Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Differences in brain changes between adults with childhood-onset epilepsy and controls: A prospective population-based study.

PURPOSE: To determine the impact of childhood-onset uncomplicated epilepsy (COE) on brain aging over 50-year prospective follow-up. METHODS: A population-based cohort of 41 aging subjects with COE and their 46 matched controls participated in a detailed in-person prospective assessment in 2012 and 2017 to characterize ongoing changes in the aging brain. RESULTS: The mean age of the COE participants was 63.2 years (SD 4.14, median 63.2, range 55.8-70.6) and 63.0 years (mean, SD 4.13, median 63.3, range 56.0-69.9) years for controls. Neurologic signs were significantly more common in COE participants not in remission (p = .015), and the most frequent abnormalities were cerebellar signs (p < .001). Neurologic signs in general (p = .008) and cerebellar signs in particular (p = .018) were significantly more common in focal than in generalized epilepsies. MRI white matter abnormalities were significantly associated with absence of vocational education (p = .011), and MRI hippocampal atrophy in COE subjects was associated with arterial hypertension versus normal blood pressure (p = .017). In the combined study cohort of COE subjects and controls, presenting neurologic signs increased both in the subjects and in the controls from the 2012 to 2017 study. CONCLUSIONS: At ultra-long-term follow-up, clinical and neuroimaging findings show tendencies to brain aging that is more accelerated in COE participants with active adult childhood-onset epilepsy, and particularly in focal epilepsy.

Whole Brain Adiabatic T1rho and Relaxation Along a Fictitious Field Imaging in Healthy Volunteers and Patients With Multiple Sclerosis: Initial Findings.

BACKGROUND: In preclinical models of multiple sclerosis (MS), both adiabatic T1rho (T1ρadiab ) and relaxation along a fictitious field (RAFF) imaging have demonstrated potential to noninvasively characterize MS. PURPOSE: To evaluate the feasibility of whole brain T1ρadiab and RAFF imaging in healthy volunteers and patients with MS. STUDY TYPE: Single institutional clinical trial. SUBJECTS: 38 healthy volunteers (24-69 years) and 21 patients (26-59 years) with MS. Five healthy volunteers underwent a second MR examination performed within 8 days. Clinical disease severity (The Expanded Disability Status Scale [EDSS] and The Multiple Sclerosis Severity Score [MSSS]) was evaluated at baseline and 1-year follow-up (FU). FIELD STRENGTH/SEQUENCE: RAFF in second rotating frame of reference (RAFF2) was performed at 3 T using 3D-fast-field echo with magnetization preparation, RF amplitude of 11.74 µT while the corresponding value for T1ρadiab was 13.50 µT. T1 -, T2 -, and FLAIR-weighted images were acquired with reconstruction voxel size 1.0 × 1.0 × 1.0 mm3 . ASSESSMENT: The parametric maps of T1ρadiab and RAFF2 (TRAFF2 ) were calculated using a monoexponential model. Semi-automatic segmentation of MS lesions, white matter (WM), and gray matter (GM), and WM tracks was performed using T1 -, T2 -, and FLAIR-weighted images. STATISTICAL TESTS: Regression analysis was used to evaluate correlation of T1ρadiab and TRAFF2 with age and disease severity while a Friedman test followed by Wilcoxon Signed Rank test for differences between tissue types. Short-term repeatability was evaluated on voxel level. RESULTS: Both T1ρadiab and TRAFF2 demonstrated good short-term repeatability with relative differences on voxel level in the range of 6.1%-11.9%. Differences in T1ρadiab and TRAFF2 between the tissue types in MS patients were significant (P < 0.05). T1ρadiab and TRAFF2 correlated (P < 0.001) with baseline EDSS/MSSM and disease progression at FU (P < 0.001). DATA CONCLUSION: Whole brain T1ρadiab and TRAFF2 at 3 T was feasible with significant differences in T1ρadiab and TRAFF2 values between tissues types and correlation with disease severity. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis.

Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.

Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity.

BACKGROUND: Cerebrospinal fluid (CSF) levels of two soluble biomarkers, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), have been shown to associate with multiple sclerosis (MS) disease progression. Now, both biomarkers can be detected reliably in serum, and importantly, their serum levels correlate well with their CSF levels. OBJECTIVE: To evaluate the usability of serum GFAP measurement as a biomarker of progressive disease and disease severity in MS. METHODS: Clinical course, Expanded Disability Status Scale (EDSS), disease duration, patient age and magnetic resonance imaging (MRI) parameters were reviewed in 79 MS patients in this cross-sectional hospital-based study. Serum samples were collected for measurement of GFAP and NfL concentrations using single molecule array (Simoa) assay. A cohort of healthy controls was evaluated for comparison. RESULTS: Higher serum concentrations of both GFAP and NfL were associated with higher EDSS, older age, longer disease duration, progressive disease course and MRI pathology. CONCLUSION: Earlier studies have demonstrated that GFAP, unlike NfL, is not increased in association with acute focal inflammation-related nervous system damage. Our work suggests that GFAP serum level associates with disease progression in MS and could potentially serve as an easily measurable biomarker of central nervous system (CNS) pathology related to disease progression in MS.

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study.

PURPOSE: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. METHODS: [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. RESULTS: There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. CONCLUSION: These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

Positron emission tomography imaging in evaluation of MS pathology in vivo.

Positron emission tomography (PET) gives an opportunity to quantitate the expression of specific molecular targets in vivo and longitudinally in brain and thus enhances our possibilities to understand and follow up multiple sclerosis (MS)-related pathology. For successful PET imaging, one needs a relevant target molecule within the brain, to which a blood-brain barrier-penetrating specific radioligand will bind. 18-kDa translocator protein (TSPO)-binding radioligands have been used to detect activated microglial cells at different stages of MS, and remyelination has been measured using amyloid PET. Several PET ligands for the detection of other inflammatory targets, besides TSPO, have been developed but not yet been used for imaging MS patients. Finally, synaptic density evaluation has been successfully tested in human subjects and gives opportunities for the evaluation of the development of cortical and deep gray matter pathology in MS. This review will discuss PET imaging modalities relevant for MS today.

Imaging of microglial activation in MS using PET: Research use and potential future clinical application.

Multiple sclerosis (MS) is a complex disease, where several processes can be selected as a target for positron emission topography (PET) imaging. Unlike magnetic resonance imaging (MRI), PET provides specific and quantitative information, and unlike neuropathology, it can be non-invasively applied to living patients, which enables longitudinal follow-up of the MS pathology. In the study of MS, PET can be useful for in vivo evaluation of specific pathological characteristics at various stages of the disease. Increased understanding of the progressive MS pathology will enhance the treatment options of this undertreated condition. The ultimate goal of developing and expanding PET in the study of MS is to have clinical non-invasive in vivo imaging biomarkers of neuroinflammation that will help to establish prognosis and accurately measure response to therapeutics. This topical review provides an overview of the promises and challenges of the use of PET in MS.

Glial Activity Load on PET Reveals Persistent "Smoldering" Inflammation in MS Despite Disease-Modifying Treatment: 18 F-PBR06 Study.

PURPOSE OF THE REPORT: 18 F-PBR06-PET targeting 18-kDa translocator protein can detect abnormal microglial activation (MA) in multiple sclerosis (MS). The objectives of this study are to develop individualized mapping of MA using 18 F-PBR06, to determine the effect of disease-modifying treatment (DMT) efficacy on reducing MA, and to determine its clinical, radiological, and serological correlates in MS patients. PATIENTS AND METHODS: Thirty 18 F-PBR06-PET scans were performed in 22 MS patients (mean age, 46 ± 13 years; 16 females) and 8 healthy controls (HCs). Logarithmically transformed "glial activity load on PET" scores (calculated as the sum of voxel-by-voxel z -scores ≥4), "lnGALP," were compared between MS and HC and between MS subjects on high-efficacy DMTs (H-DMT, n = 13) and those on no or lower-efficacy treatment, and correlated with clinical measures, serum biomarkers, and cortical thickness. RESULTS: Cortical gray matter (CoGM) and white matter (WM) lnGALP scores were higher in MS versus HC (+33% and +48%, P < 0.001). In H-DMT group, CoGM and WM lnGALP scores were significantly lower than lower-efficacy treatment ( P < 0.01) but remained abnormally higher than in HC group ( P = 0.006). Within H-DMT patients, CoGM lnGALP scores correlated positively with physical disability, fatigue and serum glial fibrillary acid protein levels ( r = 0.65-0.79, all P 's < 0.05), and inversely with cortical thickness ( r = -0.66, P < 0.05). CONCLUSIONS: High-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such "residual" MA in CoGM is associated with clinical disability, serum biomarkers, and cortical degeneration. Individualized mapping of translocator protein PET using 18 F-PBR06 is clinically feasible and can potentially serve as an imaging biomarker for evaluating "smoldering" inflammation in MS patients.

Adenosine A2A receptor availability in cerebral gray and white matter of patients with Parkinson's disease.

OBJECTIVE: Atrophic changes in cerebral gray matter of patients with PD have been reported extensively. There is evidence suggesting an association between cortical gyrification changes and white matter abnormalities. Adenosine A2A receptors have been shown to be upregulated in cerebral white matter and on reactive astrocytes in preclinical models of neurodegenerative diseases. We, therefore, sought to investigate in vivo changes in A2A receptor availability in cerebral gray and white matter of PD patients and its association with gray matter atrophy. METHODS: Eighteen patients with PD without dyskinesia and seven healthy controls were enrolled for this study. Brain MRI and dynamic PET scan was acquired with [11C]TMSX radioligand which binds selectively to A2A receptors. FreeSurfer software was used to segment cerebral gray and white matter structures. The resulting masks were used to calculate region specific volumes and to derive distribution volume ratios (DVRs), after co-registration with PET images, for the quantification of specific [11C]TMSX binding. RESULTS: We showed an increase in A2A receptor availability in frontal (P < 0.001) and parietal (P < 0.001) white matter and a decrease in occipital (P = 0.02) gray matter of PD patients as compared to healthy controls. A decrease in gray matter volume ratios was observed in frontal (P < 0.01), parietal (P < 0.001), temporal (P < 0.01) and occipital (P < 0.01) ROIs in patients with PD versus healthy controls. CONCLUSIONS: Our results suggest a role of A2A receptor-based signaling in the neurodegenerative changes seen in the cerebral gray and white matter of patients with PD.

Assessment of Microglial Activation in Alzheimer Disease Using 18 F-PBR06 PET.

ABSTRACT: A 69-year-old woman with progressive short-term memory deficits was diagnosed with Alzheimer disease (MMSE 26/30, CDR 0.5) and underwent PET using 18 F-PBR06, a second-generation 18-kDa translocator protein ligand, targeting brain microglia and astrocytes. SUV and voxel-by-voxel binding potential maps (using simplified reference tissue method and a cerebellar pseudo-reference region) were generated. Images showed evidence of increased glial activation in biparietal cortices (including bilateral precuneus and posterior cingulate gyri) and bilateral frontal cortices. After 6 years of clinical follow-up, patient progressed to moderate cognitive impairment (CDR 2.0) and required assistance for activities of daily living.

Adenosine A2A receptor availability in patients with early- and moderate-stage Parkinson's disease.

INTRODUCTION: Adenosine 2A (A2A) receptors co-localize with dopamine D2 receptors in striatopallidal medium spiny neurons of the indirect pathway. A2A receptor activation in the striatum or pallidum decreases D2 signaling. In contrast, A2A receptor antagonism may help potentiate it. Furthermore, previous PET studies have shown increased A2A receptor availability in striatum of late-stage PD patients with dyskinesia. However, human in vivo evidence for striatal A2A receptor availability in early-stage PD is limited. This study aimed to investigate possible differences in A2A receptor availability in the striatum and pallidum of early- and moderate-stage PD patients without dyskinesias. METHODS: Brain MRI and PET with [11C]TMSX radioligand, targeting A2A receptors, was performed in 9 patients with early- and 9 with moderate-stage PD without dyskinesia and in 6 healthy controls. Distribution volume ratios (DVR) were calculated to assess specific [11C]TMSX binding in caudate, putamen and pallidum. RESULTS: A2A receptor availability (DVR) was decreased in the bilateral caudate of early-stage PD patients when compared with healthy controls (P = 0.02). Conversely, DVR was increased bilaterally in the pallidum of moderate-stage PD patients compared to healthy controls (P = 0.03). Increased mean striatal DVR correlated with higher motor symptom severity ([Formula: see text] = 0.47, P = 0.02). CONCLUSION: Our results imply regional and disease stage-dependent changes in A2A receptor signaling in PD pathophysiology and in response to dopaminergic medication.

Innate Immune Cell-Related Pathology in the Thalamus Signals a Risk for Disability Progression in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Our aim was to investigate whether 18-kDa translocator protein (TSPO) radioligand binding in gray matter (GM) predicts later disability progression in multiple sclerosis (MS). METHODS: In this prospective imaging study, innate immune cells were investigated in the MS patient brain using PET imaging. The distribution volume ratio (DVR) of the TSPO-binding radioligand [11C]PK11195 was determined in 5 GM regions: thalamus, caudate, putamen, pallidum, and cortical GM. Volumetric brain MRI parameters were obtained for comparison. The Expanded Disability Status Scale (EDSS) score was assessed at baseline and after follow-up of 3.0 ± 0.3 (mean ± SD) years. Disability progression was defined as an EDSS score increase of 1.0 point or 0.5 point if the baseline EDSS score was ≥6.0. A forward-type stepwise logistic regression model was constructed to compare multiple imaging and clinical variables in their ability to predict later disability progression. RESULTS: The cohort consisted of 66 patients with MS and 18 healthy controls. Patients with later disability progression (n = 17) had more advanced atrophy in the thalamus, caudate, and putamen at baseline compared with patients with no subsequent worsening. TSPO binding was significantly higher in the thalamus among the patients with later worsening. The thalamic DVR was the only measured imaging variable that remained a significant predictor of disability progression in the regression model. The final model predicted disability progression with 52.9% sensitivity and 93.9% specificity with an area under the curve value of 0.82 (receiver operating characteristic curve). DISCUSSION: Increased TSPO radioligand binding in the thalamus has potential in predicting short-term disability progression in MS and seems to be more sensitive for this than GM atrophy measures.

Circulating neurofilament is linked with morbid obesity, renal function, and brain density.

Neurofilament light chain (NfL) is a novel biomarker reflecting neuroaxonal damage and associates with brain atrophy, and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation, associated with several neurodegenerative diseases. Since obesity is associated with increased risk for several neurodegenerative disorders, we hypothesized that circulating NfL and GFAP levels could reflect neuronal damage in obese patients. 28 morbidly obese and 18 lean subjects were studied with voxel based morphometry (VBM) MRI to assess gray and white matter densities. Serum NfL and GFAP levels were determined with single-molecule array. Obese subjects were re-studied 6 months after bariatric surgery. Morbidly obese subjects had lower absolute concentrations of circulating NfL and GFAP compared to lean individuals. Following bariatric surgery-induced weight loss, both these levels increased. Both at baseline and after weight loss, circulating NfL and GFAP values correlated inversely with eGFR. Cross-sectionally, circulating NfL levels correlated inversely with gray matter (GM) density, and this association remained significant also when accounting for age and total eGFR. GFAP values did not correlate with GM density. Our data suggest that when determining circulating NfL and GFAP levels, eGFR should also be measured since renal function can affect these measurements. Despite the potential confounding effect of renal function on NfL measurement, NfL correlated inversely with gray matter density in this group of subjects with no identified neurological disorders, suggesting that circulating NfL level may be a feasible biomarker of cerebral function even in apparently neurologically healthy subjects.

Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Fingolimod treatment reverses signs of diffuse white matter damage in multiple sclerosis: A pilot study.

BACKGROUND: In multiple sclerosis (MS) diffuse normal appearing white matter (NAWM) damage may drive chronic worsening independent of relapse activity. Diffusion tensor imaging (DTI) is a nonconventional MRI technique that can be used to assess microstructural alterations in myelin and axons. The aim of our study was to investigate the effect of six months fingolimod treatment on the integrity of entire and segmented NAWM in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Ten RRMS patients initiating fingolimod treatment were included in the study. Patients underwent 3 T MRI including diffusion tensor sequences at baseline before the initiation of treatment and at six months. The mean values for fractional anisotropy (FA), and mean, radial and axial diffusivities (MD, RD and AD) were calculated within the whole NAWM and in six segmented sub-regions of NAWM (frontal, parietal, temporal, occipital, cingulate and deep NAWM). Clinical characteristics, Expanded Disability Status Scale (EDSS) and volumetric MRI data were also evaluated. RESULTS: In the cingulate NAWM FA was increased and RD was decreased significantly at six months compared to baseline (0.462 vs. 0.472, P = 0.027 and 0.000646 vs. 0.000634, P = 0.041, respectively), indicating improvements in myelin and axonal integrity following fingolimod treatment, whereas there were no alterations in cingulate MD or AD. Cingulate and temporal FA and RD correlated with T2 lesion volume percentage of cingulate and temporal areas. EDSS change correlated with change of the whole NAWM AD. CONCLUSIONS: Increased FA and decreased RD in the cingulate NAWM might suggest microstructural fingolimod-induced improvements in the normal appearing cingulate white matter. Our results support the concept that DTI can be used as a marker of diffuse neuronal damage also in interventional settings.

Widespread Glial Activation in Primary Progressive Multiple Sclerosis Revealed by 18F-PBR06 PET: A Clinically Feasible, Individualized Approach.

ABSTRACT: A 64-year-old man with primary progressive multiple sclerosis (Expanded Disability Status Scale 3.5) underwent PET using 18F-PBR06, a second-generation 18-kDa translocator protein ligand targeting activated brain microglia and astrocytes. Voxel-by-voxel statistical comparison of patient's PET images (acquired 60-90 minutes postinjection) with a healthy control data set was performed to generate a 3-dimensional z-score map of increased radiotracer uptake, which showed widespread increased glial activation in normal-appearing cerebral white matter, white matter lesional and perilesional areas, brainstem and cerebellum. In contrast, patient's 3-T MRI scan showed only a few small white matter brain lesions without contrast enhancement.

Effect of dopaminergic medication on adenosine 2A receptor availability in patients with Parkinson's disease.

OBJECTIVE: To assess the necessity of withdrawing dopaminergic medication in Parkinson's disease (PD) patients for accurate estimation of adenosine 2A receptor (A2AR) availability using [11C]TMSX PET imaging. This was accomplished by studying the short-term effect of the cessation of dopaminergic medication on A2AR availability in non-dyskinetic patients with PD treated with dopaminergic medication. METHODS: Eight PD patients (age 67.9 ± 5.6 years; 6 men, 2 women) without dyskinesia were enrolled in this study. A2AR availability was measured using PET imaging with a [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) radioligand after a short term cessation of dopaminergic medication (12hrs for levodopa, 24hrs for dopamine agonists and MAO-B inhibitors). Repeated PET imaging was performed while the patients were back 'on' their regular dopaminergic medication (median 13 days after first imaging). Conventional MRI was acquired for anatomical reference. Specific binding of [11C]TMSX was quantified as distribution volume ratios (DVR) for caudate, pallidum and putamen using Logan graphical method with clustered gray matter reference region. RESULTS: No significant differences were observed for the DVRs in all three striatal regions between 'on' and 'off' medication states. Strong correlations were also observed between the two states. Statistical equivalence was found in pallidum (TOST equivalence test, p = 0.045) and putamen (TOST equivalence test, p = 0.022), but not in caudate DVR (TOST equivalence test, p = 0.201) between the two medication states. CONCLUSIONS: Our results show that dopaminergic medication has no significant short-term effect on the availability of A2A receptors in putamen and pallidum of patients with PD. However, relatively poor repeatability was demonstrated in the caudate.

High serum neurofilament associates with diffuse white matter damage in MS.

OBJECTIVE: To evaluate to which extent serum neurofilament light chain (NfL) increase is related to diffusion tensor imaging-MRI measurable diffuse normal-appearing white matter (NAWM) damage in MS. METHODS: Seventy-nine patients with MS and 10 healthy controls underwent MRI including diffusion tensor sequences and serum NfL determination by single molecule array (Simoa). Fractional anisotropy and mean, axial, and radial diffusivities were calculated within the whole and segmented (frontal, parietal, temporal, occipital, cingulate, and deep) NAWM. Spearman correlations and multiple regression models were used to assess the associations between diffusion tensor imaging, volumetric MRI data, and NfL. RESULTS: Elevated NfL correlated with decreased fractional anisotropy and increased mean, axial, and radial diffusivities in the entire and segmented NAWM (for entire NAWM ρ = -0.49, p = 0.005; ρ = 0.49, p = 0.005; ρ = 0.43, p = 0.018; and ρ = 0.48, p = 0.006, respectively). A multiple regression model examining the effect of diffusion tensor indices on NfL showed significant associations when adjusted for sex, age, disease type, the expanded disability status scale, treatment, and presence of relapses. In the same model, T2 lesion volume was similarly associated with NfL. CONCLUSIONS: Our findings suggest that elevated serum NfL in MS results from neuroaxonal damage both within the NAWM and focal T2 lesions. This pathologic heterogeneity ought to be taken into account when interpreting NfL findings at the individual patient level.