IMAGING ARACHIDONIC ACID SIGNALING IN THE HUMAN BRAIN DURING VISUAL STIMULATION. ? We developed a positron emission tomography (PET) method in human subjects to image regional brain signaling involving arachidonic acid (AA, 20:4n-6), under a two-stimulus paradigm in the same session (rest and activation), to examine effects of sensory or pharmacological stimulation. We imaged AA signals in 16 healthy volunteers subjected to visual stimulation at flash frequencies of 2.9 or 7.8 Hz, compared with a dark (0 Hz) condition. Regional cerebral blood flow (rCBF) was measured with intravenous 15Owater under comparable conditions, and data were correcting for partial volume errors. We demonstrated frequency-dependent increases in AA incorporation coefficients in primary and association brain visual areas, which corresponded in part to changes in rCBF (although K* is not influenced by changes in rCBF). The increments in AA incorporation likely represented effects of glutamate release on the AA cascade (1). Based on these positive results with the two-stimulus paradigm, we have initiated a drug-activation protocol involving dopamine in patients with attention deficit hyperactivity disorder (ADHD).? ? IMAGING REGIONAL DOCOSAHEXAENOIC ACID CONSUMPTION BY HUMAN BRAIN. ? Docosahexaenoic acid (DHA, 22:6n-3) is a critical constituent of brain cell membranes and participates in multiple metabolic processes, but its rate of metabolic consumption by the human brain is not known. Furthermore, considerable controversy exists about dietary DHA requirements to maintain normal brain function, and about the livers ability to elongate shorter chain n-3 PUFAs precursors to DHA. To begin to address these issues, we conducted a PET protocol to quantify regional and global rates of brain DHA consumption in 14 healthy volunteers. Subjects were injected intravenously with 1-11CDHA, and dynamic PET scans of regional brain radioactivity were acquired. Arterial plasma was obtained to measure plasma 1-11CDHA and unesterified unlabeled DHA concentrations. Regional cerebral blood flow (CBF) was quantified using 15Owater and PET. Each subjects PET images were co-registered with his corresponding anatomical magnetic resonance images and data were corrected for partial volume errors. For the entire brain, the rate of DHA incorporation from plasma equaled 3.8 mg/day, which, according to our model, represents the rate of brain DHA metabolic loss. This rate is 2% of the daily dietary consumption rate of long-chain n-3 PUFAs in the United States. We now hope to measure regional and global brain DHA consumption rates in chronic alcoholic patients and in other subjects with deficient liver function, and in relation to dietary n-3 PUFA content.? ? IMAGING NEUROINFLAMMATION IN PATIENTS WITH ALZHEIMER DISEASE. ? Neuroinflammation is thought to contribute to cognitive decline in Alzheimer disease, and we demonstrated that arachidonic acid (AA) incorporation from plasma was increased in an animal model of neuroinflammation. We used PET and intravenously injected 1-11CAA to image AA incorporation into brain in 8 mildly-severely demented Alzheimer disease patients and 9 healthy aged-matched volunteers. We also measured rCBF with intravenous 15Owater. We are finding that AA incorporation was increased significantly in wide areas of the Alzheimer compared with control brain, whereas rCBF was reduced. Thus, we may have a novel in vivo marker of human neuroinflammation that can be used to examine Alzheimer disease progression and response to medication. An abstract of this work has been published (Rapoport et al. Neuropsychopharmacology 30 (Suppl 1) S225-S226, 2005). ? ? PATTERNS OF GRAY MATTER ATROPHY WITH HEALTHY HUMAN AGING. ? Healthy aging has been associated with atrophy. We used a network model of regional covariance with magnetic resonance imaging voxel-based morphometry, to identify the regional distribution of gray matter atrophy associated with aging in healthy adults 22-77 years old. Older age was associated with less gray matter in bilateral frontal, temporal, thalamic, and right cerebellar regions. Gender differences suggested more advanced brain aging in the men. Thus, healthy aging is associated with a pattern of gray matter atrophy most prominently involving the frontal and temporal cortices (2).
Showing the most recent 10 out of 24 publications
