[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Quantitative transport mapping of multi-delay arterial spin labeling MRI detects early blood perfusion alteration in Alzheimer's disease.

Background: Quantitative transport mapping (QTM) of blood velocity, based on the transport equation has been demonstrated higher accuracy and sensitivity of perfusion quantification than the traditional Kety's method-based blood flow (Kety flow). This study aimed to investigate the associations between QTM velocity and cognitive function in Alzheimer's disease (AD) using multiple post-labeling delay arterial spin labeling (ASL) MRI. Methods: A total of 128 subjects (21 normal controls (NC), 80 patients with mild cognitive impairment (MCI), and 27 AD) were recruited prospectively. All participants underwent MRI examination and neuropsychological evaluation. QTM velocity and traditional Kety flow maps were computed from multiple delay ASL. Regional quantitative perfusion measurements were performed and compared to study group differences. We tested the hypothesis that cognition declines with reduced cerebral blood flow with consideration of age and gender effects. Results: In cortical gray matter (GM) and the hippocampus, QTM velocity and Kety flow showed decreased values in AD group compared to NC and MCI groups; QTM velocity, but not Kety flow, showed a significant difference between MCI and NC groups. QTM velocity and Kety flow showed values decreasing with age; QTM velocity, but not Kety flow, showed a significant gender difference between male and female. QTM velocity and Kety flow in the hippocampus were positively correlated with cognition, including global cognition, memory, executive function, and language function. Conclusion: This study demonstrated an increased sensitivity of QTM velocity as compared with the traditional Kety flow. Specifically, we observed only in QTM velocity, reduced perfusion velocity in GM and the hippocampus in MCI compared with NC. Both QTM velocity and Kety flow demonstrated reduction in AD vs controls. Decreased QTM velocity and Kety flow in the hippocampus were correlated with cognitive measures. These findings suggest QTM velocity as an improved biomarker for early AD blood flow alterations.

Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Clinical Arterial Spin-Labeling MR Imaging to Screen for Typical and Atypical Neurodegenerative Disease in the New Era of Alzheimer Treatment.

The clinical standard of care in the diagnosis of neurodegenerative diseases relies on [18F] FDG-PET/CT or PET MR imaging. Limitations of FDG-PET include cost, the need for IV access, radiation exposure, and availability. Arterial spin-labeling MR imaging has been shown in research settings to be useful as a proxy for FDG-PET in differentiating Alzheimer disease from frontotemporal dementia. However, it is not yet widely used in clinical practice, except in cerebrovascular disease. Here, we present 7 patients, imaged with our routine clinical protocol with diverse presentations of Alzheimer disease and other neurodegenerative diseases, in whom arterial spin-labeling-derived reduced CBF correlated with hypometabolism or amyloid/tau deposition on PET. Our case series illustrates the clinical diagnostic utility of arterial spin-labeling MR imaging as a fast, accessible, and noncontrast screening tool for neurodegenerative disease. Arterial spin-labeling MR imaging can guide patient selection for subsequent PET or fluid biomarker work-up, as well as for possible therapy with antiamyloid monoclonal antibodies.

Impaired sleep is associated with tau deposition on 18F-flortaucipir PET and accelerated cognitive decline, accounting for medications that affect sleep.

BACKGROUND: Impaired sleep is commonly associated with Alzheimer's disease (AD), although the underlying mechanisms remain unclear. Furthermore, the moderating effects of sleep-affecting medications, which have been linked to AD pathology, are incompletely characterized. Using data from the Alzheimer's Disease Neuroimaging Initiative, we investigated whether a medical history of impaired sleep, informant-reported nighttime behaviors, and sleep-affecting medications are associated with beta-amyloid and tau deposition on PET and cognitive change, cross-sectionally and longitudinally. METHODS: We included 964 subjects with 18F-florbetapir PET scans. Measures of sleep impairment and medication use were obtained from medical histories and the Neuropsychiatric Inventory Questionnaire. Multivariate models, adjusted for covariates, were used to assess associations among sleep-related features, beta-amyloid and tau, and cognition. Cortical tau deposition, categorized by Braak stage, was assessed using the standardized uptake value peak alignment (SUVP) method on 18F-flortaucipir PET. RESULTS: Medical history of sleep impairment was associated with greater baseline tau in the meta-temporal, Braak 1, and Braak 4 regions (p = 0.04, p < 0.001, p = 0.025, respectively). Abnormal nighttime behaviors were also associated with greater baseline tau in the meta-temporal region (p = 0.024), and greater cognitive impairment, cross-sectionally (p = 0.007) and longitudinally (p < 0.001). Impaired sleep was not associated with baseline beta-amyloid (p > 0.05). Short-term use of selective serotonin reuptake inhibitors and benzodiazepines slightly weakened the sleep-tau relationship. CONCLUSIONS: Sleep impairment was associated with tauopathy and cognitive decline, which could be linked to increased tau secretion from neuronal hyperactivity. Clinically, our results help identify high-risk individuals who could benefit from sleep-related interventions aimed to delay cognitive decline and AD.

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET.

INTRODUCTION: Mapping of microscopic changes in the perivascular space (PVS) of the cerebral cortex, beyond magnetic resonance-visible PVS in white matter, may enhance our ability to diagnose Alzheimer's disease (AD) early. METHODS: We used the cerebrospinal fluid (CSF) water fraction (CSFF), a magnetic resonance imaging-based biomarker, to characterize brain parenchymal CSF water, reflecting microscopic PVS in parenchyma. We measured CSFF and amyloid beta (Aß) using 11 C Pittsburgh compound B positron emission tomography to investigate their relationship at both the subject and voxel levels. RESULTS: Our research has demonstrated a positive correlation between the parenchymal CSFF, a non-invasive imaging biomarker indicative of parenchymal glymphatic clearance, and Aß deposition, observed at both individual and voxel-based assessments in the posterior cingulate cortex. DISCUSSION: This study shows that an increased parenchymal CSFF is associated with Aß deposition, suggesting that CSFF could serve as a biomarker for brain glymphatic clearance, which can be used to detect early fluid changes in PVS predisposing individuals to the development of AD. HIGHLIGHTS: Cerebrospinal fluid fraction (CSFF) could be a biomarker of parenchymal perivascular space. CSFF is positively associated with amyloid beta (Aß) deposition at subject level. CSFF in an Aß+ region is higher than in an Aß- region in the posterior cingulate cortex. Correspondence is found between Aß deposition and glymphatic clearance deficits measured by CSFF.

Multimodal assessment of brain fluid clearance is associated with amyloid-beta deposition in humans.

PURPOSE: The present study investigates a multimodal imaging assessment of glymphatic function and its association with brain amyloid-beta deposition. METHODS: Two brain CSF clearance measures (vCSF and DTI-ALPS) were derived from dynamic PET and MR diffusion tensor imaging (DTI) for 50 subjects, 24/50 were Aß positive (Aß+). T1W, T2W, DTI, T2FLAIR, and 11C-PiB and 18F-MK-6240 PET were acquired. Multivariate linear regression models were assessed with both vCSF and DTI-ALPS as independent variables and brain Aß as the dependent variable. Three types of models were evaluated, including the vCSF-only model, the ALPS-only model and the vCSF+ALPS combined model. Models were applied to the whole group, and Aß subgroups. All analyses were controlled for age, gender, and intracranial volume. RESULTS: Sample demographics (N=50) include 20 males and 30 females with a mean age of 69.30 (sd=8.55). Our results show that the combination of vCSF and ALPS associates with Aß deposition (p < 0.05, R2 = 0.575) better than either vCSF (p < 0.05, R2 = 0.431) or ALPS (p < 0.05, R2 = 0.372) alone in the Aß+ group. We observed similar results in whole-group analyses (combined model: p < 0.05, R2 = 0.287; vCSF model: p <0.05, R2 = 0.175; ALPS model: p < 0.05, R2 = 0.196) with less significance. Our data also showed that vCSF has higher correlation (r = -0.548) in subjects with mild Aß deposition and DTI-ALPS has higher correlation (r=-0.451) with severe Aß deposition subjects. CONCLUSION: The regression model with both vCSF and DTI-ALPS is better associated with brain Aß deposition. These two independent brain clearance measures may better explain the variation in Aß deposition than either term individually. Our results suggest that vCSF and DTI-ALPS reflect complementary aspects of brain clearance functions.

Association of brain tissue cerebrospinal fluid fraction with age in healthy cognitively normal adults.

Background and purpose: Our objective was to apply multi-compartment T2 relaxometry in cognitively normal individuals aged 20-80 years to study the effect of aging on the parenchymal CSF fraction (CSFF), a potential measure of the subvoxel CSF space. Materials and methods: A total of 60 volunteers (age range, 22-80 years) were enrolled. Voxel-wise maps of short-T2 myelin water fraction (MWF), intermediate-T2 intra/extra-cellular water fraction (IEWF), and long-T2 CSFF were obtained using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) sequence and three-pool non-linear least squares fitting. Multiple linear regression analyses were performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. ROIs include the cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM). In each model, a quadratic term for age was tested using an ANOVA test. A Spearman's correlation between the normalized lateral ventricle volume, a measure of organ-level CSF space, and the regional CSFF, a measure of tissue-level CSF space, was computed. Results: Regression analyses showed that there was a statistically significant quadratic relationship with age for CSFF in the cortex (p = 0.018), MWF in the cerebral WM (p = 0.033), deep GM (p = 0.017) and cortex (p = 0.029); and IEWF in the deep GM (p = 0.033). There was a statistically highly significant positive linear relationship between age and regional CSFF in the cerebral WM (p < 0.001) and deep GM (p < 0.001). In addition, there was a statistically significant negative linear association between IEWF and age in the cerebral WM (p = 0.017) and cortex (p < 0.001). In the univariate correlation analysis, the normalized lateral ventricle volume correlated with the regional CSFF measurement in the cerebral WM (ρ = 0.64, p < 0.001), cortex (ρ = 0.62, p < 0.001), and deep GM (ρ = 0.66, p < 0.001). Conclusion: Our cross-sectional data demonstrate that brain tissue water in different compartments shows complex age-dependent patterns. Parenchymal CSFF, a measure of subvoxel CSF-like water in the brain tissue, is quadratically associated with age in the cerebral cortex and linearly associated with age in the cerebral deep GM and WM.

Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions.

Importance: The U.S. government has named post-acute sequelae of COVID-19 (longCOVID) as influential on disability rates. We previously showed that COVID-19 carries a medical/functional burden at 1 year, and that age and other risk factors of severe COVID-19 were not associated with increased longCOVID risk. Long-term longCOVID brain fog (BF) prevalence, risk factors and associated medical/functional factors are poorly understood, especially after mild SARS-CoV-2 infection. Methods: A retrospective observational cohort study was conducted at an urban tertiary-care hospital. Of 1,032 acute COVID-19 survivors from March 3-May 15, 2020, 633 were called, 530 responded (59.2 ± 16.3 years, 44.5% female, 51.5% non-White) about BF prevalence, other longCOVID, post-acute ED/hospital utilization, perceived health/social network, effort tolerance, disability. Results: At approximately 1-year, 31.9% (n = 169) experienced BF. Acute COVID-19 severity, age, and premorbid cardiopulmonary comorbidities did not differ between those with/without BF at 1 year. Patients with respiratory longCOVID had 54% higher risk of BF than those without respiratory longCOVID. BF associated with sleep disturbance (63% with BF vs.29% without BF, p < 0.0001), shortness of breath (46% vs.18%, p < 0.0001), weakness (49% vs.22%, p < 0.0001), dysosmia/dysgeusia (12% vs.5%, p < 0.004), activity limitations (p < 0.001), disability/leave (11% vs.3%, p < 0.0001), worsened perceived health since acute COVID-19 (66% vs.30%, p < 0.001) and social isolation (40% vs.29%, p < 0.02), despite no differences in premorbid comorbidities and age. Conclusions and relevance: A year after COVID-19 infection, BF persists in a third of patients. COVID-19 severity is not a predictive risk factor. BF associates with other longCOVID and independently associates with persistent debility.

Peripheral immune cell imbalance is associated with cortical beta-amyloid deposition and longitudinal cognitive decline.

Neuroinflammation is believed to be a key process in Alzheimer's disease (AD) pathogenesis. Recently, the neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) have been proposed to be useful peripheral markers of inflammation. However, it is unclear how these inflammatory ratios relate to AD pathology, such as ß-amyloid (Aß) plaques and tau tangles. Using 18F-florbetapir and 18F-flortaucipir positron emission tomography (PET), we sought to determine how the NLR and LMR are associated with AD pathology both cross-sectionally and longitudinally. We further evaluated associations between the NLR and LMR and longitudinal cognitive decline. Using data from the Alzheimer's Disease Neuroimaging Initiative, we analyzed blood, PET, and cognitive data from 1544 subjects-405 cognitively normal, 838 with mild cognitive impairment (MCI), and 301 with AD. Associations between the NLR and LMR and Aß and tau on PET were assessed using ordinary least-squares and mixed-effects regression models, while adjusting for age, sex, years of education, and apolipoprotein E ε2 or ε4 carrier status. Associations between the NLR and LMR and cognitive function, as measured by the AD Assessment Scale-Cognitive Subscale, 13-item version, were also assessed. MCI and AD subjects had higher NLR (p = 0.017, p < 0.001, respectively) and lower LMR (p = 0.013, p = 0.023). The NLR, but not the LMR, was significantly associated with Aß (p = 0.028), suggesting that higher NLR was associated with greater Aß deposition in the brain. Neither the NLR nor the LMR was associated with tau deposition (p > 0.05). A higher NLR was associated with greater longitudinal cognitive decline (p < 0.001). A higher ratio of peripheral neutrophils to lymphocytes, possibly reflecting an imbalance in innate versus adaptive immunity, is related to greater Aß deposition and longitudinal cognitive decline. As the field moves toward blood-based biomarkers of AD, the altered balance of innate versus adaptive immunity could be a useful biomarker of underlying pathology and may also serve as a potential therapeutic target.

Distinct and joint effects of low and high levels of Aß and tau deposition on cortical thickness.

Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.

Brain PET Imaging: Approach to Cognitive Impairment and Dementia.

Alzheimer disease (AD) is the most common cause of dementia, accounting for 50% to 60% of cases and affecting nearly 6 million people in the United States. Definitive diagnosis requires either antemortem brain biopsy or postmortem autopsy. However, clinical neuroimaging has been playing a greater role in the diagnosis and management of AD, and several PET tracers approach the sensitivity of tissue diagnosis in identifying AD pathologic condition. This review will focus on the utility of PET imaging in the setting of cognitive impairment, with an emphasis on its role in the diagnosis of AD.

Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease.

Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aß), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.

Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals.

BACKGROUND AND PURPOSE: We investigated the effects of aging, white matter hyperintensities (WMH), and cognitive impairment on brain iron levels and cerebral oxygen metabolism, known to be altered in Alzheimer's disease (AD), using quantitative susceptibility mapping and MR-based cerebral oxygen extraction fraction (OEF). METHODS: In 100 individuals over the age of 50 (68/32 cognitively impaired/intact), OEF and neural tissue susceptibility (χn ) were computed retrospectively from MRI multi-echo gradient echo data, obtained on a 3 Tesla MRI scanner. The effects of age and WMH on OEF and χn were assessed within groups, and OEF and χn were assessed between groups, using multivariate regression analyses. RESULTS: Cognitively impaired subjects were found to have 19% higher OEF and 34% higher χn than cognitively intact subjects in the cortical gray matter and several frontal, temporal, and parietal regions (p < .05). Increased WMH burden was significantly associated with decreased OEF in the cognitively impaired, but not in the cognitively intact. Older age had a stronger association with decreased OEF in the cognitively intact group. Both older age and increased WMH burden were significantly associated with increased χn in temporoparietal regions in the cognitively impaired. CONCLUSIONS: Higher brain OEF and χn in cognitively impaired older individuals may reflect altered oxygen metabolism and iron in areas with underlying AD pathology. Both age and WMH have associations with OEF and χn but are modified by the presence of cognitive impairment.

Overview of tau PET molecular imaging.

PURPOSE OF REVIEW: This article reviews tau PET imaging with an emphasis on first-generation and second-generation tau radiotracers and their application in neurodegenerative disorders, including Alzheimer's disease and non-Alzheimer's disease tauopathies. RECENT FINDINGS: Tau is a critical protein, abundant in neurons within the central nervous system, which plays an important role in maintaining microtubules by binding to tubulin in axons. In its abnormal hyperphosphorylated form, accumulation of tau has been linked to a variety of neurodegenerative disorders, collectively referred to as tauopathies, which include Alzheimer's disease and non-Alzheimer's disease tauopathies [e.g., corticobasal degeneration (CBD), argyrophilic grain disease, progressive supranuclear palsy (PSP), and Pick's disease]. A number of first-generation and second-generation tau PET radiotracers have been developed, including the first FDA-approved agent [18F]-flortaucipir, which allow for in-vivo molecular imaging of underlying histopathology antemortem, ultimately guiding disease staging and development of disease-modifying therapeutics. SUMMARY: Tau PET is an emerging imaging modality in the diagnosis and staging of tauopathies.

Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.

DCE-MRI quantitative transport mapping for noninvasively detecting hypoxia inducible factor-1α, epidermal growth factor receptor overexpression, and Ki-67 in nasopharyngeal carcinoma patients.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the potential to noninvasively detect expression of hypoxia inducible factor-1-alpha (HIF-1α), epidermal growth factor receptor (EGFR), and Ki-67 in nasopharyngeal carcinoma (NPC) by quantitatively measuring tumor blood flow, vascularity, and permeability. PURPOSE: We aim to explore the utility of DCE-MRI in detecting HIF-1α, EGFR, and Ki-67 expression levels using traditional Kety's/Tofts' modeling and quantitative transport mapping (QTM). MATERIALS AND METHODS: Eighty-nine NPC patients underwent DCE-MRI before treatment were enrolled. DCE-MRI was processed to generate the following kinetic parameters: |u| and D from the QTM model, tumor blood flow (TBF) from Kety's model, and Ktrans, Ve, and Kep from Tofts' model. Pretreatment levels of HIF-1α, EGFR, and Ki-67 were assessed by immunohistochemistry and classified into low and high expression groups. RESULTS: |u| (p < 0.001) and TBF (p = 0.015) values were significantly higher in the HIF-1α high-expression group compared to low-expression group. Only Ktrans (p = 0.016) was significantly higher in the EGFR high-expression group. Only |u| (p < 0.001) values were significantly higher in the Ki-67 high-expression group compared to low-expression group. Multiple linear regression analyses showed that |u| independently correlated with HIF-1α and Ki-67 expression, and Ktrans independently correlated with EGFR. The areas under the ROC curves of |u| for HIF-1α and Ki-67, and Ktrans for EGFR were 0.83, 0.74, and 0.70, respectively. CONCLUSION: |u| and Ktrans derived from DCE-MRI may be considered as noninvasive imaging markers for detecting hypoxia and proliferation in NPC patients.

Heuristic scoring method utilizing FDG-PET statistical parametric mapping in the evaluation of suspected Alzheimer disease and frontotemporal lobar degeneration.

Distinguishing frontotemporal lobar degeneration (FTLD) and Alzheimer Disease (AD) on FDG-PET based on qualitative review alone can pose a diagnostic challenge. SPM has been shown to improve diagnostic performance in research settings, but translation to clinical practice has been lacking. Our purpose was to create a heuristic scoring method based on statistical parametric mapping z-scores. We aimed to compare the performance of the scoring method to the initial qualitative read and a machine learning (ML)-based method as benchmarks. FDG-PET/CT or PET/MRI of 65 patients with suspected dementia were processed using SPM software, yielding z-scores from either whole brain (W) or cerebellar (C) normalization relative to a healthy cohort. A non-ML, heuristic scoring system was applied using region counts below a preset z-score cutoff. W z-scores, C z-scores, or WC z-scores (z-scores from both W and C normalization) served as features to build random forest models. The neurological diagnosis was used as the gold standard. The sensitivity of the non-ML scoring system and the random forest models to detect AD was higher than the initial qualitative read of the standard FDG-PET [0.89-1.00 vs. 0.22 (95% CI, 0-0.33)]. A categorical random forest model to distinguish AD, FTLD, and normal cases had similar accuracy than the non-ML scoring model (0.63 vs. 0.61). Our non-ML-based scoring system of SPM z-scores approximated the diagnostic performance of a ML-based method and demonstrated higher sensitivity in the detection of AD compared to qualitative reads. This approach may improve the diagnostic performance.