Aberrant type 2 dopamine receptor availability in violent offenders with psychopathy.

Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.

Midlife insulin resistance, APOE genotype, and change in late-life brain beta-amyloid accumulation - A 5-year follow-up [11C]PIB-PET study.

We studied if midlife insulin resistance (IR) and APOE genotype would predict brain beta-amyloid (Aß) accumulation and Aß change in late-life in 5-year follow-up [11C]PIB-PET study. 43 dementia-free participants were scanned twice with [11C]PIB-PET in their late-life (mean age at follow-up 75.4 years). Participants were recruited from the Finnish Health2000 study according to their HOMA-IR values measured in midlife (mean age at midlife 55.4 years; IR+ group, HOMA-IR > 2.17; IR- group, HOMA-IR <1.25), and their APOEε4 genotype. At late-life follow-up, [11C]PIB-PET composite SUVr was significantly higher in IR+ group than IR- group (median 2.3 (interquartile range 1.7-3.3) vs. 1.7 (1.5-2.4), p = 0.03). There was no difference between IR- and IR+ groups in [11C]PIB-PET SUVr 5-year change, but the change was significantly higher in IR+/APOEε4+ group (median change 0.8 (0.60-1.0)) than in IR-/APOEε4- (0.28 (0.14-0.47), p = 0.02) and in IR+/APOEε4- group (0.24 (0.06-0.40), p = 0.046). These results suggest that APOEε4 carriers with midlife IR are at increased risk for late-life Aß accumulation.

Seasonal variation in D2/3 dopamine receptor availability in the human brain.

PURPOSE: Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. METHODS: Based on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex. RESULTS: Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability. CONCLUSIONS: Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.

Impaired Gait, Postural Instability, and Rigidity in Relation to CB1 Receptor Availability in Parkinson's Disease.

BACKGROUND: In Parkinson's disease (PD), postural instability and gait disorder (PIGD) symptoms are associated with a worse prognosis for an unknown reason. OBJECTIVE: The objective was to explore the relationship between cannabinoid receptor type 1 (CB1R) availability and motor symptoms in PD with [18F]FMPEP-d2 positron emission tomography (PET). METHODS: Fifteen individuals with PD underwent [18F]FMPEP-d2 PET to measure cerebral CB1R availability. The Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) was used to evaluate the motor symptoms. RESULTS: A negative correlation was observed between [18F]FMPEP-d2 VT and PIGD score (P = 0.002) as well as rigidity subscore (P < 0.001). Both clusters covered widespread areas of both hemispheres. In contrast, tremor or bradykinesia did not correlate to [18F]FMPEP-d2 VT. CONCLUSIONS: Gait, postural instability, and rigidity in PD are associated with decreased CB1R availability, unlike tremor or bradykinesia, suggesting that the endocannabinoid system has a role in the pathophysiology of different motor symptoms in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes.

INTRODUCTION: We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aß) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers. METHODS: Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n = 14; APOE ε3/ε4 n = 16; APOE ε3/ε3 n = 16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aß, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. RESULTS: Hippocampal synaptic density was different among the APOE groups (PANOVA = 0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p = 0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho = -0.052, p = 0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho = 0.17, p = 0.28), or [11C]PiB uptake (rho = -0.10, p = 0.50). DISCUSSION: Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals. HIGHLIGHTS: Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

Cannabinoid Receptor Type 1 in Parkinson's Disease: A Positron Emission Tomography Study with [18 F]FMPEP-d2.

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 [18 F]FMPEP-d2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18 F]FMPEP-d2 binding. METHODS: The data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18 F]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 [18 F]FMPEP-d2 binding, 15 subjects with PD underwent [18 F]FMPEP-d2 PET twice, both on and off antiparkinsonian medication. RESULTS: [18 F]FMPEP-d2 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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

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

Alterations in the brain's µ-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 [11C]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 [11C]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.

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.

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort.

PURPOSE: Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. METHODS: Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson's disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability. We also analyzed the interregional correlation in D2R availability within each group. RESULTS: Subjects with PD showed the clearest decline in D2R availability. Overall, the groups showed high interregional correlation in D2R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. CONCLUSION: We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.

Insulin-stimulated brain glucose uptake correlates with brain metabolites in severe obesity: A combined neuroimaging study.

The human brain undergoes metabolic adaptations in obesity, but the underlying mechanisms have remained largely unknown. We compared concentrations of often reported brain metabolites measured with magnetic resonance spectroscopy (1H-MRS, 3 T MRI) in the occipital lobe in subjects with obesity and lean controls under different metabolic conditions (fasting, insulin clamp, following weight loss). Brain glucose uptake (BGU) quantified with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)) was also performed in a subset of subjects during clamp. In dataset A, 48 participants were studied during fasting with brain 1H-MRS, while in dataset B 21 participants underwent paired brain 1H-MRS acquisitions under fasting and clamp conditions. In dataset C 16 subjects underwent brain 18F-FDG-PET and 1H-MRS during clamp. In the fasting state, total N-acetylaspartate was lower in subjects with obesity, while brain myo-inositol increased in response to hyperinsulinemia similarly in both lean participants and subjects with obesity. During clamp, BGU correlated positively with brain glutamine/glutamate, total choline, and total creatine levels. Following weight loss, brain creatine levels were increased, whereas increases in other metabolites remained not significant. To conclude, insulin signaling and glucose metabolism are significantly coupled with several of the changes in brain metabolites that occur in obesity.

SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.

OBJECTIVE: The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET). RESEARCH DESIGN AND METHODS: In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups. RESULTS: A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] µmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] µmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions. CONCLUSIONS: Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.

Insulin resistance and body mass index are associated with TSPO PET in cognitively unimpaired elderly.

Metabolic risk factors are associated with peripheral low-grade inflammation and an increased risk for dementia. We evaluated if metabolic risk factors i.e. insulin resistance, body mass index (BMI), serum cholesterol values, or high sensitivity C-reactive protein associate with central inflammation or beta-amyloid (Aß) accumulation in the brain, and if these associations are modulated by APOE4 gene dose. Altogether 60 cognitively unimpaired individuals (mean age 67.7 years (SD 4.7); 63% women; 21 APOE3/3, 20 APOE3/4 and 19 APOE4/4) underwent positron emission tomography with [11C]PK11195 targeting TSPO (18 kDa translocator protein) and [11C]PIB targeting fibrillar Aß. [11C]PK11195 distribution value ratios and [11C]PIB standardized uptake values were calculated in a cortical composite region of interest typical for Aß accumulation in Alzheimer's disease. Associations between metabolic risk factors, [11C]PK11195, and [11C]PIB uptake were evaluated with linear models adjusted for age and sex. Higher logarithmic HOMA-IR (standardized beta 0.40, p = 0.002) and BMI (standardized beta 0.27, p = 0.048) were associated with higher TSPO availability. Voxel-wise analyses indicated that this association was mainly seen in the parietal cortex. Higher logarithmic HOMA-IR was associated with higher [11C]PIB (standardized beta 0.44, p = 0.02), but only in APOE4/4 homozygotes. BMI and HOMA-IR seem to influence TSPO availability in the brain.

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.

Endogenous Opioid Release After Orgasm in Man: A Combined PET/Functional MRI Study.

The endogenous µ-opioid receptor (MOR) system plays a key role in the mammalian reward circuit. Human and animal experiments suggest the involvement of MORs in human sexual pleasure, yet this hypothesis currently lacks in vivo support. Methods: We used PET with the radioligand [11C]carfentanil, which has high affinity for MORs, to quantify endogenous opioid release after orgasm in man. Participants were scanned once immediately after orgasm and once in a baseline state. Hemodynamic activity was measured with functional MRI during penile stimulation. Results: The PET data revealed significant opioid release in the hippocampus. Hemodynamic activity in the somatosensory and motor cortices and in the hippocampus and thalamus increased during penile stimulation, and thalamic activation was linearly dependent on self-reported sexual arousal. Conclusion: Our data show that endogenous opioidergic activation in the medial temporal lobe is centrally involved in sexual arousal, and this circuit may be implicated in orgasmic disorders.

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.

APOE ε4 gene dose effect on imaging and blood biomarkers of neuroinflammation and beta-amyloid in cognitively unimpaired elderly.

BACKGROUND: Neuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer's disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aß) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD. METHODS: Sixty 60-75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent 11C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), 11C-PiB PET (targeting Aß), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). 11C-PK11195 distribution volume ratios and 11C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aß accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aß1-42/1.40. RESULTS: In our cognitively unimpaired sample, cortical 11C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38-1.66) in non-carriers, 1.55 (1.43-2.02) in heterozygotes, and 2.13 (1.61-2.83) in homozygotes, P = 0.002). In contrast, cortical composite 11C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aß-positive and Aß-negative individuals (P = 0.81) and associated with higher Aß burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical 11C-PiB (Rho = 0.35, P = 0.040), but not 11C-PK11195-binding (Rho = 0.13, P = 0.47) in Aß-positive individuals. In the total cognitively unimpaired population, both higher composite 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated 11C-PiB-binding was associated with lower APCC scores. CONCLUSIONS: Only Aß burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aß.

Quantitative Perfusion Imaging with Total-Body PET.

Recently, PET systems with a long axial field of view have become the current state of the art. Total-body PET scanners enable unique possibilities for scientific research and clinical diagnostics, but this new technology also raises numerous challenges. A key advantage of total-body imaging is that having all the organs in the field of view allows studying biologic interaction of all organs simultaneously. One of the new, promising imaging techniques is total-body quantitative perfusion imaging. Currently, 15O-labeled water provides a feasible option for quantitation of tissue perfusion at the total-body level. This review summarizes the status of the methodology and the analysis and provides examples of preliminary findings on applications of quantitative parametric perfusion images for research and clinical work. We also describe the opportunities and challenges arising from moving from single-organ studies to modeling of a multisystem approach with total-body PET, and we discuss future directions for total-body imaging.

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using 18 kDa translocator protein-PET.

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 promotes lesion growth and thereby induces 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 18 kDa translocator protein-PET imaging for phenotyping chronic multiple sclerosis lesions at a large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients (67 relapsing-remitting patients and 24 secondary progressive patients). Innate immune cell activation at the lesion rim was measured using PET imaging and the 18 kDa translocator protein-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 the 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, versus 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 the Expanded Disability Status Scale (R = 0.43, P < 0.001), and the volume of the rim-active lesions similarly correlated with the 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 18 kDa translocator protein-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.