Kjell Någren

Conversion of amyloid positive and negative MCI to AD over 3 years An 11C-PIB PET study

Background: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). 11C-PIB PET is an in vivo marker of brain amyloid load. Objective: To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters. Methods: Thirty-one subjects with MCI with baseline 11C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 ± 0.6 years). Raised cortical 11C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping. Results: Seventeen of 31 (55%) subjects with MCI had increased 11C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were ε4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035). Conclusions: PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

Amyloid load in Parkinson’s disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography

Background: Neuropathological studies have reported varying amounts of amyloid pathology in dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). [11C]PIB positron emission tomography (PET) is a marker of brain amyloid deposition. The aim of this study was to quantify in vivo amyloid load in DLB and PDD compared with control subjects and subjects with Parkinson’s disease (PD) without dementia. Methods: 13 DLB, 12 PDD, 10 PD subjects and 41 age matched controls (55–82 years) were recruited. Each subject underwent clinical evaluation, neuropsychological assessment, T1 and T2 MRI, and [11C]PIB PET. The amyloid load was estimated from 60–90’ target region:cerebellar [11C]PIB uptake ratios. Object maps were created by segmenting individual MRIs and convolving them with a probabilistic atlas. Cortical [11C]PIB uptake was assessed by region of interest analysis. Results: The DLB cohort showed a significant increase in mean brain [11C]PIB uptake and individually 11 of the 13 subjects with DLB had a significantly increased amyloid load. In contrast, mean [11C]PIB uptake was normal for the PDD group although two of 12 patients with PDD individually showed a raised amyloid load. Where significant increases in [11C]PIB uptake were found, it was increased in cortical association areas, cingulate and striatum. None of the subjects with PD showed significantly raised cortical [11C]PIB uptake. Conclusion: This study suggests that amyloid load is significantly raised in over 80% of subjects with DLB, while amyloid pathology is infrequent in PDD. These in vivo PET findings suggest that the presence of amyloid in DLB could contribute to the rapid progression of dementia in this condition and that anti-amyloid strategies may be relevant.

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.

Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain.

Loss of dopamine D2-like receptors in the striatum has been associated with both normal human aging and impairment of cognitive and motor functions in the elderly. To investigate whether there are age-associated changes in dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the striatum, a D2/3R selective high-affinity radioligand [11C]FLB 457 was used in positron emission tomography (PET) examinations for 24 normal healthy male subjects (age range 19-74 years). Significant age-related declines of D2/3Rs were detected in all the brain regions studied: the anterior cingulate cortex (decline of 13% per increase of a decade in age, P < 0.001). the frontal cortex (11%, P < 0.001), the lateral temporal cortex (10%, P < 0.001), the hippocampus (10%, P < 0.01), the medial temporal cortex (9%, P < 0.001), the amygdala (7%, P < 0.01), the medial thalamus (6%, P < 0.001) and the lateral thalamus (5%, P < 0.01). The rate of D2/3R decline was significantly faster in the frontal cortex as compared to the medial temporal cortex (P < 0.05, Bonferroni corrected) and as compared to the medial thalamus (P < 0.05, Bonferroni corrected). These results indicate that the previously demonstrated age-related decline in striatal dopamine D2 receptors extends to several extrastriatal regions in normal human males. Further, the rate of D2/3R decline may be faster in the frontal cortex as compared to the temporal and thalamic regions.

Frontal and Temporal Dopamine Release during Working Memory and Attention Tasks in Healthy Humans: a Positron Emission Tomography Study Using the High-Affinity Dopamine D2 Receptor Ligand [11C]FLB 457

Experimental studies on animals have shown that dopamine is a key neurotransmitter in the regulation of working memory (WM) functions in the prefrontal cortex. In humans, blood flow studies show prefrontal involvement in WM functions, but direct evidence for the involvement of the dopaminergic system in WM is lacking. Using positron emission tomography with a recently developed high-affinity dopamine D2 receptor tracer, [11C]FLB 457, we explored frontal, temporal, and parietal D2 receptor availability in 12 healthy volunteers while they were performing verbal WM and sustained attention tasks. During the performance of both tasks, reduced D2 receptor availability was observed in the left ventral anterior cingulate, suggesting an attention or arousal-related increase in dopamine release during these tasks. Compared with the sustained attention task, the verbal WM task reduced D2 receptor availability in the ventrolateral frontal cortex bilaterally and in the left medial temporal structures (amygdala, hippocampus), suggesting that dopamine release in these regions might have a specific role in WM. In addition, correlation analyses indicated that increased dopamine release in the right ventrolateral frontal cortex and the left ventral anterior cingulate during the WM task was associated with faster and more stable WM performance, respectively. Our results indicate that regionally specific components of the frontotemporal dopaminergic network are functionally involved in WM performance in humans.

Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence

Striatal D2 dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1–68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D2 receptor ligand [11C]raclopride and equilibrium model was used for D2 receptor density (Bmax) and affinity (Kd) measurements. A trend for a decreased striatal D2 receptor density and for reduced D2 receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D2 receptor density and affinity (Bmax/Kd or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D2 dopamine receptor Bmax/Kd ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [11C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D2 receptors in alcoholics, which is in line with the idea that D2 dopaminergic mechanisms are involved in the biology of alcohol dependence in man.

Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer’s disease

ObjectiveThe objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL).Materials and methodsAD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI).ResultsAD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps < 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%.ConclusionFor AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI.

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.

Myocardial efficiency during levosimendan infusion in congestive heart failure

Levosimendan, a novel calcium‐dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure.

EANM procedure guidelines for PET brain imaging using [ 18 F]FDG, version 2

These guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The purpose of the guidelines is to assist nuclear medicine practitioners in making recommendations, performing, interpreting, and reporting the results of fluorine-18 fluoro-2-deoxyglucose ([18F]FDG) PET imaging of the brain. The aim is to help achieve a high standard of FDG imaging, which will increase the diagnostic impact of this technique in neurological and psychiatric practice. The present document replaces a former version of the guidelines that were published in 2002 [1] and includes an update in the light of advances in PET technology, the introduction of hybrid PET/CT systems and the broadening clinical indications for FDG brain imaging. These guidelines are intended to present information specifically adapted for European practice. The information provided should be taken in the context of local conditions and regulations.