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.

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.

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.

Integrated PET-MRI for Glioma Surveillance: Perfusion-Metabolism Discordance Rate and Association With Molecular Profiling.

OBJECTIVE: Both 18F-FDG PET and perfusion MRI are commonly used techniques for posttreatment glioma surveillance. Using integrated PET-MRI, we assessed the rate of discordance between simultaneously acquired FDG PET images and dynamic contrast-enhanced (DCE) perfusion MR images and determined whether tumor genetics predicts discordance. MATERIALS AND METHODS: Forty-one consecutive patients with high-grade gliomas (20 with grade IV gliomas and 21 with grade III gliomas) underwent a standardized tumor protocol performed using an integrated 3-T PET-MRI scanner. Quantitative measures of standardized uptake value, plasma volume, and permeability were obtained from segmented whole-tumor volumes of interest and targeted ROIs. ROC curve analysis and the Youden index were used to identify optimal cutoffs for FDG PET and DCE-MRI. Two-by-two contingency tables and percent agreement were used to assess accuracy and concordance. Twenty-six patients (63%) from the cohort underwent next-generation sequencing for tumor genetics. RESULTS: The best-performing FDG PET and DCE-MRI cutoffs achieved sensitivities of 94% and 91%, respectively; specificities of 56% and 89%, respectively; and accuracies of 80% and 83%, respectively. FDG PET and DCE-MRI findings were discordant for 11 patients (27%), with DCE-MRI findings correct for six of these patients (55%). Tumor grade, tumor volume, bevacizumab exposure, and time since radiation predicted discordance between FDG PET and DCE-MRI findings, with an ROC AUC value of 0.78. Isocitrate dehydrogenase gene and receptor tyrosine kinase gene pathway mutations increased the ROC AUC value to 0.83. CONCLUSION: FDG PET and DCE-MRI show comparable accuracy and sensitivity in identifying tumor progression. These modalities were shown to have discordant findings for more than a quarter of the patients assessed. Tumor genetics may contribute to perfusion-metabolism discordance, warranting further investigation.

Quantitative transport mapping of multi-delay arterial spin labeling MRI detects early blood perfusion alterations 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 cerebral blood flow (CBF). 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 CBF 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 perfusion with consideration of age and gender effects. RESULTS: In cortical gray matter (GM) and the hippocampus, QTM velocity and CBF showed decreased values in the AD group compared to NC and MCI groups; QTM velocity, but not CBF, showed a significant difference between MCI and NC groups. QTM velocity and CBF showed values decreasing with age; QTM velocity, but not CBF, showed a significant gender difference between male and female. QTM velocity and CBF 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's method-based CBF. Specifically, we observed only in QTM velocity, reduced perfusion velocity in GM and the hippocampus in MCI compared with NC. Both QTM velocity and CBF demonstrated a reduction in AD vs. controls. Decreased QTM velocity and CBF in the hippocampus were correlated with poor cognitive measures. These findings suggest QTM velocity as potential biomarker for early AD blood perfusion alterations and it could provide an avenue for early intervention of AD.

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.

Increased between-network connectivity: A risk factor for tau elevation and disease progression.

One of the pathologic hallmarks of Alzheimer's disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases. Building upon increased between-network connectivity, our study hypothesizes that this increase may play a critical role in facilitating tau spread in early stages. We conducted a longitudinal study over two to three years intervals on a cohort of 46 healthy elderly participants (mean age 64.23 ± 3.15 years, 26 females). Subjects were examined clinically and utilizing advanced imaging techniques that included resting-state functional MRI (rs-fMRI), structural magnetic resonance imaging (MRI), and a second-generation positron emission tomography (PET) tau tracer, 18F-MK6240. Through unsupervised agglomerative clustering and increase in between-network connectivity, we successfully identified individuals at increased risk of future tau elevation and AD progression. Our analysis revealed that individuals with increased between-network connectivity are more likely to experience more future tau deposition, entorhinal cortex thinning, and lower selective reminding test (SRT) delayed scores. Additionally, in the limbic network, we found a strong association between tau progression and increased between-network connectivity, which was mainly driven by beta-amyloid (Aß) positive participants. These findings provide evidence for the hypothesis that an increase in between-network connectivity predicts future tau deposition and AD progression, also enhancing our understanding of AD pathogenesis in the preclinical stages.

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.

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.

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.

Alzheimer's Disease Anti-Amyloid Immunotherapies: Imaging Recommendations and Practice Considerations for ARIA Monitoring.

With the full FDA approval and centers for Medicare & Medicaid services (CMS) coverage of lecanemab and donanemab, a growing number of practices are offering anti-amyloid immunotherapy to appropriate patients with cognitive impairment (MCI) or mild dementia due to amyloid-positive Alzheimer's disease (AD). The goal of this paper is to provide updated practical considerations for radiologists, including implementation of MR imaging protocols, workflows and reporting and communication practices relevant to anti-amyloid immunotherapy and monitoring for amyloid-related imaging abnormalities (ARIA). Based on consensus discussion within an expanded ASNR Alzheimer's, ARIA, and Dementia study group, we will: (1) summarize the FDA guidelines for evaluation of radiographic ARIA; (2) review the three key MRI sequences for ARIA monitoring and standardized imaging protocols based on ASNR-industry collaborations; (3) provide imaging recommendations for three key patient scenarios; (4) highlight the role of the radiologist in the care team for this population; (5) discuss implementation of MRI protocols to detect ARIA in diverse practice settings; and (6) present results of the 2023 ASNR international neuroradiologist practice survey on dementia and ARIA imaging.ABBREVIATIONS: AD = Alzheimer's disease; ARIA = amyloid-related imaging abnormalities; APOE = apolipoprotein-E; CMS = centers for Medicare & Medicaid services; MCI = mild cognitive impairment.

[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.

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.

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.