ravulizumab and was maintained over 1 year of treatment. Efficacy measures (how well it works) remained stable in patients taking subcutaneous ravulizumab for 1 year and side effects were comparable with those of intravenous ravulizumab. Patients reported more satisfaction with subcutaneous ravulizumab than intravenous eculizumab, as assessed by the Treatment Administration Satisfaction Questionnaire. This study showed that patients with PNH can switch from intravenous eculizumab or ravulizumab to subcutaneous ravulizumab without loss of efficacy. Subcutaneous ravulizumab provides an additional treatment choice for patients with PNH.

Free water derived by multi-shell diffusion MRI reflects tau/neuroinflammatory pathology in Alzheimer's disease.

Introduction: Free-water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods: Seventy-one participants underwent multi-shell diffusion MRI, 18F-THK5351 PET, 11C-Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) (n = 40) and AD-spectrum group (AD-S) (n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results: In AD-S group, there was a significant positive correlation between FW and 18F-THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18F-THK5351 and cognitive function in the same regions. Discussion: FW imaging could be a biomarker for tau in AD alongside clinical correlations.

Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies.

OBJECTIVES: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years. METHODS: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed. RESULTS: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%). CONCLUSIONS: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults.

OBJECTIVE: Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I] FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults. METHODS: We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject's striatum and then converted the [123I] FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60 years). RESULTS: When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding. CONCLUSION: Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 µg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 µg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.

The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment. METHODS: Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4-8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period. RESULTS: No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m2 at baseline, 93.5 mL/min/1.73m2 at 26 weeks, and 104 mL/min/1.73m2 at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study. CONCLUSIONS: Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4-8 weeks. TRIAL REGISTRATION: Trial identifiers: Trial ID: ALXN1210-aHUS-312 Clinical trials.gov : NCT03131219 EudraCT number: 2016-002499-29 Graphical abstract.

Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

INTRODUCTION: The molecular mechanism of neurodegeneration, including tau and neurite complexity, is an important topic in Alzheimer's disease (AD) research. METHODS: We recruited 27 amyloid-positive individuals identified through 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) and 31 amyloid-negative individuals with normal cognition. All participants underwent 11C-PiB and 18F-THK5351 PET and magnetic resonance imaging (MRI) with neurite orientation dispersion and density imaging (NODDI) protocol. The neurite density index (NDI), orientation dispersion index (ODI), and PET images were analyzed to calculate voxel-wise correlations among the imaging modalities and correlations with cognitions. RESULTS: In the amyloid-positive participants, there were significant negative correlations between 18F-THK5351 and NDI and between 18F-THK5351 and ODI. The bilateral mesial and lateral temporal lobes were mainly involved. Regarding cognition, 18F-THK5351 showed more marked associations with all cognitive domains than the other modalities. DISCUSSION: Tau and neuroinflammation in AD may reduce the neurite density and orientation dispersion, particularly in the mesial and lateral temporal lobes.

Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

Quantitative Evaluation of 18F-Flutemetamol PET in Patients With Cognitive Impairment and Suspected Alzheimer's Disease: A Multicenter Study.

Background: In clinical practice, equivocal findings are inevitable in visual interpretation of whether amyloid positron emission tomography (PET) is positive or negative. It is therefore necessary to establish a more objective quantitative evaluation method for determining the indication for disease-modifying drugs currently under development. Aims: We aimed to determine cutoffs for positivity in quantitative analysis of 18F-flutemetamol PET in patients with cognitive impairment and suspected Alzheimer's disease (AD). We also evaluated the clinical efficacy of amyloid PET in the diagnosis of AD. This study was registered in the Japan Registry of Clinical Trials (jRCTs, 031180321). Methods: Ninety-three patients suspected of having AD underwent 18F-flutemetamol PET in seven institutions. A PET image for each patient was visually assessed and dichotomously rated as either amyloid-positive or amyloid-negative by two board-certified nuclear medicine physicians. If the two readers obtained different interpretations, the visual rating was rerun until they reached consensus. The PET images were quantitatively analyzed using the standardized uptake value ratio (SUVR) and standardized Centiloid (CL) scale with the whole cerebellum as a reference area. Results: Visual interpretation obtained 61 positive and 32 negative PET scans. Receiver operating characteristic analysis determined the best agreement of quantitative assessments and visual interpretation of PET scans to have an area under curve of 0.982 at an SUVR of 1.13 and a CL of 16. Using these cutoff values, there was high agreement between the two approaches (kappa = 0.88). Five discordant cases had SUVR and CL values ranging from 1.00 to 1.22 and from 1 to 26, respectively. In these discordant cases, either diffuse or mildly focal elevation of cortical activity confused visual interpretation. The amyloid PET outcome significantly altered the diagnosis of AD (χ2 = 51.3, p < 0.0001). PET imaging elevated the proportions of the very high likelihood category from 20.4 to 46.2% and the very low likelihood category from 0 to 22.6%. Conclusion: Quantitative analysis of amyloid PET using 18F-flutemetamol can objectively evaluate amyloid positivity using the determined cutoffs for SUVR and CL. Moreover, amyloid PET may have added value over the standard diagnostic workup in dementia patients with cognitive impairment and suspected AD.

Voxel-based correlation of 18F-THK5351 accumulation and gray matter volume in the brain of cognitively normal older adults.

BACKGROUNDS: Although neurofibrillary tangles (NFTs) mainly accumulate in the medial temporal lobe with human aging, only a few imaging studies have investigated correlations between NFT accumulation and gray matter (GM) volume in cognitively normal older adults. Here, we investigated the correlations between 18F-THK5351 accumulation and GM volume at the voxel level. MATERIAL AND METHODS: We recruited 47 amyloid-negative, cognitively normal, older adults (65.0 ± 7.9 years, 26 women), who underwent structural magnetic resonance imaging, 11C-Pittsburgh compound-B and 18F-THK5351 PET scans, and neuropsychological assessment. The magnetic resonance and 18F-THK5351 PET images were spatially normalized using Statistical Parametric Mapping 12. Voxel-wise correlations between 18F-THK5351 accumulation and GM volume were evaluated using the Biological Parametric Mapping toolbox. RESULTS: A significant negative correlation (p < 0.001) between 18F-THK5351 accumulation and GM volume was detected in the bilateral medial temporal lobes. CONCLUSIONS: Voxel-wise correlation analysis revealed a significant negative correlation between 18F-THK5351 accumulation and GM volume in the medial temporal lobe in individuals without amyloid-ß deposits. These results may contribute to a better understanding of the pathophysiology of primary age-related tauopathy in human aging.

Longitudinal analysis of risk factors for dementia based on Mild Cognitive Impairment Screen results and questionnaire responses from healthy Japanese individuals registered in an online database.

INTRODUCTION: Despite an urgent need for developing remedial measures against dementia, no disease-modifying drugs have been developed. Efficient protocols for participant recruitment need to be established for conducting clinical trials. To meet this need, a large-scale online registry system, the Integrated Registry of Orange Plan (IROOP®), was created for healthy individuals. Although the risk factors for dementia have been discussed in our previous studies for a short interval of 6 months, some factors remain controversial. The present study aimed to explore factors affecting longitudinal changes in cognitive function for a longer interval of 18 months using the IROOP® data. METHODS: This study assessed the longitudinal changes in the collated data for predicting the risk of dementia and included 473 individuals (175 men and 298 women; mean age 59.6 ± 10.1 years) registered in the IROOP® between July 5, 2016 and January 15, 2018 who completed the initial questionnaire and brief assessment of cognitive function (Mild Cognitive Impairment Screen) at baseline and the regular questionnaire and the Mild Cognitive Impairment Screen at least once after baseline. Statistical analyses were performed using IBM SPSS, version 23.0, for Windows for demographic data and the MIXED procedure in SAS, version 9.4, for the linear mixed-effect model. In each analysis, the statistical significance level was set at P < .05. RESULTS: Mood, sleep, quality of life, and medical histories including cognition were found to influence longitudinal changes in cognitive function. DISCUSSION: Given the multifactorial etiology of dementia, preventive measures targeting multiple domains are required for maintaining cognitive function, instead of focusing on one lifestyle factor.

Association between subfield volumes of the medial temporal lobe and cognitive assessments.

Cognitive assessments and neuroimaging are routinely combined in clinical practice to diagnose dementia represented by Alzheimer's disease (AD). The Montreal Cognitive Assessment (MoCA) is reported to be more suitable than the Mini-Mental State Examination (MMSE) for screening mild cognitive impairment (MCI) and mild AD. On the other hand, attention to the subfield volumes of the medial temporal lobe has recently been considered important for the differential diagnosis and early detection of AD. The aim of this study was to uncover which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits in cognitive assessment scores in patients with MCI and AD. We recruited from our institute 31 Japanese patients-14 with amnestic MCI and 17 with probable AD, with a clinical dementia rating (CDR) of 0.5 and 1, respectively-and 50 healthy elderly individuals with a CDR of 0. All participants underwent magnetic resonance imaging and cognitive assessments with the MMSE, Wechsler Memory Scale-Revised Logical Memory I and II, and Japanese version of the MoCA (MoCA-J). With adjustment for age and sex, we performed partial correlation analysis of the cognitive assessment scores with the subfield volumes of the medial temporal lobe measured by software-mediated automatic segmentation of hippocampal subfields using high-resolution T1-and T2-weighted images. Compared with normal controls, patients with MCI and AD showed subfield volume reductions in cornu ammonis (CA) 1, CA2, Brodmann area (BA) 35, BA36, the dentate gyrus (DG), the subiculum, and the entorhinal cortex (ERC). All participants showed high correlation coefficients (above 0.6) between cognitive assessment scores and subfield volumes in CA1, the DG, the subiculum, the ERC, and BA36. In patients with MCI and AD, the MoCA-J showed higher correlations than the MMSE with subfield volumes in CA1, the DG, the subiculum, and the ERC. These results suggest that the combination of the in vivo analysis of subfield morphometry of the medial temporal lobe with the MoCA-J paradigm provides important insights into whether changes within specific subfields are related to the cognitive profile in MCI and AD.

Automated Volumetry of Medial Temporal Lobe Subregions in Mild Cognitive Impairment and Alzheimer Disease.

PURPOSE: Hippocampal subfield volumetry should be more useful than whole hippocampal (WH) volumetry for diagnosing Alzheimer disease (AD). This study sought to confirm this. METHODS: We investigated cognitively normal (CN) participants and patients with mild cognitive impairment (MCI) or AD using high-resolution T2-weighted and 3-dimensional T1-weighted magnetic resonance imaging. Using medial temporal subregion volumetry, we investigated discriminative power for MCI and AD versus CN. PATIENTS: We recruited 30 CN participants, 30 amnestic MCI patients, and 49 AD patients between April 2015 and October 2016. RESULTS: For AD, discriminative power of the combined volumes of the subiculum, entorhinal cortex, and cornu ammonis 1 was highest [area under the curve (AUC)=0.915; 85.7% sensitivity, 86.7% specificity, 86.1% accuracy], and was significantly higher than that of the WH volume (AUC=0.887; 90.0% sensitivity, 75.5% specificity, 84.5% accuracy) (P=0.019). For MCI, discriminative power of the subiculum volume was highest (AUC=0.747; 80.0% sensitivity, 73.3% specificity, 76.7% accuracy), but was only slightly higher than that of the WH volume (AUC=0.730; 56.7% sensitivity, 90.0% specificity, 73.3% accuracy). CONCLUSIONS: Using the combined volumes of the subiculum, entorhinal cortex, and cornu ammonis 1 may enable greater diagnostic accuracy compared with the WH volume or any single subfield in AD patients.

Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies.

The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).

Association of deposition of tau and amyloid-ß proteins with structural connectivity changes in cognitively normal older adults and Alzheimer's disease spectrum patients.

INTRODUCTION: Alzheimer's disease (AD) is characterized by accumulation of extracellular amyloid-ß and intracellular tau neurofibrillary tangles. The recent advent of tau positron emission tomography (PET) has enabled in vivo assessment of tau pathology. The aim of this study was to explore whether tau deposition influences the structural connectivity in amyloid-negative and amyloid-positive groups, and further explore the difference between the groups. METHODS: We investigated 18 patients with amnestic mild cognitive impairment/mild AD (AD-spectrum group) and 35 cognitively normal older adults (CN group) using diffusion MRI, amyloid, and tau PET imaging. Diffusion connectometry was performed to identify white matter pathways correlated with each of the six variables of tau deposition in the bilateral hippocampi, temporal lobes, posterior and anterior cingulate cortices, precunei, orbitofrontal lobes, and entire cerebrum. RESULTS: The CN group showed increased connectivity along with an increased tau deposition in the bilateral hippocampi, temporal lobes, and entire cerebrum, whereas the AD-spectrum group showed decreased connectivity in the bilateral hippocampi, temporal lobes, anterior and posterior cingulate cortices, precunei, and entire cerebrum. CONCLUSION: These findings suggest that tau deposition in the CN group seems to induce a compensatory response against early neuronal injury or chronic inflammation associated with normal aging, whereas the coexistence of amyloid and tau in the AD-spectrum group seems to outweigh the compensatory response leading to decreased connectivity, suggesting that amyloid plays a crucial role in alternating structural connectivity.

Dissociation of Tau Deposits and Brain Atrophy in Early Alzheimer's Disease: A Combined Positron Emission Tomography/Magnetic Resonance Imaging Study.

The recent advent of tau-specific positron emission tomography (PET) has enabled in vivo assessment of tau pathology in Alzheimer's disease (AD). However, because PET scanners have limited spatial resolution, the measured signals of small brain structures or atrophied areas are underestimated by partial volume effects (PVEs). The aim of this study was to determine whether partial volume correction (PVC) improves the precision of measures of tau deposits in early AD. We investigated tau deposits in 18 patients with amyloid-positive early AD and in 36 amyloid-negative healthy controls using 18F-THK5351 PET. For PVC, we applied the SPM toolbox PETPVE12. The PET images were then spatially normalized and subjected to voxel-based group analysis using SPM12 for comparison between the early AD patients and healthy controls. We also compared these two groups in terms of brain atrophy using voxel-based morphometry of MRI. We found widespread neocortical tracer retention predominantly in the posterior cingulate and precuneus areas, but also in the inferior temporal lobes, inferior parietal lobes, frontal lobes, and occipital lobes in the AD patients compared with the controls. The pattern of tracer retention was similar between before and after PVC, suggesting that PVC had little effect on the precision of tau load measures. Gray matter atrophy was detected in the medial/lateral temporal lobes and basal frontal lobes in the AD patients. Interestingly, only a few associations were found between atrophy and tau deposits, even after PVC. In conclusion, PVC did not significantly affect 18F-THK5351 PET measures of tau deposits. This discrepancy between tau deposits and atrophy suggests that tau load precedes atrophy.

Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer's Disease.

Voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) software is widely used in clinical practice in Alzheimer's disease (AD). The existing VSRAD is based on the normal database with 1.5-tesla MRI scans (VSRAD-1.5T), and its utility for patients have undergone 3-tesla MRI is still controversial. We recruited 19 patients with early AD and 28 healthy controls who had undergone 3-tesla MRI scans at our institute (Cohort 1). We also used the 3-tesla MRI data of 30 patients with early AD and 13 healthy controls from the Japanese Alzheimer's Disease Neuroimaging Initiative (Cohort 2). We also created a new VSRAD based on 65 normal subjects' 3-tesla MRI scans (VSRAD-3T), and compared the detectability of AD between VSRAD-1.5T and VSRAD-3T, using receiver operating characteristic curve and area under the curve (AUC) analyses. As a result, there were no significant differences in the detectability of AD between VSRAD-3T and VSRAD-1.5T, except for the whole white matter atrophy score, which showed significantly better AUC in VSRAD-3T than in VSRAD-1.5T in both Cohort 1 (p=0.04) and 2 (p<0.01). Generally, there were better diagnostic values in Cohort 2 than in Cohort 1. The optimal cutoff values varied but were generally lower than in the previously published data. In conclusion, for patients with 3-tesla MRI, the detectability of early AD by the existing VSRAD was not different from that by the new VSRAD based on 3-tesla database. We should exercise caution when using the existing VSRAD for 3-tesla white matter analyses or for setting cutoff values.

Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.