Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein.

OBJECTIVES: Neuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology. METHODS: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video-electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1-weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral - contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (VT /fP ) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age-matched volunteers (5 high-affinity and 6 medium affinity) who had metabolite-corrected arterial input functions measured. RESULTS: Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured. SIGNIFICANCE: Our study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability.

Thoughts of death and self-harm in patients with epilepsy or multiple sclerosis in a tertiary care center.

BACKGROUND: Patients with epilepsy or multiple sclerosis (MS) have high risks of depression and increased risks of suicide, but little is known about their risks of suicidal ideation. OBJECTIVE: We sought to (1) estimate the prevalence of thoughts of being better off dead or of self-harm among patients with epilepsy or MS, (2) identify risk factors for such thoughts, and (3) determine whether any risk factors interact with depression to predict such thoughts. METHODS: A Cleveland Clinic database provided information on 20,734 visits of 6586 outpatients with epilepsy or MS. Outcome measures were thoughts of death or self-harm (Patient Health Questionnaire [PHQ] item-9), and total score ≥10 for the 8 remaining PHQ items (probable major depression). Generalized estimating equations accounted for repeat visits in tests of associations of PHQ item-9 responses with depression, age, sex, race, household income, disease severity, and quality of life. RESULTS: Prevalence of thoughts of death or self-harm averaged 14.4% overall (epilepsy, 14.0% and MS, 14.7%). Factors associated with positive PHQ item-9 responses in epilepsy were depression and male sex, modified by poor quality of life. Factors associated with positive PHQ item-9 in MS were depression, male sex, medical comorbidity, and poor quality of life; the effect of depression was worse with greater MS severity and being unmarried. CONCLUSIONS: Among patients with common neurologic disorders (epilepsy or MS), 14%-15% reported thoughts of death or self-harm associated with illness severity, depression, quality of life, male sex, and being unmarried. Such patients require further evaluation of clinical outcomes and effects of treatment.

Recognizing, managing medical consequences of eating disorders in primary care.

Eating disorders can lead to serious health problems, and as in many other disorders, primary care physicians are on the front line. Problems that can arise from intentional malnutrition and from purging affect multiple organ systems. Treatment challenges include maximizing weight gain while avoiding the refeeding syndrome.

Downregulation of brain phosphodiesterase type IV measured with 11C-(R)-rolipram positron emission tomography in major depressive disorder.

BACKGROUND: Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of 11C-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme's activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects. METHODS: 11C-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age- and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. 11C-(R)-Rolipram binding in the brain was measured using arterial 11C-(R)-rolipram levels to correct for the influence of cerebral blood flow. RESULTS: Major depressive disorder subjects showed a widespread, approximately 20% reduction in 11C-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms. CONCLUSIONS: This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects.

Comparison of 18F- and 11C-labeled aryloxyanilide analogs to measure translocator protein in human brain using positron emission tomography.

PURPOSE: Translocator protein (TSPO) is a promising biomarker for neuroinflammation. We developed two new PET ligands, (18)F-PBR06 and (11)C-PBR28, to image TSPOs. Although our prior studies suggest that either of the two ligands could be used to quantify TSPOs in human brain, the studies were done in different sets of subjects. In this study, we directly compared (18)F-PBR06 and (11)C-PBR28 in eight human subjects to determine (1) whether either ligand provides more precise measurements of TSPOs and (2) whether the higher in vitro affinity of PBR06 compared to PBR28 led to higher in vivo binding of (18)F-PBR06 compared to (11)C-PBR28. METHODS: In vivo binding was calculated as total distribution volume (V(T)), using an unconstrained two-tissue compartment model. V(T) was corrected for plasma free fraction (f (P)) to measure ligand binding based on free ligand concentration in brain. RESULTS: Both ligands measured V(T) with similar precision, as evidenced by similarly good identifiability. However, V(T) for both radioligands increased with increasing lengths of data acquisition, consistent with the accumulation of radiometabolites in brain. Despite its higher lipophilicity and higher in vitro affinity, V(T)/f(P) of (18)F-PBR06 was similar to that of (11)C-PBR28. CONCLUSION: Both (18)F-PBR06 and (11)C-PBR28 are similar in terms of precision, sensitivity to accumulation of radiometabolites, and magnitude of in vivo binding. Thus, selection between the two radioligands will be primarily determined by the logistical impact of the different half-lives of the two radionuclides (110 vs 20 min).

Biodistribution and radiation dosimetry in humans of a new PET ligand, (18)F-PBR06, to image translocator protein (18 kDa).

UNLABELLED: As a PET biomarker for inflammation, translocator protein (18 kDa) (TSPO) can be measured with an (18)F-labeled aryloxyanilide, (18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ((18)F-PBR06), in the human brain. The objective of this study was to estimate the radiation absorbed doses of (18)F-PBR06 based on biodistribution data in humans. METHODS: After the injection of (18)F-PBR06, images were acquired from head to thigh in 7 healthy humans. Urine was collected at various time points. Radiation absorbed doses were estimated by the MIRD scheme. RESULTS: Moderate to high levels of radioactivity were observed in organs with high densities of TSPO and in organs of metabolism and excretion. Bone had low levels of radioactivity. The effective dose was 18.5 muSv/MBq. CONCLUSION: The effective dose of (18)F-PBR06, compared with other (18)F radioligands, was moderate. This radioligand had negligible defluorination, as indirectly assessed by bone radioactivity. Doses to the gallbladder wall and spleen may limit the amount of permissible injected radioactivity.