Positron Emission Tomography with [18 F]-DPA-714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression.

OBJECTIVE: To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years. METHODS: Thirty-six people with MS (disease duration 9 ± 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration. RESULTS: Patients with MS had higher innate inflammation in normal-appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (ß = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (ß = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. INTERPRETATION: The [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366-383.

Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration.

In multiple sclerosis, spontaneous remyelination is generally incomplete and heterogeneous across patients. A high heterogeneity in remyelination may also exist across lesions within the same individual, suggesting the presence of local factors interfering with myelin regeneration. In this study we explored in vivo the regional distribution of myelin repair and investigated its relationship with neurodegeneration. We first took advantage of the myelin binding property of the amyloid radiotracer 11C-PiB to conduct a longitudinal 11C-PiB PET study in an original cohort of 19 participants with a relapsing-remitting form of multiple sclerosis, followed-up over a period of 1-4 months. We then replicated our results on an independent cohort of 40 people with multiple sclerosis followed-up over 1 year with magnetization transfer imaging, an MRI metrics sensitive to myelin content. For each imaging method, voxel-wise maps of myelin content changes were generated according to modality-specific thresholds. We demonstrated a selective failure of remyelination in periventricular white matter lesions of people with multiple sclerosis in both cohorts. In both the original and the replication cohort, we estimated that the probability of demyelinated voxels to remyelinate over the follow-up increased significantly as a function of the distance from ventricular CSF. Enlarged choroid plexus, a recently discovered biomarker linked to neuroinflammation, was found to be associated with the periventricular failure of remyelination in the two cohorts (r = -0.79, P = 0.0018; r = -0.40, P = 0.045, respectively), suggesting a role of the brain-CSF barrier in affecting myelin repair in surrounding tissues. In both cohorts, the failure of remyelination in periventricular white matter lesions was associated with lower thalamic volume (r = 0.86, P < 0.0001; r = 0.33; P = 0.069, respectively), an imaging marker of neurodegeneration. Interestingly, we also showed an association between the periventricular failure of remyelination and regional cortical atrophy that was mediated by the number of cortex-derived tracts passing through periventricular white matter lesions, especially in patients at the relapsing-remitting stage. Our findings demonstrate that lesion proximity to ventricles is associated with a failure of myelin repair and support the hypothesis that a selective periventricular remyelination failure in combination with the large number of tracts connecting periventricular lesions with cortical areas is a key mechanism contributing to cortical damage in multiple sclerosis.

[18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) PET imaging repurposed for quantitative estimation of blood-brain barrier permeability in a rat model of Alzheimer's disease.

Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS), which can be easily obtained from simple chemical reduction of commercial [18F]2-fluoro-2-deoxy-glucose ([18F]FDG), was investigated as a small-molecule marker of BBB permeability, in a pre-clinical model of AD using in vivo PET imaging. Chemical reduction of [18F]FDG to [18F]FDS was obtained with a 100% conversion yield. Dynamic PET acquisitions were performed in the APP/PS1 rat model of AD (TgF344-AD, n=3) compared with age-matched littermates (WT, n=4). The brain uptake of [18F]FDS was determined in selected brain regions, delineated from a coregistered rat brain template. The brain uptake of [18F]FDS in the brain regions of AD rats versus WT rats was compared using a 2-way ANOVA. The uptake of [18F]FDS was significantly higher in the whole brain of AD rats, as compared with WT rats (P<0.001), suggesting increased BBB permeability. Enhanced brain uptake of [18F]FDS in AD rats was significantly different across brain regions (P<0.001). Minimum difference was observed in the amygdala (+89.0±7.6%, P<0.001) and maximum difference was observed in the midbrain (+177.8±29.2%, P<0.001). [18F]FDS, initially proposed as radio-pharmaceutical to estimate renal filtration using PET imaging, can be repurposed for non-invasive and quantitative determination of BBB permeability in vivo. Making the best with the quantitative properties of PET imaging, it was possible to estimate the extent of enhanced BBB permeability in a rat model of AD.

The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment.

The 18kD translocator protein (TSPO) is used as a positron emission tomography (PET) target to quantify neuroinflammation in patients. In Alzheimer's disease (AD), the cerebellum is the pseudo-reference region for comparison with the cerebral cortex due to the absence of AD pathology and lower levels of TSPO. However, using the cerebellum as a pseudo-reference region is debated, with other brain regions suggested as more suitable. This paper aimed to establish the neuroinflammatory differences between the temporal cortex and cerebellar cortex, including TSPO expression. Using 60 human post-mortem samples encompassing the spectrum of Braak stages (I-VI), immunostaining for pan-Aß, hyperphosphorylated (p)Tau, TSPO and microglial proteins Iba1, HLA-DR and MSR-A was performed in the temporal cortex and cerebellum. In the cerebellum, Aß but not pTau, increased over the course of the disease, in contrast to the temporal cortex, where both proteins were significantly increased. TSPO increased in the temporal cortex, more than twofold in the later stages of AD compared to the early stages, but not in the cerebellum. Conversely, Iba1 increased in the cerebellum, but not in the temporal cortex. TSPO was associated with pTau in the temporal cortex, suggesting that TSPO positive microglia may be reacting to pTau itself and/or neurodegeneration at later stages of AD. Furthermore, the neuroinflammatory microenvironment was examined, using MesoScale Discovery assays, and IL15 only was significantly increased in the temporal cortex. Together this data suggests that the cerebellum maintains a more homeostatic environment compared to the temporal cortex, with a consistent TSPO expression, supporting its use as a pseudo-reference region for quantification in TSPO PET scans.

TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies.

INTRODUCTION: The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. METHODS: We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. RESULTS: 156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). CONCLUSION: This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.

Tau-PET imaging predicts cognitive decline and brain atrophy progression in early Alzheimer's disease.

OBJECTIVES: To explore whether regional tau binding measured at baseline is associated with the rapidity of Alzheimer's disease (AD) progression over 2 years, as assessed by the decline in specified cognitive domains, and the progression of regional brain atrophy, in comparison with amyloid-positron emission tomography (PET), MRI and cerebrospinal fluid (CSF) biomarkers. METHODS: Thirty-six patients with AD (positive CSF biomarkers and amyloid-PET) and 15 controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging, and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in patients with AD. RESULTS: Baseline tau-PET was strongly associated with the subsequent cognitive decline in regions that are usually associated with each cognitive domain. No significant relationship was observed between the cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarkers. Baseline tau tracer binding in the superior temporal gyrus was associated with subsequent atrophy in an inferomedial temporal volume of interest, as was the voxelwise tau tracer binding with subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices. CONCLUSIONS: These results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, which provides important insights into the interaction between tau burden and neurodegeneration, and is of the utmost importance to develop new prognostic markers that will help improve the design of therapeutic trials.

Spontaneous remyelination in lesions protects the integrity of surrounding tissues over time in multiple sclerosis.

BACKGROUND AND PURPOSE: Lesion remyelination preserves axonal integrity in animal models of multiple sclerosis (MS), but an in vivo demonstration of its protective effect on surrounding tissues in humans is lacking. METHODS: Nineteen persons with MS were enrolled in a cohort study and underwent two positron emission tomography (PET)/magnetic resonance imaging (MRI) scans 1-4 months apart. Voxelwise maps of Pittsburgh compound B distribution volume ratio, reflecting myelin content, were used to calculate an index of baseline demyelination, and of dynamic demyelination and remyelination over the follow-up in 549 single white matter lesions. Changes in fractional anisotropy and mean diffusivity, reflecting microstructural damage, were calculated in the proximal and distal 3-mm-thick rings surrounding each lesion, and used to classify perilesional microstructure as "preserved" or "worsening" over the follow-up. Mixed-effect linear models and logistic regressions were employed to investigate whether PET-derived lesional indices were associated with changes in MRI metrics in perilesions, and to identify which of them best predicted the microstructural evolution of perilesions over time. RESULTS: A higher index of remyelination, and a lower index of baseline and dynamic demyelination in lesions were associated with a less severe microstructural deterioration of the corresponding proximal and distal perilesions over time (p-value range: <0.001-0.012), but the index of remyelination was the best predicting variable of perilesional fate. For every extra 1% of remyelination within each lesion, the probability of the corresponding perilesional microstructure remaining preserved over time increased by 39% (odds ratio = 6.62, 95% confidence interval = 2.16-20.32, p < 0.001). CONCLUSIONS: Intralesional remyelination is associated with the microstructural preservation of surrounding tissues, possibly preventing neuroaxonal damage resulting from Wallerian degeneration.

Choroid Plexus Enlargement in Inflammatory Multiple Sclerosis: 3.0-T MRI and Translocator Protein PET Evaluation.

Background Choroid plexuses (CPs) have been suggested as a key gateway for inflammation in experimental autoimmune encephalitis, but in vivo evidence of their involvement in multiple sclerosis (MS) is lacking. Purpose To assess CP volumetric and inflammatory changes in patients with MS versus healthy control participants. Materials and Methods This was a secondary analysis of 97 patients (61 with relapsing-remitting MS [RRMS] and 36 with progressive MS) and 44 healthy control participants who participated in three prospective 3.0-T brain MRI studies between May 2009 and September 2017. A subgroup of 37 patients and 19 healthy control participants also underwent translocator protein fluorine 18 (18F)-DPA-714 PET for neuroinflammation. Relapses and disability scores were collected at baseline and over 2 years. CPs were manually segmented on three-dimensional T1-weighted images; other brain volumes were additionally segmented. Volumes were expressed as a ratio of intracranial volume. The 18F-DPA-714 distribution volume ratio was quantified in parenchymal regions, whereas standardized uptake value was used for CP inflammation. Multivariable linear regression analyses were performed to assess CP volumetric and inflammatory differences between patients with MS and healthy control participants and correlations between CP volume and lesion load, brain volumes, 18F-DPA-714 uptake, and annualized relapse rate. Results Ninety-seven patients with MS (mean age, 42 years ± 12 [standard deviation]; 49 women) and 44 healthy control participants (mean age, 39 years ± 14; 23 women) underwent MRI. Thirty-seven patients with MS and 19 healthy control participants underwent PET. CPs were 35% larger in patients with MS (mean value, 15.9 × 10-4 ± 4.5) than in healthy control participants (mean value, 11.8 × 10-4 ± 3.8; P = .004). Subgroup analysis confirmed greater CP volume in patients with RRMS (mean value, 15.5 × 10-4 ± 4.6; P = .008) than in healthy control participants. CP enlargement was greater in patients with active lesions at MRI (mean volume, 18.2 × 10-4 ± 4.9 in patients with lesions that enhanced with gadolinium vs 14.9 × 10-4 ± 4 in patients with lesions that did not enhance with gadolinium; P < .001) and correlated with white matter lesion load (r = 0.39; 95% CI: 0.20, 0.55; P < .001) and 18F-DPA-714 binding in the thalami (r = 0.44; 95% CI: 0.22, 0.72; P = .04) and normal-appearing white matter (r = 0.5; 95% CI: 0.20, 0.71; P = .005). Moreover, it correlated with annualized relapse rate in patients with RRMS (r = 0.37; 95% CI: 0.1, 0.55; P = .005). Finally, patients with MS showed 18.5% higher CP 18F-DPA-714 uptake than control participants (mean value, 0.778 ± 0.23 vs 0.635 ± 0.15, respectively; P = .01). CP volume in patients with RRMS (r = 0.57; 95% CI: 0.37, 0.73; P = .009) correlated with higher 18F-DPA-714 uptake. Conclusion Choroid plexuses (CPs) are enlarged and inflamed in patients with multiple sclerosis (MS), particularly in those with relapsing-remitting MS with inflammatory profiles; CP volumetric analysis could represent an MS imaging marker. © RSNA, 2021 EudraCT no. 2008-004174-40; clinical trial registration nos. NCT02305264 and NCT01651520 Online supplemental material is available for this article.

RF heating measurement using MR thermometry and field monitoring: Methodological considerations and first in vivo results.

PURPOSE: A MR thermometry (MRT) method with field monitoring is proposed to improve the measurement of small temperature variations induced in brain MRI exams. METHODS: MR thermometry experiments were performed at 7 Tesla with concurrent field monitoring and RF heating. Images were reconstructed with nominal k-space trajectories and with first-order spherical harmonics correction. Experiments were performed in vitro with deliberate field disturbances and on an anesthetized macaque in 2 different specific absorption rate regimes, that is, at 50% and 100% of the maximal specific absorption rate level allowed in the International Electrotechnical Commission normal mode of operation. Repeatability was assessed by running a second separate session on the same animal. RESULTS: Inclusion of magnetic field fluctuations in the reconstruction improved temperature measurement accuracy in vitro down to 0.02°C. Measurement precision in vivo was on the order of 0.15°C in areas little affected by motion. In the same region, temperature increase reached 0.5 to 0.8°C after 20 min of heating at 100% specific absorption rates and followed a rough factor of 2 with the 50% specific absorption rate scans. A horizontal temperature plateau, as predicted by Pennes bioheat model with thermal constants from the literature and constant blood temperature assumption, was not observed. CONCLUSION: Inclusion of field fluctuations in image reconstruction was beneficial for the measurement of small temperature rises encountered in standard brain exams. More work is needed to correct for motion-induced field disturbances to extract reliable temperature maps.

Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers.

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.

What can 7T sodium MRI tell us about cellular energy depletion and neurotransmission in Alzheimer's disease?

The pathophysiological processes underlying the development and progression of Alzheimer's disease (AD) on the neuronal level are still unclear. Previous research has hinted at metabolic energy deficits and altered sodium homeostasis with impaired neuronal function as a potential metabolic marker relevant for neurotransmission in AD. Using sodium (23 Na) magnetic resonance (MR) imaging on an ultra-high-field 7 Tesla MR scanner, we found increased cerebral tissue sodium concentration (TSC) in 17 biomarker-defined AD patients compared to 22 age-matched control subjects in vivo. TSC was highly discriminative between controls and early AD stages and was predictive for cognitive state, and associated with regional tau load assessed with flortaucipir-positron emission tomography as a possible mediator of TSC-associated neurodegeneration. TSC could therefore serve as a non-invasive, stage-dependent, metabolic imaging marker. Setting a focus on cellular metabolism and potentially disturbed interneuronal communication due to energy-dependent altered cell homeostasis could hamper progressive cognitive decline by targeting these processes in future interventions.

A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model.

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.

Repurposing radiotracers for myelin imaging: a study comparing 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol,11C-MeDAS, and 11C-PiB.

PURPOSE: Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative 11C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol, 11C-MeDAS, and 11C-PiB with regard to brain kinetics and binding in white matter (WM). METHODS: Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for 18F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR75-90), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models. RESULTS: In WM, 18F-florbetapir had the highest SUVR75-90 (1.38 ± 0.03), followed by 18F-flutemetamol (1.34 ± 0.02), 18F-florbetaben (1.32 ± 0.07), 11C-MeDAS (1.27 ± 0.04), and 11C-PiB (1.25 ± 0.07). With regard to BP, 18F-florbetaben had the highest value (0.32 ± 0.06) compared with 18F-flutemetamol (0.20 ± 0.03), 11C-MeDAS (0.17 ± 0.03), and 11C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18F-florbetaben (1.26 ± 0.06) and 18F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18F-flutemetamol (1.17 ± 0.02), 11C-MeDAS (1.16 ± 0.03), and 11C-PiB (1.14 ± 0.02). CONCLUSIONS: Given their higher binding and longer half-life, our study indicates that 18F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

Neutrophil hyperactivation correlates with Alzheimer's disease progression.

OBJECTIVE: Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimer's disease (AD). Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in AD. METHODS: We analyzed neutrophil phenotypes and functions in 42 patients with AD (16 with mild cognitive impairment and 26 with dementia), and compared them to 22 age-matched healthy subjects. This study was performed directly in whole blood to avoid issues with data interpretation related to cell isolation procedures. RESULTS: Blood samples from AD patients with dementia revealed neutrophil hyperactivation associated with increased reactive oxygen species production and increased levels of intravascular neutrophil extravascular traps. The homeostasis of circulating neutrophils in these patients also changed: The ratio between the harmful hyperreactive CXCR4high /CD62Llow senescent and the CD16bright /CD62Ldim immunosuppressive neutrophil subsets rose in the later stage of the disease. These abnormalities were greater in fast-decliner than in slow-decliner patients. INTERPRETATION: Our results indicate that the inflammatory properties of circulating neutrophils shift as the percentage of aged neutrophils expands in patients with AD-changes that may play an instrumental role in establishing systemic chronic inflammation. Most important, our data strongly suggest that the neutrophil phenotype may be associated with the rate of cognitive decline and may thus constitute an innovative and prognostic blood biomarker in patients with AD. Ann Neurol 2018;83:387-405.

Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease.

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

In vivo PET imaging of neuroinflammation in Alzheimer's disease.

Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia. In the present review, we describe the most widely used PET tracers targeting the TSPO, the methodological issues in tracer quantification and summarize the results obtained by TSPO PET imaging in AD, as well as in neurodegenerative disorders associated with AD, in psychiatric disorders and ageing. We also briefly describe alternative PET targets and imaging modalities to study neuroinflammation. Lastly, we question the meaning of PET imaging data in the context of a highly complex and multifaceted role of neuroinflammation in neurodegenerative diseases. This overview leads to the conclusion that PET imaging of neuroinflammation is a promising way of deciphering the enigma of the pathophysiology of AD and of monitoring the effect of new therapies.

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis.

BACKGROUND: Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11 C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS. METHODS: Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11 C]PiB and magnetic resonance imaging. Voxel-wise maps of [11 C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination. RESULTS: At baseline, there was a progressive reduction in [11 C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = -0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = -0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index. INTERPRETATION: [11 C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726-738.

Acute Morphine Exposure Increases the Brain Distribution of [18F]DPA-714, a PET Biomarker of Glial Activation in Nonhuman Primates.

Background: The neuroinflammatory response to morphine exposure modulates its antinociceptive effects, tolerance, and dependence. Positron emission tomography radioligands for translocator protein-18kDa such as [18F]DPA-714 are noninvasive biomarkers of glial activation, a hallmark of neuroinflammation. Methods: [18F]DPA-714 positron emission tomography imaging was performed in 5 baboons at baseline and 2 hours after i.m. morphine injection (1 mg/kg). Brain kinetics and metabolite-corrected input function were measured to estimate [18F]DPA-714 brain distribution. Results: Morphine significantly increased [18F]DPA-714 brain distribution by a 1.3 factor (P<.05; paired t test). The effect was not restricted to opioid receptor-rich regions. Differences in baseline [18F]DPA-714 binding were observed among baboons. The response to morphine predominated in animals with the highest baseline uptake. Conclusions: [18F]DPA-714 positron emission tomography imaging may be useful to noninvasively investigate the brain immune component of morphine pharmacology. Correlation between baseline brain distribution and subsequent response to morphine exposure suggest a role for priming parameters in controlling the neuroinflammatory properties of opioids.

Cholinergic Changes in Aging and Alzheimer Disease: An [18F]-F-A-85380 Exploratory PET Study.

The central cholinergic system undergoes changes during the physiological process of aging and the pathologic process of Alzheimer disease (AD). We aimed to analyze the impairment of cholinergic pathways by positron emission tomography using the [F]-F-A-85380 (FA85) tracer, which has a high affinity for nicotinic acetylcholine receptors (nAChRs). Aging was assessed by comparing young (n=10) and elderly (n=4) healthy subjects, and the pathologic process of AD was assessed by comparing elderly controls and age-matched AD patients (n=8). We measured an index of the nAChR density in the cortex and the hippocampus and the total number of FA85-binding sites by taking into account the volume changes. In AD, the nAChR density was preserved in both the cortex and hippocampus. The total estimated number of FA85-binding sites was decreased in the hippocampus despite the lack of a significant loss of volume, whereas the difference in the cortex did not withstand the adjustment for multiple comparisons despite a significant loss of volume. In contrast, in aging, the estimated number of FA85-binding sites was decreased in both the cortex and hippocampus with significant hippocampal atrophy. These findings suggest a preferential impairment of cholinergic pathways in the cortex during aging, whereas in AD, this damage predominated in the hippocampus with a potential compensatory cholinergic effect in the cortex.