Every year, millions of brain MRI scans are acquired in hospitals, which is a figure considerably larger than the size of any research dataset. Therefore, the ability to analyze such scans could transform neuroimaging research. Yet, their potential remains untapped since no automated algorithm is robust enough to cope with the high variability in clinical acquisitions (MR contrasts, resolutions, orientations, artifacts, and subject populations). Here, we present SynthSeg ⁺ , an AI segmentation suite that enables robust analysis of heterogeneous clinical datasets. In addition to whole-brain segmentation, SynthSeg ⁺ also performs cortical parcellation, intracranial volume estimation, and automated detection of faulty segmentations (mainly caused by scans of very low quality). We demonstrate SynthSeg ⁺ in seven experiments, including an aging study on 14,000 scans, where it accurately replicates atrophy patterns observed on data of much higher quality. SynthSeg ⁺ is publicly released as a ready-to-use tool to unlock the potential of quantitative morphometry.

Every year, millions of brain magnetic resonance imaging (MRI) scans are acquired in hospitals across the world. These have the potential to revolutionize our understanding of many neurological diseases, but their morphometric analysis has not yet been possible due to their anisotropic resolution. We present an artificial intelligence technique, “SynthSR,” that takes clinical brain MRI scans with any MR contrast (T1, T2, etc.), orientation (axial/coronal/sagittal), and resolution and turns them into high-resolution T1 scans that are usable by virtually all existing human neuroimaging tools. We present results on segmentation, registration, and atlasing of >10,000 scans of controls and patients with brain tumors, strokes, and Alzheimer’s disease. SynthSR yields morphometric results that are very highly correlated with what one would have obtained with high-resolution T1 scans. SynthSR allows sample sizes that have the potential to overcome the power limitations of prospective research studies and shed new light on the healthy and diseased human brain.

Tau accumulation in patients with Alzheimer’s disease tracks closely with cognitive decline and plays a role in the later stages of disease progression. This phase 2 study evaluated the safety and efficacy of tilavonemab, an anti-tau monoclonal antibody, in patients with early Alzheimer’s disease. In this 96-week, randomized, double-blind, placebo-controlled study (NCT02880956), patients aged 55–85 years meeting clinical criteria for early Alzheimer’s disease with a Clinical Dementia Rating-Global Score of 0.5, a Mini-Mental State Examination score of 22 to 30, a Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory Index score of ≤85, and a positive amyloid PET scan were randomized 1:1:1:1 to receive one of three doses of tilavonemab (300 mg, 1000 mg, or 2000 mg) or placebo via intravenous infusion every 4 weeks. The primary end point was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Safety evaluations included adverse event monitoring and MRI assessments. A total of 453 patients were randomized, of whom 337 were treated with tilavonemab (300 mg, n = 108; 1000 mg, n = 116; 2000 mg, n = 113) and 116 received placebo. Baseline demographics and disease characteristics were comparable across groups. The mean age was 71.3 (SD 7.0) years, 51.7% were female, and 96.5% were White. At baseline, the mean CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. The least squares mean change from baseline at Week 96 in the CDR-SB score with tilavonemab was not significantly different compared with placebo [300 mg (n = 85): −0.07 (95% confidence interval, CI: −0.83 to 0.69); 1000 mg (n = 91): −0.06 (95% CI: −0.81 to 0.68); 2000 mg (n = 81): 0.16 (95% CI: −0.60 to 0.93); all P ≥ 0.05]. The incidence of any adverse event and MRI findings were generally comparable across groups. Tilavonemab was generally well tolerated but did not demonstrate efficacy in treating patients with early Alzheimer’s disease. Further investigations of tilavonemab in early Alzheimer’s disease are not warranted.

The core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers; amyloid-β (Aß), total tau (t-tau), and phosphorylated tau (p-tau181), are strong indicators of the presence of AD pathology, but do not correlate well with disease progression, and can be difficult to implement in longitudinal studies where repeat biofluid sampling is required. As a result, blood-based biomarkers are increasingly being sought as alternatives. In this study, we aimed to evaluate a promising blood biomarker discovery technology, Olink Proximity Extension Assays for technical reproducibility characteristics in order to highlight the advantages and disadvantages of using this technology in biomarker discovery in AD. We evaluated the performance of five Olink Proteomic multiplex proximity extension assays (PEA) in plasma samples. Three technical control samples included on each plate allowed calculation of technical variability. Biotemporal stability was measured in three sequential annual samples from 54 individuals with and without AD. Coefficients of variation (CVs), analysis of variance (ANOVA), and variance component analyses were used to quantify technical and individual variation over time. We show that overall, Olink assays are technically robust, with the largest experimental variation stemming from biological differences between individuals for most analytes. As a powerful illustration of one of the potential pitfalls of using a multi-plexed technology for discovery, we performed power calculations using the baseline samples to demonstrate the size of study required to overcome the need for multiple test correction with this technology. We show that the power of moderate effect size proteins was strongly reduced, and as a result investigators should strongly consider pooling resources to perform larger studies using this multiplexed technique where possible.

Background: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2–4 months, and conducted a pilot longitudinal study over 10–20 months. Results: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2–4 months in N = 29 participants and over 10–20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. Conclusions: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, “secondary prevention” based on prodromal pathology may prove challenging; instead, “primary prevention” trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.