Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

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.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

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.

Clinically relevant profiles of myelin content changes in patients with multiple sclerosis: A multimodal and multicompartment imaging study.

OBJECTIVE: To investigate the clinical relevance of individual profiles of cortical and white matter lesion myelin content changes combining magnetisation transfer imaging (MTI) and 11C-PiB-positron emission tomography (PET) in patients with multiple sclerosis (MS). METHODS: MTI and [11C]PiB-PET acquired in 19 patients with MS followed up over 2-4 months and in seven healthy controls (HCs), were employed to generate individual maps of cortical and white matter (WM) lesion myelin content changes, respectively. These maps were used to calculate individual indices of demyelination and remyelination, and to investigate their association with clinical scores. RESULTS: Cortical remyelination ranged between 1% and 5% of the total cortical volume (17%-45% of the cortical volume demyelinated at baseline). WM lesion remyelination ranged between 8% and 22% of the lesional volume. An extensive cortical remyelination was associated with a shorter disease duration (rho = -0.63, p = 0.01) and, in combination with WM lesion remyelination, explained 68%-70% of the variance of clinical scores (p < 0.01). CONCLUSION: Our multimodal and multicompartment approach allows us to explore single-patient cortical and WM lesion demyelination and remyelination, and to generate clinically relevant indices of myelin repair. These indices may be used as outcome measures in clinical trials, thus increasing the chance to identify successful promyelinating treatments in patients with MS.

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.

Supervised clustering for TSPO PET imaging.

PURPOSE: This technical note seeks to act as a practical guide for implementing a supervised clustering algorithm (SVCA) reference region approach and to explain the main strengths and limitations of the technique in the context of 18-kilodalton translocator protein (TSPO) positron emission tomography (PET) studies in experimental medicine. BACKGROUND: TSPO PET is the most widely used imaging technique for studying neuroinflammation in vivo in humans. Quantifying neuroinflammation with PET can be a challenging and invasive procedure, especially in frail patients, because it often requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is SVCA, which identifies the voxels with minimal specific binding in the PET images, thus extracting a pseudo-reference region for non-invasive quantification. Unlike other reference region approaches, SVCA does not require specification of an anatomical reference region a priori, which alleviates the limitation of TSPO contamination in anatomically-defined reference regions in individuals with underlying inflammatory processes. Furthermore, SVCA can be applied to any TSPO PET tracer across different neurological and neuropsychiatric conditions, providing noninvasivequantification of TSPO expression. METHODS: We provide an overview of the development of SVCA as well as step-by-step instructions for implementing SVCA with suggestions for specific settings. We review the literature on SVCAapplications using first- and second- generation TSPO PET tracers and discuss potential clinically relevant limitations and applications. CONCLUSIONS: The correct implementation of SVCA can provide robust and reproducible estimates of brain TSPO expression. This review encourages the standardisation of SVCA methodology in TSPO PET analysis, ultimately aiming to improve replicability and comparability across study sites.

Thalamic energy dysfunction is associated with thalamo-cortical tract damage in multiple sclerosis: A diffusion spectroscopy study.

BACKGROUND: Diffusion-weighted 1H magnetic resonance spectroscopy (DW-MRS) allows to quantify creatine-phosphocreatine brain diffusivity (ADC(tCr)), whose reduction in multiple sclerosis (MS) has been proposed as a proxy of energy dysfunction. OBJECTIVE: To investigate whether thalamic ADC(tCr) changes are associated with thalamo-cortical tract damage in MS. METHODS: Twenty patients with MS and 13 healthy controls (HC) were enrolled in a DW-MRS and DW imaging (DWI) study. From DW-MRS, ADC(tCr) and total N-acetyl-aspartate diffusivity (ADC(tNAA)) were extracted in the thalami. Three thalamo-cortical tracts and one non-thalamic control tract were reconstructed from DWI. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD), reflecting microstructural integrity, were extracted for each tract. Associations between thalamic ADC(tCr) and tract metrics were assessed using linear regression models adjusting for age, sex, thalamic volume, thalamic ADC(tNAA), and tract-specific lesion load. RESULTS: Lower thalamic ADC(tCr) was associated with higher MD and RD of thalamo-cortical projections in MS (MD: p = 0.029; RD: p = 0.017), but not in HC (MD: p = 0.625, interaction term between thalamic ADC(tCr) and group = 0.019; RD: p = 0.320, interaction term = 0.05). Thalamic ADC(tCr) was not associated with microstructural changes of the control tract. CONCLUSION: Reduced thalamic ADC(tCr) correlates with thalamo-cortical tract damage in MS, showing that pathologic changes in thalamic energy metabolism are associated with structural degeneration of connected fibers.

Predicting PET-derived myelin content from multisequence MRI for individual longitudinal analysis in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS). The demyelination process can be repaired by the generation of a new sheath of myelin around the axon, a process termed remyelination. In MS patients, the demyelination-remyelination cycles are highly dynamic. Over the years, magnetic resonance imaging (MRI) has been increasingly used in the diagnosis of MS and it is currently the most useful paraclinical tool to assess this diagnosis. However, conventional MRI pulse sequences are not specific for pathological mechanisms such as demyelination and remyelination. Recently, positron emission tomography (PET) with radiotracer [11C]PIB has become a promising tool to measure in-vivo myelin content changes which is essential to push forward our understanding of mechanisms involved in the pathology of MS, and to monitor individual patients in the context of clinical trials focused on repair therapies. However, PET imaging is invasive due to the injection of a radioactive tracer. Moreover, it is an expensive imaging test and not offered in the majority of medical centers in the world. In this work, by using multisequence MRI, we thus propose a method to predict the parametric map of [11C]PIB PET, from which we derived the myelin content changes in a longitudinal analysis of patients with MS. The method is based on the proposed conditional flexible self-attention GAN (CF-SAGAN) which is specifically adjusted for high-dimensional medical images and able to capture the relationships between the spatially separated lesional regions during the image synthesis process. Jointly applying the sketch-refinement process and the proposed attention regularization that focuses on the MS lesions, our approach is shown to outperform the state-of-the-art methods qualitatively and quantitatively. Specifically, our method demonstrated a superior performance for the prediction of myelin content at voxel-wise level. More important, our method for the prediction of myelin content changes in patients with MS shows similar clinical correlations to the PET-derived gold standard indicating the potential for clinical management of patients with MS.

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.

Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling.

Longitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging. METHODS: Using dynamic, whole-body 18F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (VT) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT and %ID parameters. RESULTS: The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the VT estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans. CONCLUSION: We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling.

Protein synthesis is associated with high-speed dynamics and broad-band stability of functional hubs in the brain.

L-[1-11C]leucine PET can be used to measure in vivo protein synthesis in the brain. However, the relationship between regional protein synthesis and on-going neural dynamics is unclear. We use a graph theoretical approach to examine the relationship between cerebral protein synthesis (rCPS) and both static and dynamical measures of functional connectivity (measured using resting state functional MRI, R-fMRI). Our graph theoretical analysis demonstrates a significant positive relationship between protein turnover and static measures of functional connectivity. We compared these results to simple measures of metabolism in the cortex using [18F]FDG PET). Whilst some relationships between [18F]FDG binding and graph theoretical measures was present, there remained a significant relationship between protein turnover and graph theoretical measures, which were more robustly explained by L-[1-11C]Leucine than [18F]FDG PET. This relationship was stronger in dynamics at a faster temporal resolution relative to dynamics measured over a longer epoch. Using a Dynamic connectivity approach, we also demonstrate that broad-band dynamic measures of Functional Connectivity (FC), are inversely correlated with protein turnover, suggesting greater stability of FC in highly interconnected hub regions is supported by protein synthesis. Overall, we demonstrate that cerebral protein synthesis has a strong relationship independent of tissue metabolism to neural dynamics at the macroscopic scale.

Simultaneous assessment of blood flow and myelin content in the brain white matter with dynamic [11 C]PiB PET: a test-retest study in healthy controls.

BACKGROUND: Exploring the relationship between oxygen supply and myelin damage would benefit from a simultaneous quantification of myelin and cerebral blood flow (CBF) in the brain's white matter (WM). To validate an analytical method for quantifying both CBF and myelin content in the WM using dynamic [11C]PiB positron emission tomography (PET). METHODS: A test-retest study was performed on eight healthy subjects who underwent two consecutive dynamic [11 C]PiB-PET scans. Three quantitative approaches were compared: simplified reference tissue model 2 (SRTM2), LOGAN graphical model, and standardized uptake value ratio (SUVR). The sensitivity of methods to the size of the region of interest was explored by simulating lesion masks obtained from 36 subjects with multiple sclerosis. Reproducibility was assessed using the relative difference and interclass correlation coefficient. Repeated measures correlations were used to test for cross-correlations between metrics. RESULTS: Among the CBF measures, the relative delivery (R1) of the simplified reference tissue model 2 (SRTM2) displayed the best reproducibility in the white matter, with a strong influence of the size of regions analyzed, the test-retest variability being below 10% for regions above 68 mm3 in the supratentorial white matter. [11C]PiB PET-derived proxies of CBF demonstrated lower perfusion of white matter compared to grey matter with an overall ratio equal to 1.71 ± 0.09 when the SRTM2-R1 was employed. Tissue binding in the white matter was well estimated by the Logan graphical model through estimation of the distribution volume ratio (LOGAN-DVR) and SRTM2 distribution volume ratio (SRTM2-DVR), with test-retest variability being below 10% for regions exceeding 106 mm3 for LOGAN-DVR and 300 mm3 for SRTM2-DVR. SRTM2-DVR provided a better contrast between white matter and grey matter. The interhemispheric variability was also dependent on the size of the region analyzed, being below 10% for regions above 103 mm3 for SRTM2-R1 and above 110 mm3 for LOGAN-DVR. Whereas the 1 to 8-minute standardized uptake value ratio (SUVR1-8) showed an intermediary reproducibility for CBF assessment, SUVR0-2 for perfusion or SUVR50-70 for tissue binding showed poor reproducibility and correlated only mildly with SRTM2-R1 and LOGAN-DVR estimations respectively. CONCLUSIONS: [11C]PiB PET imaging can simultaneously quantify perfusion and myelin content in WM diseases associated with focal lesions. For longitudinal studies, SRTM2-R1 and DVR should be preferred over SUVR for the assessment of regional CBF and myelin content, respectively. TRIAL REGISTRATION: European Union Clinical Trials Register EUDRACT; EudraCT Number: 2008-004174-40; Date: 2009-03-06; https//www.clinicaltrialsregister.eu ; number 2008-004174-40.

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models.

Purpose: We evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [18F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM). Methods: We applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden-level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates. Results: The VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability. Conclusion: The results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [18F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test-retest variability. Clinical trial registration: NCT02640092 and NCT03289143.

Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer's disease? A 2-year longitudinal study.

BACKGROUND: Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer's disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline. METHODS: Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline. RESULTS: We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression. CONCLUSIONS: Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially "more aggressive" clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Comparison of Group-Level and Individualized Brain Regions for Measuring Change in Longitudinal Tau Positron Emission Tomography in Alzheimer Disease.

Importance: Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-level) is used for each participant. Objective: To compare group- and participant-level ROIs in participants at different stages of the AD clinical continuum in terms of annual percentage change in tau-PET standardized uptake value ratio (SUVR) and sample size requirements. Design, Setting, and Participants: This was a longitudinal cohort study with consecutive participant enrollment between September 18, 2017, and November 15, 2021. Included in the analysis were participants with mild cognitive impairment and AD dementia from the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID 05e, Expedition-3, Alzheimer's Disease Neuroimaging Initiative [ADNI], and BioFINDER-1 study cohorts) was also included. Exposures: Tau PET (BioFINDER-2, [18F]RO948; validation sample, [18F]flortaucipir), 7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs. Main Outcomes and Measures: Annual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated. Results: A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%]) from the BioFINDER-2 study were included in this analysis: 97 amyloid-ß (Aß)-positive cognitively unimpaired (CU) individuals, 77 with Aß-positive mild cognitive impairment (MCI), and 41 with AD dementia. In the validation sample were 137 Aß-positive CU participants, 144 with Aß-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years. Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in Aß-positive CU individuals was seen in a composite ROI combining the entorhinal cortex, hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aß-positive MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI, 4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual percentage change were found using several of the participant-specific ROIs. Importantly, the simplest participant-specific approach, where change in tau PET was calculated in an ROI that best matched the participant's data-driven disease stage, performed best in all 3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared with the best-performing group-level ROIs. Findings were replicated using [18F]flortaucipir. Conclusions and Relevance: Finding suggest that certain individualized ROIs carry an advantage over group-level ROIs for assessing longitudinal tau changes and increase the power to detect treatment effects in AD clinical trials using longitudinal tau PET as an outcome.

Positron emission tomography in multiple sclerosis - straight to the target.

Following the impressive progress in the treatment of relapsing-remitting multiple sclerosis (MS), the major challenge ahead is the development of treatments to prevent or delay the irreversible accumulation of clinical disability in progressive forms of the disease. The substrate of clinical progression is neuro-axonal degeneration, and a deep understanding of the mechanisms that underlie this process is a precondition for the development of therapies for progressive MS. PET imaging involves the use of radiolabelled compounds that bind to specific cellular and metabolic targets, thereby enabling direct in vivo measurement of several pathological processes. This approach can provide key insights into the clinical relevance of these processes and their chronological sequence during the disease course. In this Review, we focus on the contribution that PET is making to our understanding of extraneuronal and intraneuronal mechanisms that are involved in the pathogenesis of irreversible neuro-axonal damage in MS. We consider the major challenges with the use of PET in MS and the steps necessary to realize clinical benefits of the technique. In addition, we discuss the potential of emerging PET tracers and future applications of existing compounds to facilitate the identification of effective neuroprotective treatments for patients with MS.