Riitta Parkkola

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.

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.

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.

Automatic attention orienting by social and symbolic cues activates different neural networks: An fMRI study

Visual attention can be automatically re-oriented by another persons non-predictive gaze as well as by symbolic arrow cues. We investigated whether the shifts of attention triggered by biologically relevant gaze cues and biologically non-relevant arrow cues rely on the same neural systems by comparing the effects of gaze-cued and arrow-cued orienting on blood oxygenation level-dependent (BOLD) signal in humans. Participants detected laterally presented reaction signals preceded by centrally presented non-predictive gaze and arrow cues. Directional gaze cues and arrow cues were presented in separate blocks. Furthermore, two separate control blocks were run in which non-directional cues (straight gaze or segment of a line) were used. The BOLD signals during the control blocks were subtracted from those during the respective blocks with directional cues. Behavioral data showed that, for both cue types, reaction times were shorter on congruent than incongruent trials. Imaging data revealed three foci of activation for gaze-cued orienting: in the left inferior occipital gyrus and right medial and inferior occipital gyri. For arrow-cued orienting, a much more extensive network was activated. There were large postcentral activations bilaterally including areas in the medial/inferior occipital gyri and medial temporal gyri and in the left intraparietal area. Interestingly, arrow cuing also activated the right frontal eye field and supplementary eye field. The results suggest that attention orienting by gaze cues and attention orienting by arrow cues are not supported by the same cortical network and that attention orienting by symbolic arrow cues relies on mechanisms associated with voluntary shifts of attention.

Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans

Inactive brown adipose tissue (BAT) may predispose to weight gain. This study was designed to measure metabolism in the BAT of obese humans, and to compare it to that in lean subjects. The impact of weight loss on BAT and the association of detectable BAT with various metabolic characteristics were also assessed.

Cerebral magnetic resonance imaging and ultrasonography findings after neonatal hypoglycemia.

Objective. The aim of this study was to investigate sequential neuroradiologic changes in the brains of infants after transient neonatal hypoglycemia. We used magnetic resonance imaging (MRI) and ultrasonography (US) head scans. Methods. Eighteen symptomatic full-term infants whose serum glucose concentrations were ≤45 mg/dL (2.5 mmol/L) without any other diseases were included in the hypoglycemic group. MRI and US head scans were performed at full-term age and at the age of 2 months. The imaging results were compared with the findings of MRI and US scans in 19 healthy normoglycemic term newborn infants at the respective ages. The neurologic outcome was followed in the both groups. Results. MRI or US showed evidence of abnormality in 39% the hypoglycemic infants. MRI detected more abnormalities in the brains than US. Four infants showed patchy hyperintensity lesions either in the occipital periventicular white matter or the thalamus on T1-weighted images. These lesions had a good tendency to recover and only 1 of these infants appeared to be neurologically affected. Of the 19 controls, 10% (2 of 19) had caudothalamic cysts, which were detected both with MRI and US. The relative risk of the hypoglycemic child compared with nonhypoglycemic child, to have any abnormality detected in the brain, was 3.7, with a 90% confidence interval from 1.11 to 12.28. Conclusions. Postnatal full-term MRI and US scans showed abnormalities four times more often after transient neonatal hypoglycemia than in the healthy control group. However, most often lesions were absent 2 months later. The clinical relevance of these abnormal findings remains to be clarified with detailed neurologic examinations and follow-up.

S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans.

Background:Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans. Methods:Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500–2,000 ng/ml) concentrations. In addition, subjects’ GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling. Results:The mean ± SD serum S-ketamine concentration was 159 ± 21 ng/ml at the subanesthetic and 1,959 ± 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia. Conclusions:S-ketamine–induced CBF increases exceeded the minor changes in CMRO2 and GMR during anesthesia.

Contribution of Glucose Tolerance and Gender to Cardiac Adiposity

CONTEXT AND OBJECTIVE To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. METHODS Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. RESULTS Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. CONCLUSIONS We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Nonalcoholic Fatty Liver Disease: Rapid Evaluation of Liver Fat Content with In-Phase and Out-of-Phase MR Imaging

PURPOSE To evaluate in-phase and out-of-phase magnetic resonance (MR) imaging in the estimation of liver fat content (LFC) in patients with nonalcoholic fatty liver disease (NAFLD), with hydrogen ((1)H) MR spectroscopy as the reference standard. MATERIALS AND METHODS Written informed consent was obtained from all subjects, and the local ethics committee approved this prospective study protocol. A total of 33 patients with type 2 diabetes mellitus who were at high risk for NAFLD (23 men, 10 women; overall mean age, 62.8 years +/- 8.3 [standard deviation]; age range, 48-77 years) underwent 1.5-T MR imaging with (1)H MR spectroscopy and in-phase and out-of-phase imaging of the liver. Three fat indexes were calculated from the signal intensity (SI) measured on the images. Two radiologists independently graded SI changes between in-phase and out-of-phase images by means of visual inspection. The Pearson correlation coefficient was used to study the relationship between the obtained parameters of SI change and LFC measured with (1)H MR spectroscopy. RESULTS Fat indexes calculated from in-phase and out-of-phase images correlated linearly with LFC measured with (1)H MR spectroscopy (P < .001, r = 0.94-0.96) and were superior (P = .004) to visual estimates (P < .001, r = 0.88). The simple difference in SI between in-phase and out-of-phase images was used to calculate the fat index. An intercept of the regression line with the x-axis was observed at 5.1%, discriminating between normal and elevated LFC with high sensitivity (95%) and specificity (98%). CONCLUSION In-phase and out-of-phase imaging can be used to rapidly estimate the LFC in patients with NAFLD. The cutoff value of 5.1% enables objective rapid and reliable discrimination of normal LFC from elevated LFC.