Lim, Seokbeen

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.

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 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 Background The tau PET imaging with 18F‐flortacipir (18F‐FTP) has focused interest in accurately tracking longitudinal tau changes in Alzheimer's disease [1]. Thus, minimizing variability is critical. Off‐target signal has the potential to complicate interpretation of tau‐PET imaging due to potential spillover or bleed‐in effects, with increased effects seen in later stages of Alzheimer's due to cerebral atrophy and proximity of off‐target areas to relevant cortical areas[2]. Previously, we demonstrated the effect of uptake period activity on 18F‐FTP signal. With increasing recent interest in demographic factors that may affect off‐target binding, we investigated the effect of age in extra‐cerebral off‐target signal in 18F‐FTP PET imaging. Method Standard 18F‐FTP PET protocol was performed in 330 participants. Two independent readers measured tau uptake in predetermined off‐target regions, including extraocular muscle, meninges, and occipital bone among others. Linear regression models assessed the relationship between participants’ age, sex, and tau uptake values (SUV and SUVr) (SUV = (Tissue radioactivity concentration / Injected dose) / Body weight & SUVr = SUV of target region/ SUV of reference region.) Result Sex had a significant effect on off‐target signal in most brain regions, with variable positive or negative correlation based on area. Notably, SUV in the eyeball‐retina, occipital bone, upper skull meninges all showed significant positive correlation with sex, with ‘male’ status generally associated with lower SUV. The greatest effect of sex was observed in superior skull meninges, occipital bone, and internal carotid artery ( p <0.001). Age showed minimally affected SUV and SUVr in off‐target regions. SUVr values show a significant correlation with SUV values of upper skull meninges in sex. Cognitive status did not significantly affect off‐target SUV. Conclusion We observed that sex significantly affected extra‐brain off‐target signal in 18F‐FTP PET imaging, while age has minimal effect, adding to previous evidence of off‐target binding within brain regions. Further evaluation is necessary to understand the age‐related effects on off‐target regions. As a result, the variability introduced by sex may pose challenges to studying tau accumulation.

Abstract Background Neuroinflammation plays a crucial role in neuronal damage, synaptic dysfunction, and impaired neurogenesis, significantly contributing to Alzheimer's Disease (AD) progression. To address this, we assessed ER176's effectiveness in detecting neuroinflammation in cognitively unimpaired (CU) A–, CU A+, mild cognitive impairment (MCI), and AD participants, with a particular focus on their amyloid and tau status. This research aims to help identify suitable candidates for specialized treatment when adversely impacted by neuroinflammation. Method Participants from the Mayo Clinic Study of Aging were recruited for this study. The study included four participant groups: CU A– ( n = 25), CU A+ ( n = 25), MCI A+ ( n = 25), and AD ( n = 15). We explored the variations in neuroinflammation PET results among different groups. Result When compared to CU A–, both CU A+ and MCI A+ groups (Figure 1) showed greater regional neuroinflammation. AD exhibited more widely affected regions with neuroinflammation (temporal, occipital, and parietal lobes) than CU A‐ over the PVC spectrum (Figure 1). Minimally more neuroinflammation was seen (temporal lobes) in MCI A+ than CU A+ (Figure 1). AD had more widespread regional neuroinflammation vs CU A+ (Figure 1) than in MCI A+ vs CU+. The least difference in neuroinflammation is seen in MCI A+ vs AD (Figure 1). For A+ vs A‐, A+ showed more widespread neuroinflammation (Figure 2). T+ (tau>=1.29) vs T‐ (tau<1.29) showed more neuro inflammation with T+ (Figure 2). Comparisons varied modestly in significance level with PVC method (Figures 1 and 2). Conclusion The findings demonstrate that neuroinflammatory changes are associated with AD pathology. Even at early stages, neuroinflammation is associated with CU+. As the condition progresses, neuroinflammation extends to more brain regions and is associated with increased A+ and T+ pathology in MCI A+ and AD. These results suggest an early and persistent role of neuroinflammation in the progression AD pathology, indicating that therapy options could include early anti‐inflammatory intervention, even prior to clinical symptoms, along with treatment during clinical manifestations. PVC methods used may provide somewhat variable results.

Abstract Background The Overlap Index (OI) as previously published (Lee et al., 2022) is a reliable method for detecting tau accumulation using tau‐PET imaging (flortaucipir; AV1451). It identifies voxel‐wise standardized uptake value ratio (SUVr) elevations across serial scans. Although OI showed more sensitivity to tau signal elevation and longitudinal change than standard ROI measures, to our knowledge, the relationship of the tau PET overlap index to neuropathologic findings is still unclear. This study aims to investigate the potential of OI to detect NFTs of the neuropathologic Braak tangle stage, especially the early Braak tangle stage (I–IV). Method This study included 57 participants from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center, all of whom underwent autopsy and at least two serial AV1451 tau‐PET scans and 3T T1‐weighted MRI within an average of 16 months. Tau‐PET SUVr images were normalized to cerebellar crus grey matter, and MR images were co‐registered to a single‐subject MRI mean. Tau‐PET scans were resampled into MRI space, and OI was calculated by applying intensity thresholds 1.3. Clusters with fewer than 20 contiguous voxels were excluded. An OI cutoff of 0.5 was used and an SUVr cutoff of 1.29. Postmortem immunohistochemistry (IHC) using phospho‐tau antibodies (AT8, PHF‐1) was performed on the amygdala, temporal cortex (middle and superior), and anterior/posterior hippocampus. Neuropathological Braak staging was determined based on AT8‐stained sections. We conducted visual comparison of tau‐PET overlap signal in these regions with IHC‐confirmed tau pathology across Braak tangle stages. Result OI‐detected voxels corresponded to NFT distribution across Braak stages. In early Braak stages, standard SUVr‐based META‐ROI values remained negative, whereas OI showed positive signals, indicating greater sensitivity to early tau pathology (Figure 1). The spatial distribution of OI‐derived overlap regions aligned with high NFT burden, suggesting that OI captures early‐stage tau pathology more effectively than conventional SUVr methods. Conclusion OI in serial tau‐PET imaging demonstrated better detection of early‐stage tau pathology than standard ROI‐based SUVr measures. The alignment between OI‐detected voxels and neuropathological tau burden supports its potential as an in vivo biomarker for detecting early neurofibrillary tangles.

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.

Abstract Background Some data suggest that neuroinflammation may be associated with pro‐inflammatory states in the body. Systemic, proinflammatory cytokines (TNFα, IL‐1, IL‐6, etc.) are produced by a variety of comorbidities. Neuroinflammation has been shown to be associated with the accumulation of amyloid in the brain (Becher, Heneka). We hypothesized that systemic cytokine production could be associated with neuroinflammation and thereby be related to brain amyloid accumulation. This study aims to evaluate the relationship between neuroinflammation, amyloid accumulation and systemic cytokines. Method 90 participants from the Mayo Clinic Study of Aging (MCSA) received a fasting cytokine panel over a 5‐year span where IL‐1, IL‐6, IL‐10, TNFa levels were measured. Participants were divided into four groups: cognitively unimpaired with normal levels of amyloid (CU A‐, n = 25), cognitively unimpaired with elevated amyloid (CU A+, n = 25), and mild cognitively impaired (MCI) with amyloid positive (MCI A+, n = 25), and Alzheimer's disease (AD) with elevated amyloid (AD A+, n = 15). To compare regional standardized uptake value ratio (SUVr) from neuroinflammation PET based on amyloid status (A+ vs A‐) and the four cytokines, Spearman's rank correlation and Fishers r‐to‐z transformations were used to assess pairwise group differences. Result Using Spearman's rank correlation and Fishers r‐to‐z transformations, no strong relationship was found between systemic inflammation and neuroinflammation. While comparing CUA‐ vs CUA+ in Figure 1, three regions (supplementary motor area, frontal superior medial lobe, and middle cingulate cortex) showed a significant difference ( p < 0.05). However, Figure 2 showed an overarching trend bias towards significance across most regions in IL10, IL6, and TNFa. Conclusion Although significant relationships between systemic inflammation, brain amyloid and neuroinflammation were limited, the data show an overarching trend bias in broad brain regions, suggesting that further analyses are needed, possibly with larger sample sizes, to assess the relationship of regional neuroinflammation and amyloid to systemic inflammation. Future analyses could also regress out factors like sex, age, and genotype to further proinflammatory cytokine research.

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.