Min, Paul H.

Abstract Introduction Quantitative interpretation of pediatric brain [ 18 F]-FDG PET is limited by the lack of age-matched normative reference databases, despite substantial developmental variation in cerebral glucose metabolism. This study aimed to construct a large-scale normative pediatric [ 18 F]-FDG PET database and develop an age-specific z-score mapping framework for quantitative evaluation of pediatric epilepsy. Method Pediatric brain PET data were retrospectively derived from clinically acquired whole-body or dedicated [ 18 F]-FDG PET examinations in participants 0–19 years of age without neurologic disease or visible brain abnormalities. A total of 417 PET scans from 341 participants were stratified into five developmental age groups: infancy, early childhood, middle childhood/school age, adolescence, and late adolescence. SUVR maps were generated using whole-brain atlas and brainstem reference regions. Voxel-wise t-test analyses were performed to characterize age- and sex-related metabolic differences. Age-specific voxel-wise mean and standard deviation maps were generated from the normative cohort and used to calculate age-matched hypometabolic z-score maps in 14 pediatric patients with epilepsy. The resulting abnormalities were qualitatively evaluated for concordance with epileptogenic findings identified on clinical MRI and/or PET by expert image review. Results Voxel-wise analyses demonstrated prominent age-dependent SUVR differences, particularly between infancy and older age groups. With whole-brain atlas normalization, older children showed progressively higher relative SUVR in cortical and cerebellar gray matter regions, whereas infancy showed relatively higher SUVR in the occipital cortex, white matter, thalamus, and brainstem. Brainstem normalization produced distinct developmental patterns, emphasizing higher white matter SUVR in infancy and broader gray matter differences in older groups. Sex-related differences were limited and regionally specific. Whole-brain atlas normalization showed lower variability than brainstem normalization and was selected for z-score mapping. In representative epilepsy cases, age-matched z-score maps identified focal or regional hypometabolism corresponding to malformations of cortical development, focal cortical dysplasia, mesial temporal sclerosis, nonlesional MRI cases, remote insult, tumor-related abnormalities, and Sturge-Weber syndrome. Discussion A large-scale normative pediatric [18F]-FDG PET database can support developmentally appropriate quantitative interpretation of pediatric brain PET. Age-matched z-score mapping may complement visual assessment by highlighting abnormal cerebral glucose metabolism in pediatric epilepsy, although findings should be interpreted with MRI, EEG, seizure semiology, and other presurgical data.

ABSTRACT Studies in humans and murine models have pointed towards a possible link between metabolic syndrome, which shows insulin resistance and metabolic dysregulation, and Alzheimer’s disease (AD) pathology marked by amyloid-beta (Aβ) accumulation at the BBB and hypometabolism in the brain. Yet, the underlying biological mechanisms by which metabolic syndrome affects these pathological changes in AD brain remain unknown. We hypothesized that insulin resistance is responsible for alterations in blood-brain barrier (BBB) transport of Aβ peptides and glucose. This hypothesis was tested by employing radiolabeled tracers ( 125 I-Aβ40, 125 I-Aβ42, and 18 F-FDG) in high-fat diet (HFD)-fed mouse models that manifest metabolic syndrome. Further, we assessed alterations in the expression of various molecular mediators within the brain microcapillaries harvested from both low-fat diet (LFD)-fed and HFD-fed mice. As expected, our studies show that HFD- fed mice developed peripheral insulin resistance and obesity. In addition, HFD-fed mice demonstrated an increase in the influx rate of Aβ peptides and a reduction in 18 F-FDG (a glucose surrogate) influx rate at the BBB compared to LFD-fed mice. These transport changes are associated with increase in the BBB endothelial expression of RAGE (receptor to traffic Aβ from plasma-to-brain) and a reduction of GLUT1 (glucose transporter) expression in HFD-fed mice compared to LFD-fed mice. Moreover, disruption in insulin signaling, as indicated by reduced pAKT and pERK expression, was observed in HFD-fed mice. Inhibiting AKT or ERK phosphorylation with specific inhibitors resulted in similar changes in Aβ and glucose uptake in polarized BBB endothelial cell monolayers in vitro. These results indicate that HFD induced metabolic syndrome may lead to BBB dysfunction, characterized by increased plasma-to-brain Aβ trafficking and diminished glucose transport at the BBB, thereby aggravating the expression of AD pathological hallmarks.

Breathing is a physiological process that extends beyond gas exchange, linking neural, cardiovascular, glymphatic, and autonomic systems. This narrative review summarizes how breathing-based practices modulate physiological processes in the body and brain, emphasizing their applicability in clinical care. Regulating the pace and depth of breathing, particularly with relaxed exhalation, may engage vagal pathways that lower heart rate and blood pressure and promote a shift toward increased parasympathetic tone relative to sympathetic activity. Neuroimaging studies show that controlled breathing reduces activity in stress-related brain regions while enhancing networks supporting calm attention and emotional steadiness. Changes in breathing depth also influence cerebrospinal fluid movement, though direct evidence of waste clearance in humans is lacking. This review identifies populations requiring caution, including individuals with panic symptoms, significant cardiopulmonary disease, or pregnancy. Clinicians should distinguish between breathing-only and multimodal protocols when interpreting research findings, as combined interventions preclude attribution of benefit to breathing alone. Study design quality, particularly the use of active rather than waitlist controls, should inform how effect sizes are interpreted. Breathing practices are not a replacement for medical treatment but may represent accessible, low-cost adjuncts for stress reduction and cardiovascular regulation.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Abstract INTRODUCTION Globular glial tauopathy (GGT) is a rare type of frontotemporal lobar degeneration (FTLD) characterized by deposition of 4‐repeat tau. Detecting GGT with tau positron emission tomography (tau‐PET) is challenging. We aim to determine the associations between tau‐PET, autoradiography, and neuropathology methods in GGT. METHODS We identified three patients with GGT who had completed antemortem tau‐PET. Healthy control and two patients with Alzheimer's disease (AD) were also included for comparison. We analyzed gray matter (GM) and white matter (WM) from the superior/middle frontal gyrus (S/M‐FG) and the superior/middle temporal gyrus (S/M‐TG). Immunohistochemical staining was performed with antibodies against phospho‐tau (AT8, PHF‐1, RD4), glial fibrillary acidic protein (GFAP), and resting microglia (ionized calcium‐binding adaptor molecule 1; Iba1). Immunofluorescence with a fluorescent tau‐PET analog (T726) was performed. Regional tau‐PET standardized uptake value ratios (SUVRs) were calculated for comparative GM and WM regions. Autoradiographic studies with 18F‐AV1451 were also conducted. RESULTS Tau‐PET showed increased uptake in the WM regions of the S/M‐FG and S/M‐TG in GGT, and the GM regions in AD. Co‐localization was observed between T726 and PHF‐1, RD4, and GFAP in the WM in the patients with GGT, whereas co‐localization was observed with PHF‐1 predominantly in the GM in AD. Little co‐localization was observed with Iba1. In vitro 18F‐AV1451 autoradiography studies demonstrated minimal binding in GGT. Tau‐PET differentiated underlying GGT from AD based on the relative involvement of the WM and GM. CONCLUSION Histopathologic findings suggest that some flortaucipir uptake in GGT may represent underlying 4R tau, whereas autoradiographic analysis suggests that uptake is likely due to off‐target binding. Further studies with larger cohorts are needed to determine the pathological basis of flortaucipir uptake in GGT.

Introduction Burnout among healthcare professionals remains a critical public health issue linked to impaired cognition, emotional exhaustion and diminished clinical performance. Structured breathing practices have demonstrated promise in improving autonomic regulation and cerebral oxygenation, yet their feasibility, acceptability and implementation in real-world healthcare settings remain underexplored. Objectives This single-arm pilot feasibility trial aims to evaluate the feasibility, acceptability and implementation appropriateness of a structured breathing-based intervention for healthcare professionals across community-based Mayo Clinic Health System (MCHS) sites. Secondary objectives include assessing usability and engagement with the mobile breathing platform, while exploratory analyses will describe magnitude of variability and feasibility of collecting psychological and cerebral haemodynamic measures. This study will commence in November 2025 and is expected to be completed by June 2026. Methods and analysis A total of 40 clinicians (MD/DO/MBBS/PA) and nurses reporting moderate or greater burnout will be enrolled across four MCHS sites. Participants will complete a 4-month structured breathing programme delivered primarily online, supported by a mobile application for practice tracking. Assessments will occur at baseline, 2 months and 4 months, with functional near-infrared spectroscopy (fNIRS) measures of cerebral oxygenation collected at baseline and 4 months in a population subset. Primary outcomes include (1) recruitment yield, retention and adherence rates; (2) acceptability and participant satisfaction (survey and qualitative feedback); and (3) implementation appropriateness measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Secondary outcomes include digital engagement and usability through mobile analytics and the System Usability Scale. Exploratory outcomes are psychological indicators (burnout, depression, anxiety, perceived stress, sleep, fatigue, professional fulfilment and resilience) and physiological endpoints (fNIRS). Analyses will be descriptive, summarising feasibility metrics with 95% CIs. Progression criteria (recruitment≥75%, retention≥80%, adherence≥70%, AIM/IAM/FIM≥4.0) will determine readiness for a definitive hybrid effectiveness–implementation trial. Ethics and dissemination The study is approved by the Mayo Clinic Institutional Review Board (IRB # 25-009320). All participants will provide informed consent. Study procedures ensure confidentiality, cultural sensitivity and participant safety. Data will be securely stored in REDCap and disseminated through peer-reviewed publications and scientific conference Trial registration number NCT07218458 .

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Abstract INTRODUCTION Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy. METHODS Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety‐six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and −, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using 11 C‐ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages. RESULTS TSPO was upregulated in human microglia under AD‐like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions. DISCUSSION These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation. Highlights TSPO expression increases in human microglia under AD‐like inflammation. 11 C‐ER176 PET shows stage‐dependent neuroinflammation across the AD spectrum. Neuroinflammation overlaps with tau and is more widespread in amyloid‐positive individuals. Activity peaks in MCI, stabilizes later, and relates to vascular and neurodegenerative changes.

Abstract Introduction Burnout among healthcare professionals remains a critical public health issue linked to impaired cognition, emotional exhaustion, and diminished clinical performance. Structured breathing practices have demonstrated promise in improving autonomic regulation and cerebral oxygenation, yet their feasibility and acceptability in real-world healthcare settings remain underexplored. Objectives This single-arm pilot feasibility trial aims to evaluate the feasibility, acceptability, and implementation appropriateness of a structured breathing-based intervention for healthcare professionals across community-based Mayo Clinic Health System (MCHS) sites. Secondary objectives include assessing usability and engagement with the mobile breathing platform, while exploratory analyses will examine preliminary signals of change in psychological well-being and cerebral hemodynamics. Methods and Analysis A total of 40 physicians and nurses reporting moderate or greater burnout will be enrolled across four MCHS sites. Participants will complete a four-month structured breathing program delivered primarily online, supported by a mobile application for practice tracking. Assessments will occur at baseline, 2 months, and 4 months, with optional functional near-infrared spectroscopy (fNIRS) measures of cerebral oxygenation collected at baseline and 4 months in a subset. Primary outcomes include (1) recruitment yield, retention, and adherence rates; (2) acceptability and participant satisfaction (survey and qualitative feedback); and (3) implementation appropriateness measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Secondary outcomes assess digital engagement and usability through mobile analytics and the System Usability Scale (SUS). Exploratory outcomes evaluate psychological indicators—burnout, depression, anxiety, perceived stress, sleep, fatigue, professional fulfillment, and resilience—and physiological endpoints (fNIRS). Analyses will be descriptive, summarizing feasibility metrics with 95% confidence intervals. Progression criteria (recruitment ≥75%, retention ≥80%, adherence ≥70%, AIM/IAM/FIM ≥4.0) will determine readiness for a definitive hybrid effectiveness–implementation trial. Ethics and Dissemination The study is approved by the Mayo Clinic Institutional Review Board (IRB # 25-009320). All participants will provide informed consent. Study procedures ensure confidentiality, cultural sensitivity, and participant safety. Data will be securely stored in REDCap and disseminated through peer-reviewed publications and scientific conference ClinicalTrials.gov ID The study has been prospectively registered at ClinicalTrials.gov (Identifier NCT07218458 ). Strengths and Limitations Evaluates a structured breathing-based intervention using both subjective and objective indicators of feasibility, including recruitment, retention, adherence, and implementation appropriateness. Integrates mobile application analytics with standardized implementation measures (AIM, IAM, FIM) to capture digital engagement and real-world usability. Incorporates functional near-infrared spectroscopy (fNIRS) to explore physiological mechanisms underlying burnout recovery, linking cerebral oxygenation to behavioral outcomes. Conducted across diverse community-based Mayo Clinic Health System sites, enhancing ecological validity and relevance to decentralized clinical settings. Limitations include the single-arm, region-restricted design, modest sample size, and reliance on volunteer participants, which constrain generalizability and preclude causal inference; exploratory outcomes are intended to guide future trial refinement.

Abstract Background Respiration has traditionally been considered a source of artifact in functional MRI (fMRI) due to chest motion. However, the respiratory cycle also induces changes in local oxygen concentration, resulting in fluctuations in the fMRI signal. These breathing‐triggered signals (BTS) may reflect underlying oxygen metabolism. This preliminary study developed a method to extract BTS from resting‐state BOLD fMRI and examined differences between healthy and mild cognitive impairment (MCI) groups. Method MRI scans were conducted under IRB approval on a compact 3T MRI system. Participants included two groups of 18 healthy volunteers (42.6±16.0 years) and 12 MCI patients (70.9±7.3 years). Each MRI scan included T 1 ‐weighted anatomy imaging and multi‐echo resting‐state fMRI acquisitions. The preprocessing pipeline was implemented by AFNI and FreeSurfer. Figure 1 illustrates the workflow for extracting and averaging fMRI data based on respiratory or cardiac cycle windows. As depicted in Figure 2(c,d), the mean fMRI signals corresponding to the breathing or cardiac cycles were modeled using a low‐order Fourier series to assess their amplitudes. A linear mixed‐effects model was employed to examine the effects of group and breathing cycle period, using MATLAB's ‘fitlme’ function with the formula: BTS ∼ Period + Group. Result As shown in Figure 2(e,f), breathing‐triggered BOLD signals were prominent, while cardiac‐driven BOLD signals were rarely observed. Figure 2(g) shows that global BTSs in the healthy group exhibited a linear relationship with the breathing cycle period, persisting even after artifact correction (RETROICOR for respiration and cardiac cycles and RVT). Figure 3 highlights significant regional differences between groups, particularly in the hippocampus and thalamus ( p < 0.05, uncorrected), where BTS amplitudes were greater in the MCI group. Potentially, the detected BTS could provide some insights into the coupling between respiration and cerebral oxygen metabolism and potentially serve as an imaging biomarker to assess brain health. However, due to the limited number of samples, these findings should be interpreted with caution, and further analysis is needed. Conclusion This preliminary study suggests that breathing‐triggered signals in resting‐state BOLD fMRI have the potential to serve as a noninvasive biomarker for early detection and monitoring of neurodegenerative conditions such as MCI.