Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer Disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS: We aimed to study CSF PDGFRß protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. RESULTS: Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRß and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRß levels were not associated with either the CSF Aß42 or the amyloid-PET. CONCLUSIONS: We demonstrated a moderate positive correlation between PDGFRß and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094939.

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.

Grading meningiomas utilizing multiparametric MRI with inclusion of susceptibility weighted imaging and quantitative susceptibility mapping.

BACKGROUND AND PURPOSE: The ability to predict high-grade meningioma preoperatively is important for clinical surgical planning. The purpose of this study is to evaluate the performance of comprehensive multiparametric MRI, including susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM) in predicting high-grade meningioma both qualitatively and quantitatively. METHODS: Ninety-two low-grade and 37 higher grade meningiomas in 129 patients were included in this study. Morphological characteristics, quantitative histogram analysis of QSM and ADC images, and tumor size were evaluated to predict high-grade meningioma using univariate and multivariate analyses. Receiver operating characteristic (ROC) analyses were performed on the morphological characteristics. Associations between Ki-67 proliferative index (PI) and quantitative parameters were calculated using Pearson correlation analyses. RESULTS: For predicting high-grade meningiomas, the best predictive model in multivariate logistic regression analyses included calcification (ß=0.874, P=0.110), peritumoral edema (ß=0.554, P=0.042), tumor border (ß=0.862, P=0.024), tumor location (ß=0.545, P=0.039) for morphological characteristics, and tumor size (ß=4×10-5, P=0.004), QSM kurtosis (ß=-5×10-3, P=0.058), QSM entropy (ß=-0.067, P=0.054), maximum ADC (ß=-1.6×10-3, P=0.003), ADC kurtosis (ß=-0.013, P=0.014) for quantitative characteristics. ROC analyses on morphological characteristics resulted in an area under the curve (AUC) of 0.71 (0.61-0.81) for a combination of them. There were significant correlations between Ki-67 PI and mean ADC (r=-0.277, P=0.031), 25th percentile of ADC (r=-0.275, P=0.032), and 50th percentile of ADC (r=-0.268, P=0.037). CONCLUSIONS: Although SWI and QSM did not improve differentiation between low and high-grade meningiomas, combining morphological characteristics and quantitative metrics can help predict high-grade meningioma.

Texture analysis on conventional MRI images accurately predicts early malignant transformation of low-grade gliomas.

OBJECTIVES: Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. This study aimed to evaluate the feasibility of texture analysis on preoperative conventional MRI images in predicting early malignant transformation from low- to high-grade glioma and compare its utility to histogram analysis alone. METHODS: A total of 68 patients with low-grade glioma (LGG) were included in this study, 15 of which showed malignant transformation. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analyses were performed to obtain the most discriminant factor (MDF) values for both training and testing data. Receiver operating characteristic (ROC) curve analyses were performed on MDF values and 9 histogram parameters in the training data to obtain cutoff values for determining the correct rates of discrimination between two groups in the testing data. RESULTS: The ROC analyses on MDF values resulted in an area under the curve (AUC) of 0.90 (sensitivity 85%, specificity 84%) for T2w FLAIR, 0.92 (86%, 94%) for ADC, 0.96 (97%, 84%) for T1w, and 0.82 (78%, 75%) for T1w + Gd and correctly discriminated between the two groups in 93%, 100%, 93%, and 92% of cases in testing data, respectively. In the astrocytoma subgroup, AUCs were 0.92 (88%, 83%) for T2w FLAIR and 0.90 (92%, 74%) for T1w + Gd and correctly discriminated two groups in 100% and 92% of cases. The MDF outperformed all 9 of the histogram parameters. CONCLUSION: Texture analysis on conventional preoperative MRI images can accurately predict early malignant transformation of LGGs, which may guide therapeutic planning. KEY POINTS: • Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. • Texture analysis based on conventional preoperative MR images can accurately predict early malignant transformation from low- to high-grade glioma. • Texture analysis is a clinically feasible technique that may provide an alternative and effective way of determining the likelihood of early malignant transformation and help guide therapeutic decisions.

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.

Multimethod Assessment of Medication Nonadherence and Barriers in Adolescents and Young Adults With Solid Organ Transplants.

Objective: To (a) examine levels of medication nonadherence in adolescent and young adult (AYA) solid organ transplant recipients based on AYA- and caregiver proxy-reported nonadherence to different medication types and the medication-level variability index (MLVI) for tacrolimus, and (b) examine associations of adherence barriers and AYA and caregiver emotional distress symptoms with reported nonadherence and the MLVI. Method: The sample included 47 AYAs (M age = 16.67 years, SD = 1.74; transplant types: 25% kidney, 47% liver, 28% heart) and their caregivers (94 total participants). AYAs and caregivers reported on AYAs' adherence barriers and their own emotional functioning. Nonadherence was measured with AYA self- and caregiver proxy-report and the MLVI for tacrolimus. Results: The majority of AYAs and caregivers denied nonadherence, with lower rates of nonadherence reported for antirejection medications. In contrast, 40% of AYAs' MLVI values indicated nonadherence to tacrolimus. AYAs and caregivers who verbally acknowledged nonadherence had more AYA barriers and greater caregiver emotional distress symptoms compared with those who denied nonadherence. AYAs with MLVIs indicating nonadherence had more barriers than AYAs with MLVIs indicating adherence. Conclusions: Multimethod nonadherence evaluations for AYA transplant recipients should assess objective nonadherence using the MLVI, particularly in light of low reported nonadherence rates for antirejection medications. Assessments should include adherence barriers measures, given associations with the MLVI, and potentially prioritize assessing barriers over gauging nonadherence via self- or proxy-reports. Caregiver emotional distress symptoms may also be considered to provide insight into family or environmental barriers to adherence.

Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.

Apparent diffusion coefficient changes predict survival after intra-arterial bevacizumab treatment in recurrent glioblastoma.

PURPOSE: Superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) has emerged as a novel therapy in the treatment of recurrent glioblastoma (GB). This study assessed the use of apparent diffusion coefficient (ADC) in predicting length of survival after SIACI BV and overall survival in patients with recurrent GB. METHODS: Sixty-five patients from a cohort enrolled in a phase I/II trial of SIACI BV for treatment of recurrent GB were retrospectively included in this analysis. MR imaging with a diffusion-weighted (DWI) sequence was performed before and after treatment. ROIs were manually delineated on ADC maps corresponding to the enhancing and non-enhancing portions of the tumor. Cox and logistic regression analyses were performed to determine which ADC values best predicted survival. RESULTS: The change in minimum ADC in the enhancing portion of the tumor after SIACI BV therapy was associated with an increased risk of death (hazard ratio = 2.0, 95% confidence interval(CI) [1.04-3.79], p = 0.038), adjusting for age, tumor size, BV dose, and prior IV BV treatments. Similarly, the change in ADC after SIACI BV therapy was associated with greater likelihood of surviving less than 1 year after therapy (odds ratio = 7.0, 95% CI [1.08-45.7], p = 0.04). Having previously received IV BV was associated with increased risk of death (OR 18, 95% CI [1.8-180.0], p = 0.014). CONCLUSION: In patients with recurrent GB treated with SIACI BV, the change in ADC value after treatment is predictive of overall survival.

Longitudinal change in magnetic susceptibility of new enhanced multiple sclerosis (MS) lesions measured on serial quantitative susceptibility mapping (QSM).

PURPOSE: To measure the longitudinal change in multiple sclerosis (MS) lesion susceptibility using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: The study was approved by our Institutional Review Board. Longitudinal changes in quantitative susceptibility values of new enhanced-with-Gd MS lesions were measured at baseline magnetic resonance imaging (MRI) and on a follow-up MRI in 29 patients within 2 years using a 3D multiple echo gradient echo sequence on a 3T scanner. Paired t-test and the generalized estimating equations (GEE) model was used to analyze the longitudinal change. RESULTS: Lesion susceptibility values relative to normal-appearing white matter (NAWM) changed from 3.61 ± 6.11 ppb when enhanced-with-Gd at the baseline MRI to 20.42 ± 10.23 ppb when not-enhanced-with-Gd at the follow-up MRI (P < 0.001). CONCLUSION: MS lesion susceptibility value increases significantly as the lesion evolves from enhanced-with-Gd to not-enhanced-with-Gd, serving as a disease biomarker. J. Magn. Reson. Imaging 2016;44:426-432.

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.

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.

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.

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.