Nina Kemppainen

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.

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.

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

The reduced risk for Alzheimers 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.

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.

Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer's disease

Post mortem studies have revealed a loss of dopamine D2 receptors in the temporal lobes in Alzheimers disease (AD). Moreover, the role of hippocampal D2 receptors on memory performance has been suggested in experimental studies. However, there are no previous in vivo studies on extrastriatal D2 receptors in AD. Our aim was to examine in vivo whether hippocampal or temporal cortical dopamine D2 receptors are affected in AD and whether D2 receptor availability is associated with the memory dysfunction seen in AD. Fourteen patients with probable AD and 11 age‐ and sex‐matched controls were studied with positron emission tomography using a dopamine D2/D3 receptor antagonist [11C]FLB 457. The D2 receptor binding potentials (BPs) were measured in extrastriatal brain regions and a neuropsychological investigation was performed on the patients with AD. In AD, the D2 receptor availability was reduced in the hippocampus: by 34% (P = 0.03) in the right hippocampus and by 14% (P = 0.78) in the left hippocampus as compared with controls. Multiple linear regression analysis showed that the BP in the right hippocampus had a significant positive association with verbal memory performance (Wechsler Memory Scale – Revised) (P = 0.001) and picture naming (the Boston Naming Test) (P = 0.002). Our findings suggest a role for temporal lobe D2 receptors in the memory and naming performance in AD, and suggest that studies to evaluate the efficiency of dopaminergic medication on patients with early AD might be warranted.

In vivo mapping of amyloid toxicity in Alzheimer disease

Objective: To study the relationship between gray matter atrophy and amyloid deposition in Alzheimer disease (AD). Methods: Volumetric magnetic resonance (MR) and [11C]-PIB PET were acquired from 23 patients with AD and 17 healthy older persons. Standardized [11C]-PIB uptake values were coregistered to MR scans in a standard space. Decreased density of and increased [11C]-PIB uptake in the gray matter of patients with AD vs controls were assessed with both voxel-based (p < 0.05 corrected) and region-of-interest (ROI) analyses. The relationship between decreased density of and increased [11C]-PIB uptake in the gray matter was investigated with voxel-based Pearson r maps (thresholded at p < 0.05) and ROI linear regression plots. Results: Atrophy mapped to the hippocampus and increased [11C]-PIB uptake to large frontal, parietal, and posterior cingulate cortical areas. ROI analysis showed the largest effect size for atrophy in the hippocampus (2.01) and amygdala (1.27) and the highest effect size for [11C]-PIB uptake in frontal (2.66), posterior cingulate/retrosplenial (2.43), insular (2.41), and temporal (2.23) regions. In the hippocampus, [11C]-PIB uptake was significantly increased, but effect size was milder (1.72). Significant correlations between atrophy and increased [11C]-PIB uptake were found in the hippocampal (r = −0.54) and amygdalar ROIs (r = −0.40) but not in the frontal, temporal, posterior cingulate/retrosplenial, insular, and caudate ROIs (r between 0.04 and 0.25). Conclusion: The medial temporal lobe might be highly susceptible to amyloid toxicity, whereas neocortical areas might be more resilient.

PET shows that striatal dopamine D1 and D2 receptors are differentially affected in AD

Objective: To study dopamine D1 and D2 receptors in the putamen and the caudate nucleus in patients with AD and age-matched healthy controls by means of PET. Methods: A dopamine D1 receptor antagonist ([11C]NNC 756) and a D2 receptor antagonist ([11C]raclopride) were used as ligands. The uptake of these ligands was calculated as a distribution volume ratio of the putamen and the caudate nucleus to the cerebellum. Results: The mean [11C]NNC 756 uptake in AD was reduced by 14% from the mean control value both in the putamen (p = 0.004) and the caudate nucleus (p = 0.009). There was no significant reduction in the mean [11C]raclopride uptake in either the putamen or the caudate nucleus in AD. There was no correlation between [11C]NNC 756 or [11C]raclopride uptake and Mini-Mental State Examination or motor Unified PD Rating Scale scores in patients with AD. Conclusions: There are changes in striatal D1 but not in D2 receptors in AD.

Carbon 11-Labeled Pittsburgh Compound B Positron Emission Tomographic Amyloid Imaging in Patients With APP Locus Duplication

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.

Age‐related loss of extrastriatal dopamine D2‐like receptors in women

Positron emission tomography (PET) studies have indicated that the in vivo availability of dopamine D2‐like receptors declines with age in the human brain. Most of the studies have been carried out with healthy male subjects, or with subject groups containing both sexes. The authors have recently demonstrated that the availability of D2‐like receptors in the frontal cortex is higher in women than in men. The present study was aimed to further examine this phenomenon. Thirty‐seven healthy women (age range 22–78 years) were examined with PET and [11C]FLB 457, a high‐affinity tracer for the extrastriatal D2‐like receptors. A negative relationship between age and dopamine D2‐like receptor availability was seen in the frontal cortex (decrease of 12% per decade of life), the temporal cortex (9%) and the thalamus (6%). A non‐linear s‐shape association explained the relationship only in the frontal cortex, while in other regions the association was linear. Neither oestradiol nor progesterone levels had a significant relationship with the [11C]FLB 457 uptake in any of the brain regions studied after the effect of age was partialled out. The results indicate that: (i) the extrastriatal D2‐like receptor availability decreases with age in healthy women with the fastest rate in the frontal cortex and with the overall rate close to the rate reported in healthy men; (ii) around midlife (age 40–60 years) in women, the frontal receptor decline plateaus while the decline continues to be linear in other extrastriatal brain regions; and (iii) serum oestradiol or progesterone levels are not associated with cortical or thalamic D2‐like receptor availability in women. The results may prove to be important in studies where the biochemical basis of clinical sex differences is examined in patients with dopamine‐related neuropsychiatric disorders.