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Mapping human brain fatty acid amide hydrolase activity with PET.

ABSTRACT: Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [(11)C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [(11)C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90?minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant K(i) and the composite parameter ?k(3) (?=K(1)/k(2)) <5%, and COV(k(3))<10%). Reducing scan time to 60?minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with K(i), but not with k(3) or ?k(3). Our data suggest that ?k(3) is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [(11)C]CURB. Simulations showed that [(11)C]CURB binding in healthy subjects is far from a flow-limited uptake.

SUBMITTER: Rusjan PM

PROVIDER: S-EPMC3587811 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Mapping human brain fatty acid amide hydrolase activity with PET.

Rusjan Pablo M PM Wilson Alan A AA Mizrahi Romina R Boileau Isabelle I Chavez Sofia E SE Lobaugh Nancy J NJ Kish Stephen J SJ Houle Sylvain S Tong Junchao J

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20121205 3

Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [(11)C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [(11)C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood samplin ...[more]

PMID: 23211960

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Project description:BackgroundThe brain's endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms.MethodsTwenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [11C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function.ResultsFAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F1,62.85 = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69 = 12.42, p = .002; Cohen's f = 0.42, large effect). Shorter duration of illness (F1,26.95 = 13.78, p = .001; Cohen's f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95 = 6.03, p = .021, Cohen's f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62 = 175.85, p < 1 × 10-56; Cohen's f > 1). Overall, FAAH was higher in female subjects than in male subjects (F1,62.84 = 10.05, p = .002; Cohen's f = 0.37).ConclusionsThis first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.

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Mapping human brain fatty acid amide hydrolase activity with PET.

Publications

Mapping human brain fatty acid amide hydrolase activity with PET.

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