Petrice M. Cogswell

Introduction: The number of microhemorrhages (mHs) increases risk of amyloid‐related imaging abnormalities (ARIAs) in those undergoing anti‐amyloid treatments for Alzheimer's disease. It is unclear whether using different magnetic resonance imaging (MRI) sequences to detect mH would alter treatment decisions. Methods: We retrospectively analyzed 55 adults (mean age 72.1 ± 7.1 years) evaluated for cognitive concerns who had MRI exams including both susceptibility‐weighted imaging (SWI) and gradient echo (GRE) sequences. Three neuroradiologists independently identified and then reached consensus on mH detection. Participants were classified into mH burden categories (none, 1, 2–4, ≥ 5). Results: Readers identified 83 mHs (mean 1.51) on SWI versus 54 (mean 0.98) on GRE. Burden categories agreed in 34 (61.8%) participants, was higher on SWI in 17 (30.9%) participants, and higher on GRE in 4 (7.3%) participants, Conclusions: Readers on average identified more mHs on SWI than GRE, altering risk categories. Prospective studies are needed to establish SWI‐based safety thresholds for anti‐amyloid therapies.

We developed a machine learning framework grounded in a computational model of brain function and FDG-PET imaging to predict Alzheimer’s disease (AD)-type tau across AD and related disorders (ADRD). The model was trained on 1088 research participants spanning normal aging and ADRD with FDG-PET and flortaucipir-PET (FTP-PET). Validation was conducted in: (1) a longitudinal subset of the training cohort ( n = 215), (2) Alzheimer’s Disease Neuroimaging Initiative ( n = 295), and (3) a heretogeneous clinical cohort ( n = 264; n = 28 with FTP-PET). Results showed that the model accurately predicted FTP-PET when applied at the participant-level ( R ² ~ 0.34-0.71). It performed well in clinical scenarios, including classification of low versus high tau stages (79–95% accuracy) and prediction of tau in a heterogeneous clinical cohort without FTP-PET. These findings advance the understanding of the relationship between neurodegeneration and AD-type tau and provide a framework for estimating AD-type tau across ADRD.

Magnetic Resonance Elastography (MRE) of the brain provides quantitative biomarkers of mechanical properties of brain tissue. Prior studies have shown that an advanced 3D MRE can differentiate idiopathic normal pressure hydrocephalus (iNPH), from other neurodegenerative disorders. In this pilot study, we assessed whether a simplified 2D MRE protocol, that is more widely available, could detect stiffness differences between iNPH and non-iNPH cognitively impaired patients, thus providing preliminary diagnostic discrimination, while using a previously developed 3D MRE classifier as a secondary exploratory comparator. In this prospective study, 10 patients with clinically diagnosed iNPH (iNPH-group) and 10 cognitively impaired patients due to non-iNPH causes (CI-group), underwent 2D brain MRE between September 2024 and April 2025. Median stiffness was extracted from a standardized, manually defined region of interest at the brain vertex. A previously validated 3D MRE pattern-analysis support vector machine (SVM) classifier was applied to this prospective cohort as a secondary exploratory comparator. Group differences were assessed using Wilcoxon rank-sum tests. Diagnostic performance was evaluated using receiver operating characteristic analysis as an exploratory assessment of discrimination. Median stiffness was higher in iNPH-group than CI-group (1.62 vs 0.98 kPa; p < 0.001). Stiffness demonstrated excellent discriminatory ability, yielding an apparent AUC of 1.00 with an optimal threshold of 1.43 kPa. The 3D SVM decision metric also yielded an apparent AUC of 1.00. The pretrained SVM model classified 18 of 20 subjects correctly (accuracy: 90.0% [95% CI: 68.3%-98.8%]). While promising, these performance estimates should be interpreted cautiously given the limited sample size. This study provides preliminary evidence that a 2D MRE protocol may help discriminate iNPH from other disorders causing cognitive impairment, providing a foundation for larger multi-center validation studies for assessing reproducibility, generalizability, and potential clinical utility.

Flow imaging targeting the cerebral aqueduct has been employed in normal pressure hydrocephalus (NPH) to (1) evaluate for imaging features supportive of a clinical diagnosis of NPH and (2) determine the NPH subtype. Two-dimensional cardiac gated phase contrast MRI has been applied to evaluate for elevated pulsatile flow through the cerebral aqueduct as one imaging feature supportive clinical diagnosis of NPH. However, aqueduct flow measurements have low sensitivity for NPH and are not well correlated with clinical outcomes. Structural and flow imaging of the aqueduct is also helpful for differentiating congenital, in some cases obstructive, NPH from idiopathic (iNPH) and determining appropriate patient management. Recent advances in flow imaging in NPH include real-time imaging that allows for evaluation of both cardiac and respiratory contributions to flow and 4D flow imaging to probe flow over a volume (rather than single slice) and provide a more comprehensive assessment of intracranial CSF dynamics. VIDEO.

Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier vs later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier vs later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed effects models to estimate how much earlier vs later each individual progresses on plasma p-tau217, amyloid PET, tau PET, and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs, and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cutpoints, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R=0.38-0.47) in the MCSA and stronger (R=0.74-0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET AD biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Background: Amyloid‐Related Imaging Abnormalities (ARIA), an adverse event associated with Alzheimer's disease anti‐amyloid immunotherapies, occur in the form of edema or sulcal effusion (ARIA‐E) and microhemorrhages and superficial siderosis (ARIA‐H). Conventional teaching is that ARIA‐H is permanent hemosiderin staining of the brain. In clinical trials we have noticed that some ARIA‐H microhemorrhages that occur with regional ARIA‐E appear to later resolve. The goal of this study is to illustrate that, opposed to current understanding, some ARIA‐H microhemorrhages may resolve. Methods: We identified participants from the Dominantly Inherited Alzheimer's Network Trial Unit (DIAN‐TU) and open label extension (OLE) gantenerumab studies that had ARIA‐E and at least one ARIA‐H microhemorrhage. The T2* GRE sequence from all available MRI exams in a patient were co‐registered and reviewed by a board‐certified neuroradiologist. Individual microhemorrhages were tracked over the serial exams. We defined disappearing/resolving microhemorrhages as those appeared with or following ARIA‐E, were visualized on at least 2 MRI exams, and were subsequently not visualized on at least 2 MRI exams. Results: A total of 12 patients met inclusion criteria of which 5 (41%) had microhemorrhages that resolved over 10‐40 months follow‐up after the incident ARIA. These microhemorrhages occurred in clusters in the region of ARIA‐E, and only some of the regional microhemorrhages resolved over follow‐up. Examples are shown in Figures 1‐3. Conclusions: The disappearance (resolution) of ARIA‐H microhemorrhages is relevant to the management and continued dosing of patients receiving anti‐amyloid immunotherapies as this is guided by the presence of ARIA (including cumulative treatment emergent microhemorrhages) as well as clinical symptoms. A microhemorrhage number alone may not be indicative of the potentially dynamic nature of ARIA‐H.