Imaging of neuroinflammation in multiple sclerosis brain : a positron emission tomography and diffusion tensor imaging study

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, where the immune system attacks the protective myelin sheet surrounding the nerve cell axons, causing neuroinflammation and neurodegeneration. In this thesis, molecular and microstructural brain changes were evaluated in MS patients using diffusion tensor imaging (DTI) and positron emission tomography (PET) with translocator protein (TSPO) binding radioligand. In MS, TSPO is expressed mainly in activated microglia and therefore TSPO is considered as a marker of inflammation. The aim of this thesis was to evaluate the association between TSPO PET radioligand uptake and DTI macroparameters, as well as their association to clinical disability, in normal appearing white matter (NAWM). Moreover, the aim was to study if the individual physiological properties including age, body mass index (BMI) and sex have influence on the observed variability, which has been reported in previous clinical PET studies. The results showed that increased TSPO uptake in NAWM was associated with altered NAWM DTI macroparameters, their regional correspondence was consistent, and they both were associated with advanced clinical disability. Increased age was associated with higher TSPO uptake in NAWM and in thalamus of MS patients, whereas in healthy control subjects, higher age was associated with higher cortical TSPO uptake. However, a multicenter data analysis of healthy volunteers revealed that higher age was associated with higher cortical and subcortical TSPO uptake only in male subjects. Additionally, higher TSPO uptake was associated with lower BMI, and females showed higher TSPO uptake compared to males. The results demonstrate that PET and DTI can be used as complementary imaging modalities in clinical MS studies. TSPO levels may be associated with age, BMI and sex suggesting that they can be confounding factors in clinical designs. Subtle microglial activation may be initially related to normal ageing but is accentuated following neuroinflammation. ’ KEYWORDS: [11C](R)-PK11195, [11C]PBR28, ageing, body mass index, BMI, DTI, microglia, multiple sclerosis, PET, sex, TSPOTIIVISTELMÄ Multippeliskleroosi (MS-tauti) on keskushermoston autoimmuunisairaus, jossa immuunijärjestelmä hyökkää hermosoluja suojaavaa myeliiniä vastaan aiheuttaen tulehdusreaktiota ja hermosolujen rappeutumista. Tässä tutkimuksessa tarkasteltiin MS-tautiin liittyviä aivojen molekulaarisia ja rakenteellisia muutoksia käyttämällä diffuusiotensorikuvantamista (DTI) ja positroniemissiotomografiaa (PET) translokaattoriproteiiniin (TSPO) sitoutuvalla merkkiaineella. MS-taudissa TSPO esiintyy pääosin aktivoituneissa mikroglia-soluissa ja siksi sitä pidetään tulehdusreaktion markkerina. Tämän tutkimuksen tarkoituksena oli arvioida TSPO-sitoutumisen yhteyttä DTI-kuvantamisen makroparametreihin ja kummankin yhteyttä kliinisiin mittaustuloksiin. Koska aiemmissa kliinisissä tutkimuksissa on havaittu runsaasti yksilöllistä vaihtelua TSPO-sitoutumisessa, oli tavoitteena tarkastella yksilöllisten fysiologisten tekijöiden, kuten iän, painoindeksin ja sukupuolen yhteyttä TSPO-sitoutumiseen. Tulosten mukaan kohonnut TSPO-sitoutuminen terveessä valkeassa aineessa (NAWM) oli yhteydessä muuttuneisiin DTI-makroparametreihin, alueellinen vastaavuus oli yhtenevää ja kummankin menetelmän tulokset olivat yhteydessä kliinisiin mittaustuloksiin. Ikääntyminen oli yhteydessä kohonneeseen TSPO-sitou-tumiseen NAWM:ssa ja talamuksissa MS-potilailla, kun taas terveillä koehenkilöillä ikääntyminen oli yhteydessä korkeampaan kortikaaliseen TSPO-sitoutumiseen. Laajempi monikeskustutkimus osoitti kuitenkin, että ikääntyminen oli yhteydessä korkeampaan kortikaaliseen ja subkortikaaliseen TSPO-sitoutumiseen vain miehillä. Lisäksi korkeampi TSPO-sitoutuminen oli yhteydessä matalampaan painoindeksiin ja naisilla TSPO-sitoutuminen oli korkeampaa miehiin verrattuna. Tulokset osoittavat, että PET- ja DTI-kuvantaminen ovat toisiaan täydentäviä menetelmiä MS-taudin kuvantamisessa. Ikä, painoindeksi ja sukupuoli voivat olla sekoittavia tekijöitä kliinisissä TSPO-tutkimuksissa. TSPO-sitoutuminen liittyy normaaliin ikääntymiseen, mutta se korostuu tulehdusreaktion yhteydessä. AVAINSANAT: [11C](R)-PK11195, [11C]PBR28, DTI, ikääntyminen, mikroglia, MS-tauti, PET, painoindeksi, sukupuoli, TSP

Association of neuroinflammation with episodic memory : a [C-11]PBR28 PET study in cognitively discordant twin pairs

Alzheimer's disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer's disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer's disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72-77 years) underwent [C-11]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([C-11]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014-17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer's disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had similar to 20% higher cortical [C-11]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05-0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer (11)[C-11]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer's disease process.Peer reviewe

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using TSPO-PET

Abstract Chronic active lesions are promotors of neurodegeneration and disease progression in multiple sclerosis. They harbour a dense rim of activated innate immune cells at the lesion edge, which promote lesion growth and thereby induce damage. Conventional MRI is of limited help in identifying the chronic active lesions, so alternative imaging modalities are needed. Objectives were to develop a PET-based automated analysis method for phenotyping of chronic lesions based on lesion-associated innate immune cell activation and to comprehensively evaluate the prevalence of these lesions in the various clinical subtypes of multiple sclerosis, and their association with disability. In this work we use TSPO-PET-imaging for phenotyping chronic multiple sclerosis lesions at large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients [67 relapsing-remitting, 24 secondary progressive]. Innate immune cell activation at the lesion rim was measured using PET-imaging and the TSPO-binding radioligand 11C-PK11195. A T1-hypointense lesion was classified as rim-active if the distribution volume ratio of 11C-PK11195-binding was low in the plaque core and considerably higher at the plaque edge. If no significant ligand-binding was observed, the lesion was classified as inactive. Plaques that had considerable ligand-binding both in the core and at the rim were classified as overall-active. Conventional MRI and disability assessment using Expanded Disability Status Scale were performed at the time of PET-imaging. In the secondary progressive cohort, an average of 19% (median, interquartile range 11-26) of T1 lesions were rim-active in each individual patient, compared to 10% (interquartile range 0-20) among relapsing remitting patients (P = 0.009). Secondary progressive patients had a median of 3 (range 0-11) rim-active lesions, vs. 1 (range 0-18) among relapsing remitting patients (P = 0.029). Among those patients who had rim-active lesions (n = 63) the average number of active voxels at the rim was higher among secondary progressive compared to relapsing remitting patients (median 158 versus 74; P = 0.022). The number of active voxels at the rim correlated significantly with Expanded Disability Status Scale (R = 0.43, P <0.001), and the volume of the rim-active lesions similarly correlated with Expanded Disability Status Scale (R = 0.45, P < 0.001). Our study is the first to report in vivo phenotyping of chronic lesions at large scale, based on TSPO-PET. Patients with higher disability displayed a higher proportion of rim-active lesions. The in vivo lesion phenotyping methodology offers a new tool for individual assessment of smouldering (rim-active) lesion burden

Cannabinoid Receptor Type 1 in Parkinson's Disease : A Positron Emission Tomography Study with [F-18]FMPEP-d(2)

Background The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). Objective The aim of this study was to investigate CB1 receptors in PD with [F-18]FMPEP-d(2) positron emission tomography (PET) and the effect of dopaminergic medication on the [F-18]FMPEP-d(2) binding. Methods The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [F-18]FMPEP-d(2) high-resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [F-18]FMPEP-d(2) binding, 15 subjects with PD underwent [F-18]FMPEP-d(2) PET twice, both on and off antiparkinsonian medication. Results [F-18]FMPEP-d(2) distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region. Conclusions Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

Association of neuroinflammation with episodic memory: a [11C]PBR28 PET study in cognitively discordant twin pairs

Alzheimer’s disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer’s disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer’s disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72–77 years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014–17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer’s disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05–0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer’s disease process.</p

Magia: Robust Automated Image Processing and Kinetic Modeling Toolbox for PET Neuroinformatics

Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [C-11]carfentanil, [C-11]raclopride, [C-11]MADAM, and [C-11]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [C-11]carfentanil and [C-11]PiB there was no bias, while for [C-11]raclopride and [C-11]MADAM Magia produced 3-5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data

Cannabinoid Receptor Type 1 in Parkinson's Disease: A Positron Emission Tomography Study with [F-18]FMPEP-d(2)

Background: The endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD). Objective: The aim of this study was to investigate CB1 receptors in PD with [18F]FMPEP-d2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18F]FMPEP-d2 binding. Methods: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18F]FMPEP-d2 high-resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [18F]FMPEP-d2) binding, 15 subjects with PD underwent [18F]FMPEP-d2 PET twice, both on and off antiparkinsonian medication. Results: [18F]FMPEP-d2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P off than in HCs globally (P Conclusions: Subjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society</p

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.</p

Interindividual variability and lateralization of mu-opioid receptors in the human brain

Alterations in the brain's mu-opioid receptor (MOR) system have been associated with several neuropsychiatric disorders. Central MOR availability also varies considerably in healthy individuals. Multiple epidemiological factors have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled [C-11] carfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on [C-11]carfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work specialization in central emotion and pain processes