Biomedical subjects

Richard E Carson

Publications and source records attributed to Richard E Carson.

At least 19 recordsLinked to original sources

PubMed2006

Imaging signal transduction via arachidonic acid in the human brain during visual stimulation, by means of positron emission tomography.

BACKGROUND: Arachidonic acid (AA, 20:4n-6), an important second messenger, is released from membrane phospholipid following receptor mediated activation of phospholipase A(2) (PLA(2)). This signaling process can be imaged in brain as a regional brain AA incorporation coefficient K*. HYPOTHESIS: K* will be increased in brain visual areas of subjects submitted to visual stimulation. SUBJECTS AND METHODS: Regional values of K* were measured with positron emission tomography (PET), following the intravenous injection of [1-(11)C]AA, in 16 healthy volunteers subjected to visual stimulation at flash frequencies 2.9 Hz (8 subjects) or 7.8 Hz (8 subjects), compared with the dark (0 Hz) condition. Regional cerebral blood flow (rCBF) was measured with intravenous [(15)O]water under comparable conditions. RESULTS: During flash stimulation at 2.9 Hz or 7.8 Hz vs. 0 Hz, K* was increased significantly by 2.3-8.9% in Brodmann areas 17, 18 and 19, and in additional frontal, parietal and temporal cortical regions. rCBF was increased significantly by 3.1-22%, often in comparable regions. Increments at 7.8 Hz often exceeded those at 2.9 Hz for both K* and rCBF. Decrements in both parameters also were produced, particularly in frontal brain regions. CONCLUSIONS: AA plays a role in signaling processes provoked by visual stimulation, since visual stimulation at flash frequencies of 2.9 and 7.8 Hz compared to 0 Hz modifies both K* for AA and rCBF in visual and related areas of the human brain. The two-stimulus condition paradigm of this study might be used with PET to image effects of other functional activations and of drugs on brain signaling via AA.

Adult↗

PubMed2006

Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC.

Dopamine, the major neurotransmitter depleted in Parkinson disease, can be synthesized and regulated in vivo with a combination of intrastriatal AAV-hAADC gene therapy and administration of the dopamine precursor l-Dopa. When tested in MPTP-lesioned monkeys, this approach resulted in long-term improvement in clinical rating scores, significantly lowered l-Dopa requirements, and a reduction in l-Dopa-induced side effects. Positron emission tomography with [(18)F]FMT confirmed persistent AADC activity, demonstrating for the first time that infusion of AAV vector into primate brain results in at least 6 years of transgene expression. AAV-hAADC restores the ability of the striatum to convert l-Dopa into dopamine efficiently. Introduction of this therapy into the clinic holds promise for Parkinson patients experiencing the motor complications that result from escalating l-Dopa requirements against a background of disease progression.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder.

CONTEXT: A variety of indirect evidence has implicated the central muscarinic-cholinergic system, and more specifically the type 2 muscarinic (M2) receptor, in the pathogenesis of depressive symptoms arising in major depressive disorder and bipolar disorder. OBJECTIVE: To assess the binding potential of muscarinic2 receptors in vivo during depression in subjects with major depressive disorder or bipolar disorder. DESIGN: The M2 receptor binding was compared between unmedicated subjects with major depressive disorder or bipolar disorder during depression vs healthy controls, using positron emission tomography and [18F]FP-TZTP (fluorodopa F 18 [3-(3-[3-fluoroproply]thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine), a selective M2 receptor radioligand. SETTING: Outpatients at the National Institutes of Health. PARTICIPANTS: Unmedicated subjects with current depression meeting DSM-IV criteria for either major depressive disorder (n = 17) or bipolar disorder (n = 16) and 23 healthy control subjects. MAIN OUTCOME MEASURES: The primary outcome parameter was [(18)F]FP-TZTP distribution volume, which is proportional to the product of receptor density and affinity and, in the case of [(18)F]FP-TZTP, is known to be sensitive to endogenous acetylcholine concentrations. The relationship between illness severity, as rated using the Montgomery-Asberg Depression and Hamilton Anxiety Rating scales, and distribution volume also was assessed. RESULTS: The mean anterior cingulate cortex distribution volume differed across groups (F55 = 3.4; P = .04), and this difference was accounted for by significantly lower binding in bipolar disorder compared with both major depressive disorder and control groups. CONCLUSIONS: The mean M2 receptor binding in subjects with bipolar disorder was reduced relative to both healthy controls and subjects with major depressive disorder, to an extent that correlated with depressive symptoms. The reduction in the bipolar disorder group could be accounted for either by a reduction in M2 receptor density or affinity or an elevation in endogenous acetylcholine levels. To our knowledge, these data provide the first direct evidence that altered M2 receptor function contributes to mood dysregulation in bipolar disorder.

Acetylcholine↗

PubMed2006

Age and APOE-epsilon4 genotype influence the effect of physostigmine infusion on the in-vivo distribution volume of the muscarinic-2-receptor dependent tracer [18F]FP-TZTP.

The apolipoprotein E-epsilon4 allele (APOE-epsilon4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), in aging healthy subjects with an APOE-epsilon4 allele. To examine the effects of aging and the APOE-epsilon4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [18F]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon4 allele and 7 without an APOE-epsilon4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon4 allele modifying the response to physostigmine in the direction of larger decreases in [18F]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon4 genotype is likely to contribute to brain structure and function prior to aging.

Adult↗

PubMed2006

The effect of antiepileptic drugs on 5-HT-receptor binding measured by positron emission tomography.

PURPOSE: To study the effect of antiepileptic drugs (AEDs) on 5-HT(1A)-receptor binding in patients with temporal lobe epilepsy. 5-HT(1A)-receptor binding, measured by positron emission tomography, is reduced in patients with temporal lobe epilepsy. Antiepileptic drugs may act on the serotonergic system, as shown in animal models, and thus affect receptor-binding measurements. METHODS: We analyzed the effect of AEDs on 5-HT(1A)-receptor binding in 31 patients and 10 normal controls. Patients with structural lesions, progressive neurologic disorders, or taking other medications were excluded. None had a seizure for >or=2 days before positron emission tomography (PET). [(18)F]FCWAY PET was performed on a GE Advance scanner with continuous EEG monitoring. Functional images of the distribution volume (V) were generated. Anatomic regions of interest were applied to co-registered PET images, after correction for partial-volume effect. RESULTS: Patients had significantly higher [(18)F]FCWAY free fraction (f(1)) than did controls. No AED effects were observed on interictal [(18)F]FCWAY binding after correction for plasma free fraction. [(18)F]FCWAY V/f1 reduction in epileptic foci was not affected by AEDs. CONCLUSIONS: 5-HT(1A)-receptor binding is reduced in temporal lobe epileptic foci after partial-volume correction. AED plasma free fractions should be measured when PET receptor studies are performed in patients with epilepsy.

Anticonvulsants↗

PubMed2005

Differential effects of paroxetine on raphe and cortical 5-HT1A binding: a PET study in monkeys.

Positron emission tomography (PET) ligands that are sensitive to transient changes in serotonin (5-HT) concentration are desirable for studies of neuropsychiatric diseases. Few studies, however, have sought to demonstrate that variations in 5-HT concentration can be closely tracked with available serotonergic ligands. Microdialysis studies in rats have shown a maximal increase in 5-HT concentration in raphe nuclei after systemic infusion of selective serotonergic re-uptake inhibitors (SSRIs). We performed PET scans with [(18)F]FPWAY, an intermediate-affinity antagonist of 5-HT(1A) receptors, in 4 anesthetized rhesus monkeys in control studies and after systemic paroxetine administration (5 mg/kg, i.v.). In addition, a paired [(11)C]DASB study revealed that this paroxetine regimen produced an occupancy of 54-83% of the serotonin transporters. According to the conventional receptor competition model, increased 5-HT concentration produces decreased binding of the radioactive ligand. Over a 3-h period following paroxetine infusion, a progressively increasing reduction (ranging from 8 +/- 6% to 27 +/- 10%) of [(18)F]FPWAY-specific binding was found in the raphe nuclei. This result is interpreted as an SSRI-induced increase in 5-HT concentration, potentially combined with reduced binding to internalized 5-HT(1A) receptors. In addition, a transient (1 h) increase in cerebral cortical binding was observed, attributed primarily to a reduction in cortical 5-HT due to the effects of raphe autoreceptor inhibition. This study is the first demonstration of the feasibility of quantifying dynamic changes in 5-HT neurotransmission in the raphe and the cortex with PET. These results lend promise to the use of these serotonergic neuroimaging techniques to study neuropsychiatric disorders.

Animals↗

PubMed2005

Measurement of regional rates of cerebral protein synthesis with L-[1-11C]leucine and PET with correction for recycling of tissue amino acids: II. Validation in rhesus monkeys.

The confounding effect of recycling of amino acids derived from tissue protein breakdown into the precursor pool for protein synthesis has been an obstacle to adapting in vivo methods for determination of regional rates of cerebral protein synthesis (rCPS) to positron emission tomography (PET). We used a kinetic modeling approach to estimate lambda, the fraction of the precursor pool for protein synthesis derived from arterial plasma, and to measure rCPS in three anesthetized adult monkeys dynamically scanned after a bolus injection of L-[1-11C]leucine. In the same animals, lambda was directly measured in a steady-state terminal experiment, and values showed excellent agreement with those estimated in the PET studies. In three additional monkeys rCPS was determined with the quantitative autoradiographic L-[1-14C]leucine method. In whole brain and cerebellum, rates of protein synthesis determined with the autoradiographic method were in excellent agreement with those determined with PET, and regional values were in good agreement when differences in spatial resolution of the two methods were taken into account. Low intrasubject variability was found on repeated PET studies. Our results in anesthetized monkey indicate that, by using a kinetic modeling approach to correct for recycling of tissue amino acids, quantitatively accurate and reproducible measurement of rCPS is possible with L-[1-11C]leucine and PET.

Amino Acids↗

PubMed2005

No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder.

OBJECTIVE: Serotonin type 1A receptors (5HT1ARs) have been shown to be affected by stress in experimental animals and related to anxiety and depression in humans. In the present study, the authors sought an association between 5HT1AR binding and posttraumatic stress disorder (PTSD). METHOD: Using positron emission tomography and the radioligand [18F]FCWAY, the authors compared 5HT1AR binding between patients with PTSD and healthy subjects. RESULTS: No significant differences in 5HT1AR distribution volume, binding potential, or tracer delivery were found. CONCLUSIONS: 5HT1AR expression may not be altered in patients with PTSD.

Adult↗

PubMed2005

5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction.

UNLABELLED: Preclinical studies suggest that serotonin 1A receptors (5-HT 1A) play a role in temporal lobe epilepsy (TLE). Previous PET studies reported decreased 5-HT 1A binding ipsilateral to epileptic foci but did not correct for the partial-volume effect (PVE) due to structural atrophy. METHODS: We used PET with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY), a 5-HT 1A receptor antagonist, to study 22 patients with TLE and 10 control subjects. In patients, 18F-FDG scans also were performed. An automated MR-based partial-volume correction (PVC) algorithm was applied. Psychiatric symptoms were assessed with the Beck Depression Inventory Scale. RESULTS: Before PVC, significant (uncorrected P < 0.05) reductions of 18F-FCWAY binding potential (BP) were detected in both mesial and lateral temporal structures, mainly ipsilateral to the seizure focus, in the insula, and in the raphe. Group differences were maximal in ipsilateral mesial temporal regions (corrected P < 0.05). After PVC, differences in mesial, but not lateral, temporal structures and in the insula remained highly significant (corrected P < 0.05). Significant (uncorrected P < 0.05) BP reductions were also detected in TLE patients with normal MR images (n = 6), in mesial temporal structures. After PVC, asymmetries in BP remained significantly greater than for glucose metabolism in hippocampus and parahippocampus. There was a significant inverse relation between the Beck Depression score and the ipsilateral hippocampal BP, both before and after PVC. CONCLUSION: Our study shows that in TLE patients, reductions of 5-HT 1A receptor binding in mesial temporal structures and insula are still significant after PVC. In contrast, partial-volume effects may be an important contributor to 5-HT 1A receptor-binding reductions in lateral temporal lobe. Reduction of 5-HT 1A receptors in the ipsilateral hippocampus may contribute to depressive symptoms in TLE patients.

Adult↗

PubMed2004

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

Toward an evolutionary perspective on conceptual representation: species-specific calls activate visual and affective processing systems in the macaque.

Non-human primates produce a diverse repertoire of species-specific calls and have rich conceptual systems. Some of their calls are designed to convey information about concepts such as predators, food, and social relationships, as well as the affective state of the caller. Little is known about the neural architecture of these calls, and much of what we do know is based on single-cell physiology from anesthetized subjects. By using positron emission tomography in awake rhesus macaques, we found that conspecific vocalizations elicited activity in higher-order visual areas, including regions in the temporal lobe associated with the visual perception of object form (TE/TEO) and motion (superior temporal sulcus) and storing visual object information into long-term memory (TE), as well as in limbic (the amygdala and hippocampus) and paralimbic regions (ventromedial prefrontal cortex) associated with the interpretation and memory-encoding of highly salient and affective material. This neural circuitry strongly corresponds to the network shown to support representation of conspecifics and affective information in humans. These findings shed light on the evolutionary precursors of conceptual representation in humans, suggesting that monkeys and humans have a common neural substrate for representing object concepts.

Acoustic Stimulation↗

PubMed2004

Species-specific calls evoke asymmetric activity in the monkey's temporal poles.

It has often been proposed that the vocal calls of monkeys are precursors of human speech, in part because they provide critical information to other members of the species who rely on them for survival and social interactions. Both behavioural and lesion studies suggest that monkeys, like humans, use the auditory system of the left hemisphere preferentially to process vocalizations. To investigate the pattern of neural activity that might underlie this particular form of functional asymmetry in monkeys, we measured local cerebral metabolic activity while the animals listened passively to species-specific calls compared with a variety of other classes of sound. Within the superior temporal gyrus, significantly greater metabolic activity occurred on the left side than on the right, only in the region of the temporal pole and only in response to monkey calls. This functional asymmetry was absent when these regions were separated by forebrain commissurotomy, suggesting that the perception of vocalizations elicits concurrent interhemispheric interactions that focus the auditory processing within a specialized area of one hemisphere.

Acoustic Stimulation↗

PubMed2004

Reduced serotonin type 1A receptor binding in panic disorder.

Recent animal models suggest that disturbances in serotonin type-1A receptor (5-HT(1A)R) function may contribute to chronic anxiety, although it is not clear at all whether such models constitute relevant models for panic disorder (PD) in humans. The selective 5-HT(1A)R radioligand [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY) permits in vivo assessment of central 5-HT(1A)R binding using positron emission tomography (PET). We studied 16 unmedicated symptomatic outpatients with PD and 15 matched healthy controls. Seven patients had an additional diagnosis of a current major depressive episode, however PD was the primary diagnosis. A 120 min PET study of 5-HT(1A)R binding was acquired using a GE Advance scanner in three-dimensional mode. Using quantitative PET image analysis, regional values were obtained for [18F]-FCWAY volume of distribution (DV), corrected for plasma protein binding, and K1, the delivery rate of [18F]-FCWAY from plasma to tissue. MRI scanning was performed using a GE Signa Scanner (3.0 Tesla) to provide an anatomical framework for image analysis and partial volume correction of PET data. PD patients showed lower DV in the anterior cingulate (t = 4.3; p < 0.001), posterior cingulate (t = 4.1; p < 0.001), and raphe (t = 3.1; p = 0.004). Comparing patients with PD, patients with PD and comorbid depression, and healthy controls revealed that DVs did not differ between PD patients and PD patients with comorbid depression, whereas both patient groups differed significantly from controls. These results provide for the first time in vivo evidence for the involvement of 5-HT(1A)Rs in the pathophysiology of PD.

Adult↗

PubMed2004

Nicotine-induced dopamine release in primates measured with [11C]raclopride PET.

Nicotine-induced dopamine (DA) release constitutes a pharmacological probe of the DA system that has potential use in patients with schizophrenia, who have abnormally elevated DA release after amphetamine administration and possibly abnormalities in nicotinic signaling. We performed positron emission tomography studies in five rhesus monkeys that received i.v. nicotine doses ranging from 0.01 to 0.06 mg/kg. [(11)C]raclopride was administered with either a bolus plus constant infusion or with paired bolus injections. The dynamics of D-2-binding potential (BP) after nicotine administration were studied and compared to amphetamine. Nicotine caused a significant albeit small reduction (5%, p<0.03) in BP, regardless of methodology of tracer administration. This effect disappeared 2.5 h after nicotine administration. Amphetamine caused much larger and prolonged displacement of [(11)C]raclopride as compared to nicotine. There was no correlation between changes in BP and nicotine dose or plasma level. Regional differences in the nicotine effect within the basal ganglia were not found. Our data are consistent with the increase in DA detected with microdialysis in animals after acute nicotine administration, however, a larger effect size would be desirable to attempt studies comparing human smokers with and without schizophrenia.

Amphetamine↗

PubMed2004

A potential cholinergic mechanism of procaine's limbic activation.

The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[18F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M(2)) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to approximately 90% of [18F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC50) for [18F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

Anesthetics, Local↗

PubMed2004

Brain incorporation of 11C-arachidonic acid, blood volume, and blood flow in healthy aging: a study with partial-volume correction.

UNLABELLED: PET with 11C-arachidonic acid (AA) can be used to quantify neural signaling related to phospholipase A2 (PLA2). Animal studies suggest reduction in the activity of this signaling system with age. The aim of this study was to evaluate the effect of healthy aging on brain incorporation of 11C-AA, before and after partial-volume correction (PVC). METHODS: Absolute measurements of cerebral blood flow (CBF) were obtained in 8 young and 7 old healthy subjects (mean age +/- SD, 27 +/- 5 y and 65 +/- 9 y) with bolus injection of 15O-water. About 15 min later, dynamic 60-min 3-dimensional scans were acquired after the injection of 11C-AA. Radioactivity frames of 11C-AA were corrected for head motion and registered to magnetic resonance (MR) images. A 3-segment (3S) and a 2-segment (2S) PVC was applied pixel-by-pixel to the activity frames. For the 3S method, the white matter value was estimated using a new automatic method by extrapolating the activity values of pixels with white matter membership > 0.99. Parametric images of the brain incorporation rate of 11C-AA (K*) and cerebral blood volume (Vb), as well as CBF, were generated and regional gray matter values were obtained. RESULTS: Among cortical areas, there were no significant differences (uncorrected P < 0.05) in K* or Vb absolute values between young and old subjects before or after PVC. A significant reduction of CBF was detected in the frontal cortex of the elderly group. After normalization to the global gray average, K*, Vb, and CBF values revealed significant reductions in the frontal lobe of old subjects; none of these differences were significant after PVC. CONCLUSION: These results confirm previous PET findings that brain function at rest is minimally affected by healthy aging. Proper PVC methodology is of critical importance in accurate quantitative assessment of PET physiologic measures.

Adult↗

PubMed2003

Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon4 allele.

The apolipoprotein E-epsilon4 allele confers an increased susceptibility to age-related memory problems and Alzheimer's disease. Abnormalities in the cholinergic system are also likely contributors to memory deficits associated with aging and AD. To determine the effect of the APOE-epsilon4 allele on the muscarinic component of the cholinergic system of aging subjects, 10 healthy subjects with APOE-epsilon4 alleles (APOE-epsilon4+) and 10 without (APOE-epsilon4-), ranging in age from 52 to 75 years, were tomographically scanned with the F-18-labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[(18)F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([(18)F]FP-TZTP). The distribution volumes (V(T)) of [(18)F]FP-TZTP were determined by compartmental modeling of partial volume and free fraction corrected PET scans. Regional cerebral blood flow (rCBF) measurements with H(2) (15)O were also performed. Global Gray V(T) (840 +/- 155 ml plasma/ml tissue) was greater in APOE-epsilon4+ subjects than APOE-epsilon4- subjects (660 +/- 113 ml plasma/ml tissue, P = 0.01), and previously studied younger subjects. There were no significant differences between the groups with respect to rCBF, but within the APOE-epsilon4+ group there was a trend for subjects with the higher Global Gray V(T)s to have lower Global Gray CBFs (r = -0.65, P < 0.06). A lower concentration of acetylcholine in the synapse of APOE-epsilon4+ older individuals is a likely explanation for the greater [(18)F]FP-TZTP distribution volumes.

Aged↗

PubMed2003

In vivo muscarinic 2 receptor imaging in cognitively normal young and older volunteers.

The precise effects of normal aging on the cholinergic system are unknown, as both in vitro and PET studies have shown conflicting results. In vivo determination of muscarinic receptor distribution and density has been hampered by both poor subtype selectivity and/or blood-brain barrier permeability of known ligands. Previous in vitro and in vivo work with the F-18 labeled muscarinic agonist, 3-(3- (3-[(18)F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ((18)FP-TZTP) suggested the use of (18)FP-TZTP to selectively quantify M2 receptors in humans. In this study, we used (18)FP-TZTP to infer M2 receptor avidity in the brains of 15 healthy younger subjects (mean age = 28.3 +/- 5.5 years) and 20 healthy older subjects (mean age = 62.1 +/- 7.7 years). Corrections for subject motion during the 120-min acquisition and partial voluming (PVC) were performed. A one-tissue compartment model was used to estimate the volumes of distribution (V(T)) of (18)FP-TZTP. Within both groups of subjects, volumes of distribution (K(1)/k(2)) in cortical, subcortical, and cerebellar areas were consistent with M2 receptor topography. Compared to younger subjects older subjects had significantly higher means and standard deviations for the volumes of distribution of (18)FP-TZTP throughout much of the cerebellum, cortex, and subcortex (Global Gray V(T) = 742 +/- 163 in older subjects and 645 +/- 74 in younger subjects, P < 0.03). Across all subjects (18)FP-TZTP, regional, and Global Gray distribution volumes were significantly correlated to age (Global Gray V(T,) r = 0.41, P < 0.01). A lower concentration of acetylcholine in the synapse of some older subjects is one possible explanation for the data.

Acetylcholine↗