Volumetric Magnetic Resonance Research Articles

High-resolution volumetric dynamic magnetic resonance imaging of the wrist using an 8-channel flexible receive coil.

Real-time imaging is useful for the evaluation of wrist instability. However, currently available real-time magnetic resonance imaging (MRI) methods are limited due to their 2D nature or provide insufficient temporal resolution and image quality for quantitative kinematic analysis. This work introduces a novel approach for volumetric dynamic MRI of the wrist joint during active motion and demonstrates the feasibility of tracking carpal bone motion. A flexible 8-element 3T wrist receive coil and 3D-printed support platform for guiding motion were designed for dynamic wrist imaging. 2D real-time images were acquired using a fat-saturated FLASH sequence with radial sampling and reconstructed with the GRASP algorithm. Corresponding volumetric dynamic wrist images were obtained by assembling 2D real-time images into 3D snapshots using autodetected MRI-visible markers for slice alignment. The proposed method was demonstrated for radial-ulnar deviation on five healthy volunteers. The flexible wrist coil provided high SNR while allowing a wide range of wrist movements. 2D real-time wrist images were acquired with a temporal resolution of 48ms/frame with negligible streaking artifacts. Carpal bones and metacarpal bones were properly aligned in the assembled dynamic volumes for all five subjects. The excellent bone-to-tissue contrast enabled accurate segmentation of the individual carpal bones on the assembled dynamic volumes. This work introduces a novel wrist coil and demonstrates that real-time volumetric dynamic examination of the moving wrist is feasible. The achieved image quality and high temporal resolution could enable automatic segmentation of carpal bones and quantitative kinematic assessment for evaluating wrist instability.

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases.

Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized. Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified. Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function. Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition.

Evaluation of Volumetric Magnetic Resonance Imaging in Determining the Indication for Total Neoadjuvant Therapy in Rectal Cancer.

This study aims to evaluate the relationship between volumetric measurements of residual tumor via magnetic resonance imaging (MRI) and pathologic complete response (pCR) in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (nCRT). Patients with locally advanced rectal cancer who had pelvic MRI for clinical staging and completed nCRT followed by radical resection were included. Two experienced radiologists measured tumor volume on MRI obtained before and after nCRT. We compared the pre- and post-CRT tumor volume and measured tumor volume reduction rates. The median value of tumor volume reduction rate in all patients was 64.7% (min-max - 81.1-98.1%). When the relationship between tumor volume and tumor regression grade (TRG) after nCRT was assessed, it was found that 18 of 21 (86%) patients with a good response (TRG 1) had a post-CRT tumor volume of ≤ 8 cm3 (p = 0.001). While 9 of 10 patients with pCR after nCRT had a tumor volume of ≤ 8 cm3, one patient had pCR despite having a tumor volume greater than 8 cm3 (p = 0.015). The correlation between post-nCRT residual tumor volume and pCR underscores the potential of volumetric MRI as a predictive tool in tailoring rectal cancer treatment. For patients with residual tumor volumes greater than 8 cm3, extending neoadjuvant chemotherapy as part of TNT may enhance the likelihood of achieving pCR. This approach advocates for a more personalized treatment strategy, potentially optimizing outcomes for rectal cancer patients.

ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma.

Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults. ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Phosphorylated tau protein serum levels increase over time in patients with chronic heart failure

Abstract Background/Introduction Amongst various potential biomarkers associated with cognitive deficits, phosphorylated Tau (pTau) appears to link brain and cardiac abnormalities through a systemic tauopathy pathway. Purpose A recent report on the potential importance of myocardial pTau in chronic heart failure (HF) prompted the here described longitudinal quantification of circulating pTau serum levels in patients with HF. We hypothesized that serum pTau accumulates in HF and is associated with markers of myocardial dysfunction. Methods Eligible patients within the prospective, investigator-initiated, monocentric follow-up study Cognition.Matters-HF were older than 18 years, suffered from stable chronic HF and were free from major neurological or psychiatric disorders. Beyond the cardiological assessment including transthoracic echocardiography and six minute walking distance (6-MWD), investigations at baseline, 1 year and 3 years comprised extensive, domain-specific psychological testing and volumetric brain magnetic resonance imaging. Serum pTau was measured using the pTau181 advantage kit. Results Serum samples were available from 78 patients. Mean age was 63±10 years and 87% were men. Serum pTau longitudinally increased from a median of 1.05 (quartiles 0.26, 1.21) pg/ml at baseline to 1.84 (1.36, 3.60) pg/ml after 3 years (p<0.001). During that time period, LVEF, NT-proBNP, 6-MWD and the hippocampal volume remained unaltered, whereas global brain volume and cortical thickness shrank age-appropriately. Cognitive testing revealed that domain-specific T-scores within 36 months remained stable for attentional intensity and executive functioning, and even improved for memory. When we entered baseline values of age and above-mentioned cardiac, brain-volumetric, and cognitive parameters into a multivariable regression model predicting log-transformed pTau, only age (β=0.34), NT-proBNP (β=0.24) and GBV (β=0.26) were independently associated with pTau serum levels (R2=0.18). Consistently, at 36 months, the same predictors were selected by the model (R2=0.29): age (β=0.41), NT-proBNP (β=0.43), and global brain volume (β=0.26). Moreover, higher baseline pTau (β=0.23) and lower 6-MWD (β=-0.39) independently predicted ΔpTau with an explained variance (R2) of 0.24. Conclusions We observed a prominent increase of serum pTau over time, which was predicted by prevalent myocardial dysfunction. Moreover, absolute NT-proBNP levels were independently associated with absolute pTau serum levels, along with age and global brain volume. Mechanistically, phosphorylation of cardiac tau is thought to destabilize its interaction with microtubules causing microtubule detyronisation and increased myocardial stiffness through enhancing the mechanical resistance of contracting cardiomyocytes. The etiological role of pTau in the development of HF and the potential of serum pTau as a novel biomarker of chronic HF warrants further studies.

Highly demarcated structural alterations in the brain and impaired social incentive learning in Tbx1 heterozygous mice.

Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain's regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.

CT1812 biomarker signature from a meta-analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease.

CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials. Unbiased analysis of tandem-mass tag mass spectrometry (TMT-MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC cohort (NCT03493282). Comparative analyses and a meta-analysis with the interim SHINE cohort (NCT03507790; SHINE-A) followed by network analysis (weighted gene co-expression network analysis [WGCNA]) were used to understand the biological impact of CT1812. CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta-analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment-associated networks driven by S2R. DISCUSSION: Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development. This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282) Comparative analyses identified biomarkers replicating across trials/cohorts Two independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE-A]) were used in a meta-analysis Amyloid beta (Aβ)& synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment-related correlates emerge Network analyses revealed sigma-2 receptor (S2R)-interacting proteins that may be "drivers" of changes.

Glenohumeral Joint Volume Measurement in Patients with Shoulder Instability: A 3D Volumetric Magnetic Resonance Arthrographic Study.

Background and Objectives: This study aimed to compare capsular volume in patients with shoulder instability to that in control subjects without instability using magnetic resonance (MR) arthrography. The objective was to develop a reliable screening method with which to assess shoulder volume. Materials and Methods: In 21 patients with atraumatic shoulder instability and 21 controls, thin-slice 3D volumetric MR arthrography sequences were obtained. MR arthrography images were uploaded to 3D reconstruction, and 3D images were generated. From the 3D reconstructed images, volumetric measurements of rotator interval (RI), anterior and posterior capsular (AC, PC) recesses, biceps tendon sheath (BS), axillary recess (AR), and total glenohumeral joint (TGJ) were performed. Individuals with any extra-articular contrast leakage were also recorded. Results: A retrospective study analyzed a patient group of 21 individuals with shoulder instability (mean age 29.52 ± 12.83 years) and a control group of 21 individuals without instability (mean age 35.71 ± 12.77 years). No statistically significant differences were identified between the groups with regard to age, gender, or side distribution. The mean total joint volume was significantly higher in the instability group (29.85 ± 6.40 cm3) compared to the control group (23.15 ± 3.48 cm3, p = 0.0001). Additionally, the mean volumes of the RI, AC, PC, BS, and AR were all significantly greater in the patient group compared to the control group. Conclusions: 3D volumetric MR arthrographic measurements of the shoulder joint capacity can provide valuable insights for clinical follow-up and guide surgical treatment decisions in cases of atraumatic shoulder instability.

Can volumetric magnetic resonance imaging evaluations be helpful in the follow-up of cognitive functions in cognitively normal Parkinson's disease patients?

In this study, besides the evaluation of gray and white matter changes in cognitively normal Parkinson's disease (PD-CN) patients with volumetric magnetic resonance imaging (MRI) parameters, it was tried to show that some neuropsychological tests may be impaired in PD-CN patients. Twenty-six PD-CN patients and 26 healthy elderly (HC) participants were included in the current study. Global cognitive status was assessed using the mini-mental state examination (MMSE), and the Montreal cognitive assessment scale (MoCA). Attention and executive functions were evaluated using the Wechsler memory scale-revised (WMS-R) digit span test and trail making test (TMT) part A and part B, the Stroop test, semantic and phonemic fluency tests, and clock drawing test. Magnetic resonance imaging (MRI) was acquired according to the Alzheimer's disease neuroimaging initiative (ADNI) protocol. There were no significant differences among groups regarding age, sex, handedness, and years of education. In the comparison of the PD-CN group and the HC group, there was a statistical decrease in the total animal scores, lexical fluency, TMT part A and TMT part B scores in the PD-CN group. Subcortical gray matter volumes (GMV) were significantly lower in PD-CN patients. The PD-CN group had a significantly reduced total volume of right putamen and left angular gyrus compared to that in the HC group. We observed that putamen and angular gyrus volumes were lower in PD-CN patients. On the other hand, TMT part B may be a useful pretest in detecting the conversion of mild cognitive impairment in PD. Significant MRI volumetric measurements and neuropsychological test batteries can be helpful in the clinical follow-up in PD-CN patients.

The Different Associations of White Matter Hyperintensities With Severity of Dementia and Cognitive Impairment According to the Distance From the Lateral Ventricular Surface in Patients With Alzheimer's Disease.

White matter hyperintensities (WMH) are common among the elderly. Although WMH play a key role in lowering the threshold for the clinical expression of dementia in Alzheimer's disease (AD)-related pathology, the clinical significance of their location is not fully understood. This study aimed to investigate the association between WMH and cognitive function according to the location of WMH in AD. Subjects underwent clinical evaluations including volumetric brain magnetic resonance imaging study and neuropsychological tests using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet. WMH were calculated using automated quantification method. According to the distance from the lateral ventricular surface, WMH within 3 mm, WMH within 3-13 mm, and WMH over 13 mm were classified as juxtaventricular WMH (JVWMH), periventricular WMH (PVWMH), and deep WMH (DWMH), respectively. Total WMH volume was associated with poor performance in categorical verbal fluency test (β=-0.197, p=0.035). JVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.201, p=0.032) and forward digit span test (β= -0.250, p=0.012). PVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.185, p=0.042) and word list memory test (β=-0.165, p=0.042), whereas DWMH volume showed no association with cognitive tests. PVWMH volume were also related to Clinical Dementia Rating Scale Sum of Boxes score (β=0.180, p=0.026). WMH appear to exhibit different associations with the severity of dementia and cognitive impairment according to the distance from ventricle surface in AD.

Multi-Dimensional Morphometric and Volumetric Analysis of the Posterior Cranial Fossa to Study Type I Chiari Malformation

Chiari malformation type I (CM-1) is a complex disorder in which tonsillar herniation through the foramen magnum manifests with a spectrum of clinical symptoms. This work analyzes morphometric and volumetric characteristics of CM-1 patients. With Institutional Review Board (IRB) approval, we retrospectively reviewed a total of 72 adult CM-1 patients and 26 healthy adult volunteers who underwent volumetric magnetic resonance brain imaging. Clinical data was retrospectively extracted from the electronic medical record. We analyzed multi-dimensional morphometric and volumetric features within the posterior cranial fossa and correlated these features with syrinx formation and the decision to undergo surgical decompression. In our study, CM-1 patients had decreased cerebellar, brainstem and 4th ventricular volumes but larger tonsillar volume with increased total tonsillar length. CM-1 patients who underwent surgery had significantly more neural tissue within the cross-sectional area of cisterna magna. Logistic regression demonstrated that combining neural tissue at foramen magnum with cerebellar & 4th ventricular volumes led to great degree of correlation with syrinx formation (AUC 0.911). Our findings suggest that the amount of tissue at the foramen magnum correlates with CM-1 patients who underwent decompressive surgery, more so than tonsillar length. Additionally, the combination of neural tissue at foramen magnum, cerebellar & 4th ventricular volumes led to great degree of correlation with syrinx formation. Together, these findings suggest that a global compressive phenomenon within the posterior fossa leads to CM-1 symptomatology and syrinx formation.

Dementia with Lewy bodies and gait neural basis: a cross-sectional study

BackgroundDementia with Lewy Bodies (DLB) is responsible for cognitive-behavioural disorders but also for gait disorders. The latter are thought to be related to parkinsonism, but the neural bases of these disorders are not well known, especially in the early stages. The aim of this study was to investigate by volumetric Magnetic Resonance Imaging the neuronal basis of gait disorders in DLB patients, compared to Healthy Elderly Controls and Alzheimer’s Disease patients.MethodsClinical examination with motor assessment including 10-meter walking speed, one-leg balance and Timed Up and Go test, a comprehensive neuropsychological evaluation and 3D brain Magnetic Resonance Imaging were performed on 84 DLB patients, 39 Alzheimer’s Disease patients and 22 Healthy Elderly Controls. We used Statistical Parametric Mapping 12 to perform a one-sample t-test to investigate the correlation between each gait score and gray matter volume (P ≤ 0.05 corrected for family-wise error).ResultsWe found a correlation for DLB patients between walking speed and gray matter decrease (P < 0.05, corrected for family-wise error) in caudate nuclei, anterior cingulate cortex, mid-cingulate cortex, hippocampi, supplementary motor area, right cerebellar cortex and left parietal operculum. We found no correlation with Timed Up and Go test and one-leg balance.ConclusionGait disorders are underpinned by certain classical regions such as the cerebellum and the supplementary motor area. Our results suggest there may be a motivational and emotional component of voluntary gait in DLB subjects, underpinned by the cingulate cortex, a spatial orientation component, underpinned by hippocampi and suggest the involvement of brain processing speed and parkinsonism, underpinned by the caudate nuclei.Trial registrationThe study protocol has been registered on ClinicalTrials.gov. (NCT01876459) on June 12, 2013.

Hippocampus and olfactory impairment in Parkinson disease: a comparative exploratory combined volumetric/functional MRI study.

Patients with Parkinson's Disease (PD) commonly experience Olfactory Dysfunction (OD). Our exploratory study examined hippocampal volumetric and resting-state functional magnetic resonance imaging (rs-fMRI) variations in a Healthy Control (HC) group versus a cognitively normal PD group, further categorized into PD with No/Mild Hyposmia (PD-N/MH) and PD with Severe Hyposmia (PD-SH). We calculated participants' relative Total Hippocampal Volume (rTHV) and performed Spearman's partial correlations, controlled for age and gender, to examine the correlation between rTHV and olfactory performance assessed by the Odor Stick Identification Test for the Japanese (OSIT-J) score. Mann-Whitney U tests assessed rTHV differences across groups and subgroups, rejecting the null hypothesis for p < 0.05. Furthermore, a seed-based rs-fMRI analysis compared hippocampal connectivity differences using a one-way ANCOVA covariate model with controls for age and gender. Spearman's partial correlations indicated a moderate positive correlation between rTHV and OSIT-J in the whole study population (ρ = 0.406; p = 0.007), PD group (ρ = 0.493; p = 0.008), and PD-N/MH subgroup (ρ = 0.617; p = 0.025). Mann-Whitney U tests demonstrated lower rTHV in PD-SH subgroup compared to both HC group (p = 0.013) and PD-N/MH subgroup (p = 0.029). Seed-to-voxel rsfMRI analysis revealed reduced hippocampal connectivity in PD-SH subjects compared to HC subjects with a single cluster of voxels. Although the design of the study do not allow to make firm conclusions, it is reasonable to speculate that the progressive involvement of the hippocampus in PD patients is associated with the progression of OD.

The deltoid ligament complex is reliably visualised as four fascicles in two layers with 3D volumetric MRI in the ankles of 20 asymptomatic volunteers.

The anatomy of the deltoid ligament is complex. There is agreement on the presence of superficial and deep layers but the number and frequency of fascicles remains controversial. Identifying injuries to specific components of the deltoid ligament may inform decision-making on their management. The anatomy was reviewed to establish the number and dimension of fascicles visible with three-dimensional (3D) volumetric magnetic resonance images (MRI). Twenty ankles from asymptomatic healthy volunteers were imaged with 3D volumetric MRI. The presence of individual fascicles was recorded and measured in 3D. The median age of participants was 26 years (range: 20-37) of which 13 (65%) were female. All 20 ankles had a deltoid ligament formed of four fascicles in two layers: three fascicles in the superficial layer; tibionavicular (mean dimensions 22.5 × 10.0 × 2.4 mm), tibiospring (16.6 × 6.7 × 1.9 mm) and tibiocalcaneal (23.8 × 4.6 × 1.8 mm) and a deep layer consisting of the tibiotalar fascicle, which could be divided into two parts: anterior tibiotalar (mean dimensions 10 × 5.6 × 4.1 mm) and the significantly larger posterior tibiotalar (14.2 × 13.8 × 17.5 mm, p < 0.01). There were no additional fascicles observed. The deltoid ligament complex was consistently visualised as four fascicles (tibionavicular, tibiospring, tibiocalcaneal, tibiotalar) in two layers (superficial and deep) in all 20 ankles. The posterior part of the tibiotalar fascicle was the thickest of all the fascicles in the deltoid ligament. It is, therefore, possible to accurately identify the components of the deltoid ligament, and 3T MRI can be used to assess fascicle-specific injury, which will guide treatment and rehabilitation. Level III.

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N=325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

IMG-30. DIFFUSE MIDLINE GLIOMA MAP TO A COMMON FUNCTIONAL NETWORK ASSOCIATED WITH TUMOUR PROGRESSION AND OVERALL SURVIVAL

Abstract BACKGROUND Gliomas form bidirectional, functional synapses with otherwise healthy neurons: increasing neuronal excitability and driving tumour growth. The prognostic significance of this phenomenon does, however, remain unknown. METHODS This study used tumour location and tumour network mapping to identify brain networks associated with tumour progression and overall survival (OS) in 90 children with diffuse midline glioma, H3K27-altered (DMG). Tumours were segmented on volumetric magnetic resonance imaging and mapped to a standard template. Brain networks functionally connected to each tumour were computed using normative paediatric resting-state functional magnetic resonance imaging (n=525). RESULTS Median OS in the discovery cohort was 9.5 months (interquartile range 7.0-14.5 months). Comparison of tumour location in short-term (&amp;lt;18 months; n=75) and long-term (≥18 months; n=15) survivors of DMG identified an area of maximal anatomic overlap associated with short-term survival in the mid-pontine tegmentum and corticospinal tracts (89%; P&amp;lt;0.05). Tumour location was, however, not associated with OS (P=0.347). We, therefore, seeded tumour-to-brain resting-state functional connectivity maps from this a priori tegmental region-of-interest, identifying a specific brain network associated with short-term survival defined by functional connectivity to the medial prefrontal cortex, thalami, and cerebellum (P&amp;lt;0.0005). High and low tumour connectivity to this network was associated with short-term and long-term OS, respectively, using both univariate (P=0.013) and multivariate models controlling for treatment and tumour volume (P=0.016). Final, subset analysis of longitudinal neuroimaging in children within one month of death (n=21) showed tumour progression mapped to this same functional network and exhibited a dominant (left) hemispheric predominance (P&amp;lt;0.05), underpinned by increased tumour connectivity to the right (P=0.0270) rather than left (P=0.1802) corticospinal tract, and associated with OS (P=0.02). DISCUSSION We map DMG to a unified and prognostically important functional network, further establishing DMG as a circuit disorder. Interventions aiming to modulate this network may inform future treatment strategies for affected children.

How to avoid genu recurvatum in leg-length discrepancy treated with tension-band plates. A volumetric magnetic resonance analysis

Aims and objectivesGenu recurvatum deformity after treatment of leg-length discrepancy (LLD) with tension-band plating is a recognized, but poorly described phenomenon in medical literature. The aim of this study was to evaluate clinical and radiological features of patients treated with tension-band plating for LLD assessing the development of a recurvatum deformity and its relationship to plate and screw disposition in a transversal plane, thus attempting to establish optimal plate positioning. Materials and methodsRetrospective study of children with LLD treated with tension-band plating. Primary endpoints were clinical and radiological knee recurvatum and anterior and posterior physeal areas measured drawing a line spanning from the lateral to the medial tension-band plates in the transverse plane using volumetric magnetic resonance imaging (vMRI). These findings were compared between patients with and without knee recurvatum. ResultsTwelve children (mean age 11.7 years) were included. Average follow-up was 2.6 years (1.5–5.0). Tension-band plating led to a significant reduction in LLD (mean, 15 mm). Six patients (50 %) developed clinical genu recurvatum (mean, 22°). According to vMRI, patients with genu recurvatum had a larger posterior to anterior physeal area ratio in both distal femur (1.6 versus 0.9, p < 0.05) and proximal tibial physes (2.2 versus 1.0, p < 0.05). ConclusionThe optimal position of the tension-band plates in distal femoral and proximal tibial physes should be in a point where a posterior to anterior physeal areas ratio is around 1.0, so as to achieve an even distribution of the physeal areas in the multidimensional physeal transverse plane. This point anatomically corresponds in the sagittal X-ray view to an imaginary line located just anterior to the posterior diaphyseal cortical bone on a true lateral radiograph for both femur and tibia.

Prenatal Maternal Psychological Distress During the COVID-19 Pandemic and Newborn Brain Development

Elevated maternal psychological distress during pregnancy is associated with altered fetal brain development. During the COVID-19 pandemic, prenatal maternal psychological distress more than doubled. To examine the association of the pandemic and rising maternal psychological distress with brain growth in newborns using quantitative 3-dimensional volumetric magnetic resonance imaging (MRI). This prospective cross-sectional study recruited mother-infant dyads at Children's National Hospital, Washington, DC, during the COVID-19 pandemic (June 1, 2020, to June 30, 2022) into a longitudinal infant brain development study and compared them with an existing normative healthy cohort (recruited March 1, 2014, to December 31, 2019). Exclusion criteria included multiple gestation pregnancy, known or suspected congenital infection, documented chromosomal abnormalities, or any maternal contraindication to MRI, as well as prenatal COVID-19 exposure. Infants with structural brain abnormalities or a postnatal confirmation of a genetic syndrome were excluded. Psychological distress during COVID-19 pandemic. Prenatal maternal mental health was evaluated using the Spielberger State-Trait Anxiety Inventory and the Perceived Stress Scale. Neonates underwent nonsedated brain MRI. An ordinary least squares linear regression model was used to measure the differences in regional brain volumes of neonates born before vs during the pandemic with and without exposure to elevated prenatal maternal psychological distress after adjustment for neonatal sex and gestational age at MRI and maternal age and educational level. A total of 159 mother-infant dyads were included in the analysis: 103 before and 56 during the pandemic (median gestational age of infants, 39.6 [IQR, 38.4-40.4] weeks; median maternal age, 34.5 [IQR, 31.0-37.0] years). Eighty-three infants (52.2%) were female. Among the mothers, 130 (81.8%) had a college degree and 87 (54.7%) had a graduate degree. Forty-four mothers (27.7%) identified as Asian, Hispanic, or multiracial; 27 (17.0%), as Black; and 88 (55.3%), as White. Scores on anxiety and stress measures were significantly increased in the pandemic cohort. Infants of mothers with elevated maternal distress showed median reductions in white matter (-0.36 [95% CI, -0.61 to -0.11] cm3; Q < .001), right hippocampal (-0.35 [95% CI, -0.65 to -0.06] cm3; Q = .04), and left amygdala (-0.49 [95% CI, -0.84 to -0.13] cm3; Q = .03) volumes compared with infants of mothers with low distress levels. After adjusting for the cohort effect of the pandemic, elevated trait anxiety remained significantly associated with decreased left amygdalar volumes (-0.71 [95% CI, -1.12 to -0.29]; Q < .001). In this cross-sectional study of maternal-infant dyads prior to and during the COVID-19 pandemic, regional neonatal brain volumes were associated with elevated maternal psychological distress.

Accuracy of Shunt Volume Measured by Three-Dimensional Echocardiography and Cardiac Magnetic Resonance in Patients With an Atrial Septal Defect and a Dilated Right Ventricle

The accuracy of right ventricular (RV) quantification by three-dimensional echocardiography (3DE) has been reported mainly in patients with a normal right ventricle (RV). However, there are no data regarding the accuracy of 3DE in patients with a dilated RV, as in shunt diseases. In this study, we evaluated the accuracy of 3DE and that of volumetric (Vol) cardiac magnetic resonance (CMR) for assessment of RV and left ventricular (LV) stroke volume (SV) and the pulmonary (Qp)/systemic (Qs) blood flow ratio in patients with an atrial septal defect (ASD) using the two-dimensional phase contrast (2DPC) method as the gold standard. We retrospectively investigated 83 patients with ASD who underwent transcatheter closure and clinically indicated CMR and 3DE examinations. The ratio Qp/Qs was calculated using RV and LV SV measured by full-volume volumetric 3DE (Vol-3DE) and CMR (Vol-CMR) and by two-dimensional pulsed Doppler quantification (2D-Dop); the parameters were compared using 2DPC-CMR as the gold standard. There was no significant difference in the Qp/Qs value between 2DPC-CMR and Vol-3DE (2.29±0.70 vs 2.21±0.63, P=.79) and 2D-Dop (vs 2.21±0.65, P=1.00); however, a significant difference was found between 2DPC-CMR and Vol-CMR (P<.001). The Qp/Qs value obtained using Vol-3DE showed the best correlation with 2DPC-CMR (r=0.93, P<.001). The RV and LV SV values obtained by Vol-3DE showed the best correlation with 2DPC-CMR (RV SV, r=0.82, P<.001; LV SV, r=0.73, P<.001), although the absolute values were underestimated. Qp/Qs was more accurately evaluated by Vol-3DE than by Vol-CMR or 2D-Dop. Three-dimensional echocardiography assessment was feasible and reproducible even in a dilated RV.