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PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment

Background: Patients with mild cognitive impairment (MCI) have increased risk to develop Alzheimer disease (AD). In AD increased brain amyloid burden has been demonstrated in vivo with PET using N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) as a tracer. Objective: To investigate whether patients with amnestic MCI would show increased [11C]PIB uptake, indicating early AD process. Methods: We studied 13 patients with amnestic MCI and 14 control subjects with PET using [11C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum ratio in each voxel over 60 to 90 minutes. Group differences in [11C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. Results: The SPM analysis showed that patients with MCI had significantly higher [11C]PIB uptake vs control subjects in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate showing the most prominent differences. These results were supported by the automated ROI analysis in which MCI patients showed in comparison with healthy control subjects increased [11C]PIB uptake in the frontal cortex (39% increase from the control mean, p < 0.01), the posterior cingulate (39%, p < 0.01), the parietal (31%, p < 0.01) and lateral temporal (28%, p < 0.001) cortices, putamen (17%, p < 0.05), and caudate (25%, p < 0.05). Individually, in the frontal cortex and posterior cingulate, 8 of 13 patients with MCI had [11C]PIB uptake values above 2 SD from the control mean. MCI subjects having at least one APOE ε4 allele tended to have higher [11C]PIB uptake than MCI subjects without APOE ε4. Conclusions: At group level the elevated N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) uptake in patients with mild cognitive impairment (MCI) resembled that seen in Alzheimer disease (AD). At the individual level, about half of the MCI patients had [11C]PIB uptake in the AD range, suggestive of early AD process.

Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease.

Background: PET studies with N-methyl-[11C]2-(4′:-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) have revealed an increased tracer uptake in several brain regions in Alzheimer disease (AD). Objective: To employ voxel-based analysis method to identify brain regions with significant increases in [11C]PIB uptake in AD vs healthy control subjects, indicative of increased amyloid accumulation in these regions. Methods: We studied 17 patients with AD and 11 control subjects with PET using [11C]PIB as tracer. Parametric images were computed by calculating a region-to-cerebellum ratio over 60 to 90 minutes in each voxel. Group differences in [11C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. Results: SPM showed increased uptake (p < 0.001) in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate and the striatum. No significant differences in uptake were found in the primary sensory and motor cortices, primary visual cortex, thalamus, and medial temporal lobe. These results were supported by automated ROI analysis, with most prominent increases in AD subjects in the frontal cortex ([11C]PIB uptake 163% of the control mean) and posterior cingulate (146%) followed by the parietal (146%) and temporal (145%) cortices and striatum (133%), as well as small increases in the occipital cortex (117%) and thalamus (115%). Conclusions: Voxel-based analysis revealed widespread distribution of increased [11C]PIB uptake in Alzheimer disease (AD). These findings are in accordance with the distribution and phases of amyloid pathology in AD, previously documented in postmortem studies.

Amyloid PET imaging in patients with mild cognitive impairment: A 2-year follow-up study

Background: Patients with amnestic mild cognitive impairment (MCI) have greater risk of conversion to Alzheimer disease (AD). Increased brain amyloid burden in AD and MCI has been demonstrated with PET using [11C] Pittsburgh compound B (PiB) as a tracer. Objective: To evaluate change in β-amyloid deposition in with MCI during 2-year follow-up. Methods: Patients with MCI and controls were studied with [11C] PiB PET, MRI, and neuropsychometry at baseline and these investigations were repeated in patients with MCI after follow-up. Results: Those patients with MCI converting to AD during follow-up had greater [11C] PiB retention in the posterior cingulate (p = 0.020), in the lateral frontal cortex (p = 0.006), in the temporal cortex (p = 0.022), in the putamen (p = 0.041), and in the caudate nucleus (p = 0.025) as compared to nonconverters. In converters, there was no significant change in [11C] PiB uptake, whereas an increase was seen as compared to baseline in nonconverters in the anterior and posterior cingulate, temporal and parietal cortices, and putamen. Hippocampal atrophy was greater in converters at baseline than in nonconverters, but increased significantly in both groups during follow-up. Conclusions: Hippocampal atrophy and amyloid deposition seem to dissociate during the evolution of MCI, the atrophy increasing clearly and [11C] PiB retention changing modestly when conversion to AD occurs. Longer follow-up is needed to determine whether nonconverters would convert to AD later, which would suggest accelerated [11C] PiB retention preceding clinical conversion.

High intensity exercise decreases global brain glucose uptake in humans

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro‐deoxy‐glucose ([18F]FDG). Fourteen healthy, right‐handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6 ± 4.6 versus 26.1 ± 5.0 μmol (100 g)−1 min−1, P < 0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37%versus 20%, P < 0.05 between 30% and 75% of ) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Follow-up of [11C]PIB uptake and brain volume in patients with Alzheimer disease and controls

Objective: In Alzheimer disease (AD), the accumulation pattern of β-amyloid over time and its relationship with dementia severity are unclear. We investigated the brain uptake of the amyloid ligand 11C-labeled Pittsburgh compound B ([11C]PIB) and volumetric brain changes over a 2-year follow-up in patients with AD and in aged healthy controls. Methods: Fourteen patients with AD (mean age 72 years, SD 6.6) and 13 healthy controls (mean age 68 years, SD 5.4) were examined at baseline and after 2 years (patients with AD: mean 2.0 years, SD 0.2; controls: mean 2.1 years, SD 0.6) with [11C]PIB PET, MRI, and neuropsychological assessments. [11C]PIB uptake was analyzed with a voxel-based statistical method (SPM), and quantitative data were obtained with automated region-of-interest analysis. MRI data were analyzed with voxel-wise tensor-based morphometry. Results: The [11C]PIB uptake of the patients with AD did not increase significantly during follow-up when compared with that of the controls. MRI showed progressive brain volume change in the patients with AD, e.g., in the hippocampal region, temporal cortex, and precuneus (p < 0.05). The mean Mini-Mental State Examination score of the patients with AD declined from 24.3 (SD 3.1) at baseline to 21.6 (SD 3.9) at follow-up (p = 0.009). Cognitive decline was also evident in other neuropsychological test results. Baseline neocortical [11C]PIB uptake ratios predicted subsequent volumetric brain changes in the controls (r = 0.725, p = 0.005). Conclusions: The results suggest no (or only little) increase in 11C-labeled Pittsburgh compound B ([11C]PIB) uptake during 2 years of Alzheimer disease progression, despite advancing brain atrophy and declining cognitive performance. Nevertheless, changes in [11C]PIB uptake during a longer follow-up cannot be excluded. High cortical [11C]PIB uptake may predict ongoing brain atrophy in cognitively normal individuals.

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

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.

Short-Term Psychodynamic Psychotherapy and Fluoxetine in Major Depressive Disorder: A Randomized Comparative Study

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 ≤7) after 4 months. 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.

Research Letter:Psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder

The serotonin 5-HT1A receptor system is implicated in the pathophysiology of major depressive disorder (MDD) (Stockmeier, 2003) and serotonergic medications are currently widely used in the treatment of MDD. Previous molecular imaging studies in patients with MDD have provided evidence of a widespread decrease in the density of serotonin 5-HT1A receptors in the disease (Drevets et al. 1999; Sargent et al. 2000 ; Bhagwagar et al. 2004 ; Meltzer et al. 2004 ; Hirvonen et al. 2008, but see Parsey et al. 2006 for opposite results). Psychotherapy usually results in clinically identical outcomes with medication in the treatment of patients with mild to moderate MDD (Ebmeier et al. 2006). However, nothing is known about the molecular mechanisms mediating the effects of psychotherapy. To test and compare the effects of fluoxetine medication and a brief psychotherapy on 5-HT1A receptor density in patients with MDD we conducted a randomized comparative study. Positron emission tomography (PET) scanning with the 5-HT1A radiotracer [carbonyl-C]WAY-100635 was performed before and after the intervention to measure alterations in 5-HT1A receptor binding.

Sevoflurane and propofol increase 11C-flumazenil binding to gamma-aminobutyric acidA receptors in humans.

Based on in vitro studies and animal data, most anesthetics are supposed to act via &ggr;-aminobutyric acid type A (GABAA) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied 11C-flumazenil binding to GABAA receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with 11C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 ± 3.0 (mean ± sd) &mgr;g/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of 11C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 ± 6 in the sevoflurane group and 28 ± 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of 11C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABAA receptors in the mechanism of action of both anesthetics in humans.

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

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 D2 receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [11C]raclopride PET scans with a 2.5-hour interval. Dopamine D2 receptor availability was quantified as binding potential (BPND) using the simplified reference tissue model. To evaluate the reproducibility of repeated BPND 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.