Publications by authors named "Sargo Aalto"

57 Publications

Intravenous ethanol increases dopamine release in the ventral striatum in humans: PET study using bolus-plus-infusion administration of [(11)C]raclopride.

J Cereb Blood Flow Metab 2015 Mar 10;35(3):424-31. Epub 2014 Dec 10.

1] Turku PET Centre, University of Turku, Turku, Finland [2] Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.

Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [(11)C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [(11)C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40-50 minutes) and intervention (60-85 minutes) revealed an average 12.6% decrease in [(11)C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=-0.87, P=0.003) and putamen (r=-0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.
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http://dx.doi.org/10.1038/jcbfm.2014.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348378PMC
March 2015

Cognitive decline and amyloid accumulation in patients with mild cognitive impairment.

Dement Geriatr Cogn Disord 2012 3;34(1):31-7. Epub 2012 Aug 3.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Background/aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI.

Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images.

Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function.

Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.
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http://dx.doi.org/10.1159/000341580DOI Listing
February 2013

Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects.

Neurosci Lett 2012 Jul 20;521(1):11-4. Epub 2012 May 20.

Pain Clinic and Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Turku, Finland.

Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects. Later, we recruited these subjects to participate in a separate psychophysical testing session to measure cold pressor pain threshold, cold pressor pain tolerance and tactile sensitivity with von Frey monofilaments. We used both voxel-by-voxel and region-of-interest image analyses to examine the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density is involved in setting individual pain threshold.
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http://dx.doi.org/10.1016/j.neulet.2012.05.042DOI Listing
July 2012

Returning from oblivion: imaging the neural core of consciousness.

J Neurosci 2012 Apr;32(14):4935-43

Turku PET Centre, University of Turku and Turku University Hospital, FI-20521 Turku, Finland.

One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge.
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http://dx.doi.org/10.1523/JNEUROSCI.4962-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620928PMC
April 2012

Delta entropy of heart rate variability along with deepening anesthesia.

Anesth Analg 2011 Mar 13;112(3):587-92. Epub 2011 Jan 13.

Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Hietalahdenkatu 1 a 5 FIN-65100 Vaasa, Finland.

Background: Conventional time and frequency domain measures of heart rate variability (HRV) are strongly influenced by anesthetic drugs, and are therefore not able to detect subtle changes in HRV, even during light anesthesia. Approximate entropy of R-R intervals is an HRV measure that has a tendency to decrease during anesthesia, but it is severely compromised by low-frequency variations of the signal. However, the negative effect of the low-frequency variations can be eliminated by differentiating the R-R interval tachogram before analysis. We designed this study to investigate characteristics of a novel HRV measure, named δ entropy (dEn), during deepening anesthesia.

Methods: Eight healthy subjects were anesthetized with sevoflurane and 8 with propofol in a stepwise manner using 3 escalating concentrations (2%, 3%, and 4% end-tidal concentration and 7.4 ± 1.7, 12.3 ± 2.6, and 18.3 ± 5.0 μg/mL plasma concentration, respectively) at 30-minute intervals. A third group of 8 subjects received a supramaximal IV dose of glycopyrrolate without anesthesia to examine the effect of cardiac vagal activity on dEn. We computed dEn at baseline, during each step of anesthesia and during the anticholinergic blockade.

Results: The dEn decreased along with deepening levels of sevoflurane and propofol anesthesia up to 33% (95% confidence interval [CI] 21%-44%) and 38% (95% CI 28%-48%), respectively. At each anesthesia level, dEn differed significantly (P < 0.05) from that measured at the preceding level, similarly in both the sevoflurane and propofol groups. Parasympathetic blockade by glycopyrrolate was found to decrease dEn by 17% (95% CI 6%-28%).

Conclusions: The dEn is a novel HRV measure able to detect subtle sympathetic- and parasympathetic-mediated alterations in HRV both during deepening levels of sevoflurane and propofol anesthesia and during exceedingly deep anesthesia.
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http://dx.doi.org/10.1213/ANE.0b013e318208074dDOI Listing
March 2011

[(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.

Parkinsonism Relat Disord 2010 Dec 25;16(10):666-70. Epub 2010 Sep 25.

Turku PET Centre, Turku University Hospital, 20520 Turku, Finland.

The objective of this study was to identify possible group differences between PD patients with dementia and without dementia by combining different functional and structural imaging methods in vivo, which might provide an opportunity to disentangle the pathophysiological correlates of cognitive impairment and dementia in PD. We performed a neuropsychological evaluation, structural brain MRI, [(18)F]FDG PET and [(11)C]PIB PET in 19 PD patients [eight non-demented (PD), eleven demented (PDD)] and 24 healthy elderly volunteers. [(11)C]PIB region-to-cerebellum ratios did not differ significantly between the groups in any brain region (p > 0.05). PDD patients showed impaired glucose metabolism in cortical brain regions and this reduction was associated with the degree of cognitive impairment. PDD patients had more atrophy both in the hippocampus and the frontal cortex compared with PD patients and controls, and hippocampal atrophy was associated with impaired memory. This cross-sectional data suggests that development of dementia in PD is associated with extensive spread of hypometabolism beyond the occipital cortex, and with hippocampal and frontal atrophy but not beta-amyloid deposition consistent with a unique biological process related to PD rather than co-incidental development of AD in persons with PD.
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http://dx.doi.org/10.1016/j.parkreldis.2010.08.021DOI Listing
December 2010

Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with [11C]raclopride PET.

J Psychopharmacol 2011 Oct 9;25(10):1329-36. Epub 2010 Sep 9.

Department of Psychiatry, University of Turku, Turku, Finland.

Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D(2/3) receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D(2/3) receptor binding was quantified before and after treatment as the binding potential (BP (ND)) using [(11)C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D(2/3) receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [(11)C]raclopride BP (ND) in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored.
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http://dx.doi.org/10.1177/0269881110376691DOI Listing
October 2011

Reproducibility of striatal and thalamic dopamine D2 receptor binding using [11C]raclopride with high-resolution positron emission tomography.

J Cereb Blood Flow Metab 2011 Jan 5;31(1):155-65. Epub 2010 May 5.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Positron emission tomography (PET) imaging of small striatal brain structures such as the ventral striatum (VST) has been hampered by low spatial resolution causing partial-volume effects. The high-resolution research tomograph (HRRT) is a brain-dedicated PET scanner that has considerably better spatial resolution than its predecessors. However, its superior spatial resolution is associated with a lower signal-to-noise ratio. We evaluated the test-retest reliability of the striatal and thalamic dopamine D(2) receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [(11)C]raclopride PET scans with a 2.5-hour interval. Dopamine D(2) receptor availability was quantified as binding potential (BP(ND)) using the simplified reference tissue model. To evaluate the reproducibility of repeated BP(ND) estimations, absolute variability (VAR) and intraclass correlation coefficients (ICCs) were calculated. VAR values indicated fairly good reproducibility and were 3.6% to 4.5% for the caudate nucleus and putamen and 4.5% to 6.4% for the lateral and medial part of the thalamus. In the VST, the VAR value was 5.8% when the definition was made in the coronal plane. However, the ICC values were only moderate, in the range of 0.34 to 0.66, for all regions except the putamen (0.87). Experimental signal processing methods improved neither ICC nor VAR values significantly.
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http://dx.doi.org/10.1038/jcbfm.2010.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049480PMC
January 2011

Visual assessment of [(11)C]PIB PET in patients with cognitive impairment.

Eur J Nucl Med Mol Imaging 2010 Jun 9;37(6):1141-7. Epub 2010 Feb 9.

Turku PET Centre, P.O. Box 52, 20521, Turku, Finland.

Purpose: The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.

Methods: We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.

Results: The evaluation of visual classification as "normal" or "abnormal" showed good interobserver agreement (kappa = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p < 0.001). The most difficult visually assessed brain area was the putamen (kappa = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60).

Conclusion: Our study shows that visual evaluation of [(11)C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.
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http://dx.doi.org/10.1007/s00259-010-1382-8DOI Listing
June 2010

The effects of lorazepam on extrastriatal dopamine D(2/3)-receptors-A double-blind randomized placebo-controlled PET study.

Psychiatry Res 2009 Nov;174(2):130-7

Turku PET Centre, University of Turku, Turku, Finland.

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic gamma-amino-butyric (GABA)-dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D(2/3) receptor binding using Positron-Emission Tomography (PET) and the high-affinity D(2/3)-receptor ligand [(11)C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D(2)/D(3) receptor binding potential was measured with the reference tissue method in several extrastriatal D(2)-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D(2)/D(3) receptor BP(ND) in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC. In conclusion, lorazepam decreased [(11)C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA-dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D(2)/D(3) receptor binding potential (BP) change further supports this hypothesis.
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http://dx.doi.org/10.1016/j.pscychresns.2009.04.006DOI Listing
November 2009

Reproducibility of automated simplified voxel-based analysis of PET amyloid ligand [11C]PIB uptake using 30-min scanning data.

Eur J Nucl Med Mol Imaging 2009 Oct 4;36(10):1651-60. Epub 2009 Jun 4.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Purpose: Positron emission tomography (PET) with 11C-labelled Pittsburgh compound B ([11C]PIB) enables the quantitation of beta-amyloid accumulation in the brain of patients with Alzheimer's disease (AD). Voxel-based image analysis techniques conducted in a standard brain space provide an objective, rapid and fully automated method to analyze [11C]PIB PET data. The purpose of this study was to evaluate both region- and voxel-level reproducibility of automated and simplified [11C]PIB quantitation when using only 30 min of imaging data.

Methods: Six AD patients and four healthy controls were scanned twice with an average interval of 6 weeks. To evaluate the feasibility of short scanning (convenient for AD patients), [11C]PIB uptake was quantitated using 30 min of imaging data (60 to 90 min after tracer injection) for region-to-cerebellum ratio calculations. To evaluate the reproducibility, a test-retest design was used to derive absolute variability (VAR) estimates and intraclass correlation coefficients at both region-of-interest (ROI) and voxel level.

Results: The reproducibility both at the region level (VAR 0.9-5.5%) and at the voxel level (VAR 4.2-6.4%) was good to excellent. Based on the variability estimates obtained, power calculations indicated that 90% power to obtain statistically significant difference can be achieved using a sample size of five subjects per group when a 15% change from baseline (increase or decrease) in [11C]PIB accumulation in the frontal cortex is anticipated in one group compared to no change in another group.

Conclusion: Our results showed that an automated analysis method based on an efficient scanning protocol provides reproducible results for [11C]PIB uptake and appears suitable for PET studies aiming at the quantitation of amyloid accumulation in the brain of AD patients for the evaluation of progression and treatment effects.
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http://dx.doi.org/10.1007/s00259-009-1174-1DOI Listing
October 2009

A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease shows nonlinear progression in the putamen.

Mov Disord 2009 May;24(7):1009-15

Turku PET Centre, University of Turku, Turku, Finland.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.
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http://dx.doi.org/10.1002/mds.22484DOI Listing
May 2009

The effects of xenon anesthesia on the relationship between cerebral glucose metabolism and blood flow in healthy subjects: a positron emission tomography study.

Anesth Analg 2009 Feb;108(2):593-600

Turku PET Centre, University of Turku, Finland.

Background: General anesthetics can alter the relationship between regional cerebral glucose metabolism (rCMR(glc)) and blood flow (rCBF). In this positron emission tomography study, our aim was to assess both rCMR(glc) and rCBF in the same individuals during xenon anesthesia.

Methods: (18)F-labeled fluorodeoxyglucose and (15)O-labeled water were used to determine rCMR(glc) and rCBF, respectively, in five healthy male subjects at baseline (awake) and during 1 minimum alveolar anesthetic concentration of xenon. Anesthesia was based solely on xenon. Changes in rCMR(glc) and rCBF were quantified using region-of-interest and voxel-based analyses.

Results: The mean (sd) xenon concentration during anesthesia was 67.2 (0.8)%. Xenon anesthesia induced a uniform reduction in rCMR(glc), whereas rCBF decreased in 7 of 13 brain regions. The mean decreases in the gray matter were 32.4 (4.0)% (P < 0.001) and 14.8 (5.9)% (P = 0.007) for rCMR(glc) and rCBF, respectively. rCMR(glc) decreased by 10.9 (6.4)% in the white matter (P = 0.030), whereas rCBF increased by 9.2 (7.3)% (P = 0.049). The rCBF/rCMR(glc) ratio was especially increased in the insula, anterior and posterior cingulate, and in the somatosensory cortex.

Conclusions: In general, the magnitude of the decreases in rCMR(glc) during 1 minimum alveolar anesthetic concentration xenon anesthesia exceeded the reductions in rCBF. As a result, the ratio between rCMR(glc) and rCBF was shifted to a higher level. Interestingly, xenon-induced changes in cerebral metabolism and blood flow resemble those induced by volatile anesthetics.
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http://dx.doi.org/10.1213/ane.0b013e31818ffc9dDOI Listing
February 2009

Posterior cortical atrophy: a rare form of dementia with in vivo evidence of amyloid-beta accumulation.

J Alzheimers Dis 2008 Nov;15(3):351-5

Department of Neurology, University of Turku, Turku, Finland.

Posterior cortical atrophy (PCA) is a rare form of degenerative dementia, which is characterized by progressive atrophy of occipital and parietal cortical areas. It usually manifests as increasing difficulties of visuoperceptive abilities. Later on, memory and other cognitive functions are involved. Various pathologies have been associated with clinical PCA presentation, but most of the patients with autopsy have had Alzheimer-type pathology. Thus, PCA has been considered to be a rare form of Alzheimer-type dementia with unusual pathological distribution. Here we describe a patient who had a typical clinical course for this syndrome and who showed a positive accumulation of amyloid-beta in posterior areas studied with positron emission tomography.
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http://dx.doi.org/10.3233/jad-2008-15301DOI Listing
November 2008

The effects of d-amphetamine on extrastriatal dopamine D2/D3 receptors: a randomized, double-blind, placebo-controlled PET study with [11C]FLB 457 in healthy subjects.

Eur J Nucl Med Mol Imaging 2009 Mar 5;36(3):475-83. Epub 2008 Nov 5.

Turku PET Centre, University of Turku, 20014 Turku, Finland.

Purpose: The dopamine D(2)/D(3) receptor ligand [(11)C]FLB 457 and PET enable quantification of low-density extrastriatal D(2)/D(3) receptors, but it is uncertain whether [(11)C]FLB 457 can be used for measuring extrastriatal dopamine release.

Methods: We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [(11)C]FLB 457 binding potential (BP(ND)) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers.

Results: The effects of d-amphetamine on [(11)C]FLB 457 BP(ND) and distribution volume (V(T)) in the frontal cortex were not different from those of placebo. Small decreases in [(11)C]FLB 457 BP(ND) were observed only in the posterior cingulate and hippocampus. The regional changes in [(11)C]FLB 457 BP(ND) did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria.

Conclusion: This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D(2)/D(3) receptor binding. Our results indicate that [(11)C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans.
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http://dx.doi.org/10.1007/s00259-008-0969-9DOI Listing
March 2009

Measurement of central mu-opioid receptor binding in vivo with PET and [11C]carfentanil: a test-retest study in healthy subjects.

Eur J Nucl Med Mol Imaging 2009 Feb 9;36(2):275-86. Epub 2008 Sep 9.

Turku PET Centre, University of Turku and Turku University Central Hospital, Turku, Finland.

Purpose: [(11)C]Carfentanil has been widely used in positron emission tomography (PET) studies for measuring micro-opioid receptor binding in humans, but the reproducibility of the binding parameter estimates is unknown.

Materials And Methods: Eight healthy volunteers were scanned twice during the same day with [(11)C]carfentanil PET, and binding to receptors was assessed with both reference tissue and arterial plasma input-based models using region of interest (ROI) and voxel-based quantification.

Results: The two-tissue compartmental model distribution volume (V(T)) was highly reproducible as indicated by low variability (VAR < 6%) and high intraclass correlation coefficients (ICC > 0.93). BP(ND) (BP relative to the nondisplaceable tissue compartment) was also highly reproducible (VAR < 10%, ICC > 0.90) both at ROI- and voxel-level, and reference tissue-based models provided stable estimates after 40 min.

Conclusions: The reproducibility of [(11)C]carfentanil binding parameter estimates is excellent with outcome measures based on both arterial plasma and reference tissue input, and a scanning time of 40 min appears sufficient.
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http://dx.doi.org/10.1007/s00259-008-0935-6DOI Listing
February 2009

Short-term psychodynamic psychotherapy and fluoxetine in major depressive disorder: a randomized comparative study.

Psychother Psychosom 2008 14;77(6):351-7. Epub 2008 Aug 14.

Department of Psychiatry, University of Helsinki, Helsinki, Finland.

Background: There are few studies comparing the efficacy of short-term psychodynamic psychotherapy (STPP) and pharmacotherapy in major depressive disorder. We conducted a comparative study on the efficacy of STPP versus fluoxetine treatment in patients with major depressive disorder in a primary care setting.

Methods: Fifty-one patients with major depressive disorder (DSM-IV) of mild or moderate severity were recruited through occupational health services providing primary health care. Patients were randomized to receive either STPP (1 session/week) or fluoxetine treatment (20-40 mg/day) for 16 weeks. The outcome measures included the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI), and the Social and Occupational Functioning Assessment Scale (SOFAS).

Results: Intent-to-treat analyses indicated that both treatments were highly effective in reducing the HDRS (p < 0.0001) and BDI (p < 0.0001) scores, as well as in improving functional ability (SOFAS; p < 0.0001), with no statistically significant differences between the treatments. Of those 40 subjects who completed the follow-up, 57% in the psychotherapy group and 68% in the fluoxetine group showed full remission (HDRS
Conclusions: Both STPP and pharmacological treatment with fluoxetine are effective in reducing symptoms and in improving functional ability of primary care patients with mild or moderate depression. This study suggests no marked differences in the therapeutic effects of these two treatment forms in a primary care setting.
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http://dx.doi.org/10.1159/000151388DOI Listing
March 2009

Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B.

Arch Neurol 2008 Oct 11;65(10):1304-9. Epub 2008 Aug 11.

Department of Neurosurgery, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland.

Objective: To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens.

Design: Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens.

Setting: Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus.

Interventions: [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests.

Main Outcome Measures: Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET.

Results: In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits.

Conclusions: Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.
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http://dx.doi.org/10.1001/archneur.65.10.noc80013DOI Listing
October 2008

Impaired cognitive performance in Parkinson's disease is related to caudate dopaminergic hypofunction and hippocampal atrophy.

Parkinsonism Relat Disord 2009 Feb 22;15(2):88-93. Epub 2008 Apr 22.

Turku University Hospital, University of Turku, FIN-20521 Turku, Finland.

Frontal lobe dysfunction and other cognitive deficits have been described in Parkinson's disease (PD), which may lead to dementia. Both striatal dopaminergic deficiency and regional or global brain volume loss have been suggested to contribute to cognitive decline in PD. We therefore performed a neuropsychological evaluation, structural brain MRI and Fdopa PET in patients with PD and healthy elderly volunteers. PD patients had impaired cognitive performance in many neuropsychological tests compared to controls, not limited just to frontal lobe function tests. Caudate Fdopa correlated positively with performance in verbal (immediate and delayed) and visual memory. Patients with PD showed atrophy in the hippocampus and the prefrontal cortex and hippocampal atrophy was related to impaired memory. Our findings suggest that striatal dopaminergic depletion and global brain volume loss contribute to cognitive impairment in non-demented PD patients, but dysfunction of extra-striatal dopaminergic or non-dopaminergic systems probably plays a role especially in more generalized cognitive impairment.
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http://dx.doi.org/10.1016/j.parkreldis.2008.03.005DOI Listing
February 2009

Carbon 11-labeled pittsburgh compound B positron emission tomographic amyloid imaging in patients with APP locus duplication.

Arch Neurol 2008 Apr;65(4):540-4

Clinical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland.

Objective: To investigate amyloid accumulation by carbon 11-labeled Pittsburgh Compound B (11C-PiB) in hereditary cerebral amyloid angiopathy and APP locus duplication.

Design, Setting, And Patients: Positron emission tomography with 11C-PiB and magnetic resonance imaging were performed for 2 patients, 49-year-old and 60-year-old siblings with APP locus duplication, with hereditary Alzheimer disease and cerebral amyloid angiopathy.

Main Outcome Measure: Change in 11C-PiB uptake.

Results: Uptake of 11C-PiB was increased especially in the striatum (caudate nucleus to 225% and 280% of the control mean and putamen to 166% and 185% of the control mean) and in the posterior cingulate (to 168% and 198% of the control mean), and it was marginally increased in other cortical brain areas. The pattern of increased 11C-PiB uptake was different from that seen in sporadic Alzheimer disease.

Conclusions: Amyloid imaging with 11C-PiB positron emission tomography is a useful tool for detecting in vivo amyloid accumulation in patients with hereditary cerebral amyloid angiopathy. However, the pattern of 11C-PiB accumulation differs between patients with typical AD and patients with APP locus duplication.
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http://dx.doi.org/10.1001/archneur.65.4.540DOI Listing
April 2008

Measurement of GABAA receptor binding in vivo with [11C]flumazenil: a test-retest study in healthy subjects.

Neuroimage 2008 Jun 4;41(2):260-9. Epub 2008 Mar 4.

Turku PET Centre, University of Turku and Department of Otorhinolaryngology--Head and Neck Surgery, Turku University Hospital, Finland.

[(11)C]Flumazenil is widely used in positron emission tomography (PET) studies to measure GABA(A) receptors in vivo in humans. Although several different methods have been applied for the quantification of [(11)C]flumazenil binding, the reproducibility of these methods has not been previously examined. The reproducibility of a single bolus [(11)C]flumazenil measurements was studied by scanning eight healthy volunteers twice during the same day. Grey matter regions were analyzed using both regions-of-interest (ROI) and voxel-based analysis methods. Compartmental kinetic modelling using both arterial and reference region input function were applied to derive the total tissue distribution volume (V(T)) and the binding potential (BP) (BP(P) and BP(ND)) of [(11)C]flumazenil. To measure the reproducibility and reliability of each [(11)C]flumazenil binding parameter, absolute variability values (VAR) and intraclass correlation coefficients (ICC) were calculated. Tissue radioactivity concentration over time was best modelled with a 2-tissue compartmental model. V(T) showed with all methods good to excellent reproducibility and reliability with low VARs (mean of all brain regions) (5.57%-6.26%) and high ICCs (mean of all brain regions) (0.83-0.88) when using conventional ROI analysis. Also voxel-based analysis methods yielded excellent reproducibility (VAR 5.75% and ICC 0.81). In contrast, the BP estimates using pons as the reference tissue yielded higher VARs (8.08%-9.08%) and lower ICCs (0.35-0.80). In conclusion, the reproducibility of [(11)C]flumazenil measurements is considerably better with outcome measures based on arterial input function than those using pons as the reference tissue. The voxel-based analysis methods are proper alternative as the reliability is preserved and analysis automated.
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http://dx.doi.org/10.1016/j.neuroimage.2008.02.035DOI Listing
June 2008

Xenon does not affect gamma-aminobutyric acid type A receptor binding in humans.

Anesth Analg 2008 Jan;106(1):129-34, table of contents

Turku PET Centre, Turku, Finland.

Background: The noble gas xenon acts as an anesthetic with favorable hemodynamic and neuroprotective properties. Based on animal and in vitro data, it is thought to exert its anesthetic effects by inhibiting glutamatergic signaling, but effects on gamma-aminobutyric acid type A (GABA(A)) receptors also have been reported. The mechanism of anesthetic action of xenon in the living human brain still remains to be determined.

Methods: We used the specific GABA(A) receptor benzodiazepine-site ligand 11C-flumazenil and positron emission tomography to study the GABAergic effects of xenon in eight healthy male volunteers. Each subject underwent two dynamic 60-min positron emission tomography studies awake and during approximately one minimum alveolar concentration of xenon (65%). Bispectral index was recorded. Cortical and subcortical gray matter regions were analyzed using both automated regions-of-interest analysis and voxel-based analysis.

Results: During anesthesia, the mean +/- sd bispectral index was 23 +/- 7, and there were no significant changes in heart rate or mean arterial blood pressure. Xenon did not significantly affect 11C-flumazenil binding in any brain region.

Conclusions: Xenon did not affect 11C-flumazenil binding in the living human brain, indicating that the anesthetic effect of xenon is not mediated via the GABA(A) receptor system.
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http://dx.doi.org/10.1213/01.ane.0000287658.14763.13DOI Listing
January 2008

Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease.

Ann Neurol 2008 Jan;63(1):112-8

Turku Positron Emission Tomography Centre, University of Turku, Turku, Finland.

Objective: The reduced risk for Alzheimer's disease (AD) in high-educated individuals has been proposed to reflect brain cognitive reserve, which would provide more efficient compensatory mechanisms against the underlying pathology, and thus delayed clinical expression. Our aim was to find possible differences in brain amyloid ligand 11C-labeled Pittsburgh Compound B ([11C]PIB) uptake and glucose metabolism in high- and low-educated patients with mild AD.

Methods: Twelve high-educated and 13 low-educated patients with the same degree of cognitive deterioration were studied with PET using [11C]PIB and 18F-fluorodeoxyglucose as ligands. The between-group differences were analyzed with voxel-based statistical method, and quantitative data were obtained with automated region-of-interest analysis.

Results: High-educated patients showed increased [11C]PIB uptake in the lateral frontal cortex compared with low-educated patients. Moreover, high-educated patients had significantly lower glucose metabolic rate in the temporoparietal cortical regions compared with low-educated patients.

Interpretation: Our results suggesting more advanced pathological and functional brain changes in high-educated patients with mild AD are in accordance with the brain cognitive reserve hypothesis and point out the importance of development of reliable markers of underlying AD pathology for early AD diagnostics.
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http://dx.doi.org/10.1002/ana.21212DOI Listing
January 2008

Different cerebral cortical areas influence the effect of subthalamic nucleus stimulation on parkinsonian motor deficits and freezing of gait.

Mov Disord 2007 Nov;22(15):2176-82

Department of Neurology, Youngdong Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Inconsistent response in freezing of gait (FOG) with levodopa treatment or STN DBS makes the pathogenesis difficult to understand. We studied brain areas associated with the expression of STN DBS effect on parkinsonian motor deficits and FOG. Ten Parkinson's disease patients with typical FOG were included. One month before STN DBS, we performed [(18)F]-deoxyglucose PET scans and measured the UPDRS motor and modified FOG (mFOG) scores during levodopa off and on periods. At two months after STN DBS, same rating scores were measured. The percentage improvement of mFOG and UPDRS motor scores by STN DBS during levodopa off period was calculated. We searched for brain areas in which glucose metabolism correlated with the improvement of mFOG and UPDRS motor scores by DBS. During levodopa off period, STN DBS improved the UPDRS motor scores by 32.3% and the mFOG scores by 56.6%. There was no correlation between the improvements of both scores. The improvement of UPDRS motor score by DBS correlated with the metabolic activities of rostral supplementary motor area (Brodmann's area 8; BA8), anterior cingulate cortex (BA32), and prefrontal cortex (BA9). On the other hand, there was a positive correlation between the improvement of mFOG score by DBS and the metabolic activity of the parietal, occipital, and temporal sensory association cortices. In conclusion, dysfunction of different cerebral cortical areas limits the beneficial effects of DBS on parkinsonian motor deficits and FOG.
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http://dx.doi.org/10.1002/mds.21609DOI Listing
November 2007

Dopamine D2/D3 receptor binding in the anterior cingulate cortex and executive functioning.

Psychiatry Res 2007 Oct 1;156(1):69-74. Epub 2007 Aug 1.

Turku PET Centre, University of Turku, c/o Turku University Central Hospital, PO Box 52, FIN-20521 Turku, Finland.

The objective was to investigate the association between extrastriatal dopamine D(2)/D(3) receptor binding and performance on the Wisconsin Card Sorting Test (WCST), a measure of executive functioning. Thirty-two healthy volunteers performed the WCST and underwent positron emission tomography and a high-affinity D(2)/D(3) receptor tracer, [(11)C]FLB 457. All WCST error parameters, in particular nonperseverative errors, correlated positively with [(11)C]FLB 457 binding in the cognitive division of the right anterior cingulate cortex. An independent voxel-based receptor parametric mapping analysis confirmed these findings. The results indicate that executive functioning in healthy volunteers is modulated by D(2)/D(3) receptors in the anterior cingulate cortex.
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http://dx.doi.org/10.1016/j.pscychresns.2006.12.012DOI Listing
October 2007

Effects of xenon anesthesia on cerebral blood flow in humans: a positron emission tomography study.

Anesthesiology 2007 Jun;106(6):1128-33

Turku PET Centre, Department of Anesthesiology and Intensive Care, Turku University Hospital, Finland.

Background: Animal studies have demonstrated a strong neuroprotective property of xenon. Its usefulness in patients with cerebral pathology could be compromised by deleterious effects on regional cerebral blood flow (rCBF).

Methods: 15O-labeled water was used to determine rCBF in nine healthy male subjects at baseline and during 1 minimum alveolar concentration (MAC) of xenon (63%). Anesthesia was based solely on xenon. Absolute changes in rCBF were quantified using region-of-interest analysis and voxel-based analysis.

Results: Mean arterial blood pressure and arterial partial pressure for carbon dioxide remained unchanged. The mean (+/-SD) xenon concentration during anesthesia was 65.2+/-2.3%. Xenon anesthesia decreased absolute rCBF by 34.7+/-9.8% in the cerebellum (P<0.001), by 22.8+/-10.4% in the thalamus (P=0.001), and by 16.2+/-6.2% in the parietal cortex (P<0.001). On average, xenon anesthesia decreased absolute rCBF by 11.2+/-8.6% in the gray matter (P=0.008). A 22.1+/-13.6% increase in rCBF was detected in the white matter (P=0.001). Whole-brain voxel-based analysis revealed widespread cortical reductions and increases in rCBF in the precentral and postcentral gyri.

Conclusions: One MAC of xenon decreased rCBF in several areas studied. The greatest decreases were detected in the cerebellum, the thalamus and the cortical areas. Increases in rCBF were observed in the white matter and in the pre- and postcentral gyri. These results are in clear contradiction with ketamine, another N-methyl-D-aspartate antagonist and neuroprotectant, which induces a general increase in cerebral blood flow at anesthetic concentrations.
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http://dx.doi.org/10.1097/01.anes.0000267596.57497.92DOI Listing
June 2007

Brain dopamine d1 receptors in twins discordant for schizophrenia.

Am J Psychiatry 2006 Oct;163(10):1747-53

Department of Psychiatry, University of Turku, Kunnallissairaalantie 20, Bldg. 9, 20700 Turku, Finland.

Objective: It has been suggested that deficits in higher-order cognitive functions serve as intermediate phenotypic indicators of genetic vulnerability to schizophrenia. The dopamine hypothesis of schizophrenia postulates that insufficiency of dopamine transmission in the prefrontal cortex contributes to the cognitive deficits observed in patients with the disease, and there is robust empirical evidence for a central role of prefrontal cortex dopamine D(1) receptors in working memory functions.

Method: The authors examined the genetic and nongenetic effects on D(1) receptor binding in schizophrenia by studying monozygotic and dizygotic twin pairs discordant for schizophrenia as well as healthy comparison twins using positron emission tomography (PET) and the D(1) receptor antagonist ligand [(11)C]SCH 23390. Performance on neuropsychological tests sensitive to frontal lobe functioning was evaluated.

Results: High D(1) receptor density in the medial prefrontal cortex, superior temporal gyrus, and heteromodal association cortex (angular gyrus) was associated with increasing genetic risk for schizophrenia (comparison twins < unaffected dizygotic co-twins < unaffected monozygotic co-twins). Medicated schizophrenia patients demonstrated a widespread reduction in D(1) receptor binding when compared with the unaffected co-twin, and higher doses of antipsychotics were associated with lower D(1) receptor binding in the frontotemporal regions.

Conclusions: This study demonstrated an association between genetic risk for schizophrenia and alterations in cortical D(1) receptor binding, an observation that has implications for future studies of the molecular genetics of schizophrenia. In addition, the data indicate a widespread reduction of D(1) receptor binding in medicated schizophrenia patients, supporting a link between antipsychotic drug action and dopamine D(1) receptor down-regulation.
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http://dx.doi.org/10.1176/ajp.2006.163.10.1747DOI Listing
October 2006

Striatal subregional 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study.

Mov Disord 2006 Jul;21(7):958-63

Turku PET Center, University of Turku, Turku, Finland.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD.
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http://dx.doi.org/10.1002/mds.20855DOI Listing
July 2006

Mobile phone affects cerebral blood flow in humans.

J Cereb Blood Flow Metab 2006 Jul 22;26(7):885-90. Epub 2006 Feb 22.

Turku PET Centre, University of Turku, Turku, Finland.

Mobile phones create a radio-frequency electromagnetic field (EMF) around them when in use, the effects of which on brain physiology in humans are not well known. We studied the effects of a commercial mobile phone on regional cerebral blood flow (rCBF) in healthy humans using positron emission tomography (PET) imaging. Positron emission tomography data was acquired using a double-blind, counterbalanced study design with 12 male subjects performing a computer-controlled verbal working memory task (letter 1-back). Explorative and objective voxel-based statistical analysis revealed that a mobile phone in operation induces a local decrease in rCBF beneath the antenna in the inferior temporal cortex and an increase more distantly in the prefrontal cortex. Our results provide the first evidence, suggesting that the EMF emitted by a commercial mobile phone affects rCBF in humans. These results are consistent with the postulation that EMF induces changes in neuronal activity.
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http://dx.doi.org/10.1038/sj.jcbfm.9600279DOI Listing
July 2006

Striatal dopamine D1 and D2 receptor balance in twins at increased genetic risk for schizophrenia.

Psychiatry Res 2006 Jan 19;146(1):13-20. Epub 2005 Dec 19.

Department of Psychiatry, University of Turku, 20520, Finland.

The dopamine hypothesis of schizophrenia postulates that a dysfunctional dopaminergic system is a major pathophysiological mechanism in the disease. Most studies have focused on striatal dopamine D2 receptors, but a disturbed link between dopamine D1 and D2 receptors has also been proposed. Schizophrenia is highly heritable, and recent evidence suggests that alterations in the dopaminergic system confer susceptibility for schizophrenia instead of being solely related to the to overt expression of the disease. To explore the impact of genetic vulnerability for schizophrenia on the balance of striatal dopamine D1 and D2 receptors, we studied monozygotic (MZ) and dizygotic (DZ) unaffected co-twins from twin pairs discordant for schizophrenia as well as healthy control twins using positron emission tomography (PET). Both [(11)C]SCH 23390 and [(11)C]raclopride were used to quantitate D1 and D2 receptor binding, respectively, in the same individuals during the same day. The association between D1 and D2 receptor binding was analyzed using conventional region of interests as well as voxel-wise D1/D2 ratio maps. All levels of analyses failed to show any differences in D1/D2 ratio between the unaffected MZ or DZ co-twins and control twins. We noted rostrocaudally declining and dorsoventrally increasing gradients in D1/D2 ratio in the striatum, with no differences between groups in these gradients. In this sample, we did not find evidence for an association between increased genetic risk for schizophrenia and altered D1/D2 receptor balance in the striatum.
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http://dx.doi.org/10.1016/j.pscychresns.2005.10.004DOI Listing
January 2006
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