Jere Virta

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.

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study:

In this study, positron emission tomography (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)—a potent regulator of inflammation—was used to gain insight into the molecular alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional mangnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [ 11 C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution volumes (VT) of [ 11 C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [ 11 C]TMSX-VT in NAWM compared with controls (mean (s.d.): 0.55 (± 0.08) vs. 0.45 (± 0.05);P = 0.036). Both the increased VT and the decreased fractional anisotropy (FA) in NAWM were associated with higher expanded disability status scale (EDSS) scores (P = 0.030 and P = 0.012, respectively), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [ 11 C]TMSX-PET provides a novel approach to learn about central nervous system pathology in SPMS in vivo.

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([18F] DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [18F]DPA-714 binding in healthy subjects and Alzheimers disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [18F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [18F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [18F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.

Cholinergic dysfunction after traumatic brain injury Preliminary findings from a PET study

Objective: There is evidence that the cholinergic system is frequently involved in the cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is altered after TBI in vivo using PET. Methods: Cholinergic function was assessed with [methyl-11C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17 subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally acting drugs for at least 4 weeks. Results: The AChE activity was significantly lower in subjects with TBI compared to controls in several areas of the neocortex (−5.9% to −10.8%, p = 0.053 to 0.004). Conclusions: Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across the neocortex.

Cerebral oxygen and glucose metabolism in patients with mitochondrial m.3243A>G mutation

The m.3243A>G mutation is the most common pathogenic mutation in mitochondrial DNA. It leads to defective oxidative phosphorylation, decreased oxygen consumption and increased glucose utilization and lactate production in vitro. However, oxygen and glucose metabolism has not been studied in the brain of patients harbouring the m.3243A>G mutation. Therefore, 14 patients with the m.3243A>G mutation, not experiencing acute stroke-like episodes and 14 age-matched controls underwent positron emission tomography using 2-[(18)F]fluoro-2-deoxyglucose, [(15)O]H(2)O and [(15)O]O(2) as the tracers during normoglycaemia. The metabolic rate of oxygen and glucose were determined using a quantitative region of interest analysis. Metabolites in unaffected periventricular tissue were measured using magnetic resonance spectroscopy. We found that the cerebral metabolic rate of oxygen was decreased by 26% (range 18%-29%) in the grey as well as the white matter of patients with the m.3243A>G mutation. A decrease in the metabolic rate of glucose was found with predilection to the posterior part of the brain. No major changes were detected in cerebral blood flow or the number of white matter lesions. Our results show that the m.3243A>G mutation leads to a global decrease in oxygen consumption in the grey matter including areas where no other signs of disease were present.

Cerebral acetylcholinesterase activity is not decreased in MS patients with cognitive impairment

Background: Neuropsychological studies have extensively described the presence of cognitive dysfunction in MS patients. One possible pharmacological treatment of the impairment could be based on acetylcholinesterase inhibitors (AChEIs), which have shown efficacy in alleviating cognitive impairment in many other disorders. The findings on the efficacy of AChEI medication in MS associated cognitive symptoms are preliminary and no studies concerning cerebral acetylcholinesterase (AChE) activity in these patients have been published. Objective: The objective of the study was to examine cerebral AChE activity in cognitively deteriorated MS patients. Cerebral AChE activity of 10 MS patients with secondary progressive disease and marked cognitive impairment, and 10 healthy controls, was studied with positron emission tomography using tracer 11C-MP4A. Methods: The cognitive profile of the patients was assessed with CERAD (Consortium to Establish a Registry for Alzheimer’s Disease). Results: No differences in cortical AChE activity between MS patients and controls were seen. Conclusions: In the patient group regional AChE activities had inverse correlations with Word learning and MMSE (Mini-Mental State Examination) scores. In the group of cognitively deteriorated MS patients no change in cerebral AChE activity, compared with controls, was observed, but within the patient group more pronounced cognitive symptoms were associated with higher cerebral AChE activity.

1-11C-Methyl-4-Piperidinyl-N-Butyrate Radiation Dosimetry in Humans by Dynamic Organ-Specific Evaluation

Deficits of cholinergic neurotransmission contribute to various neurologic and psychiatric conditions. The neurotransmitter acetylcholine is hydrolyzed in the synaptic clefts by 2 enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 1-[11C]-Methyl-4-piperidinyl-N-butyrate (11C-MP4B) is a radioligand for the assessment study of BuChE activity in human brain with PET. In the present study the radiation-absorbed doses of the 11C-MP4B were estimated in humans according to the guidelines of the International Commission on Radiological Protection. Two different data acquisition protocols—dynamic organ-specific evaluation (DOSE) and whole-body scanning—were compared. Both methods are widely used for evaluation of radiation burden of 11C-labeled PET tracers. Methods: Fixed-bed PET on the upper neck, thorax, abdomen, or pelvic region was performed on 7 healthy subjects after injection of 707 ± 34 MBq (mean ± SD) of 11C-MP4B. Brain input was derived from our previous studies on 18 healthy control subjects and 10 patients with Alzheimers disease. Regions of interest were drawn on transverse images of all visible organs. Radiation dose estimates were calculated from organ residence times using the MIRDOSE3 software. Urine samples were collected after imaging to estimate tracer extraction. To compare the estimates for absorbed doses between the whole-body scan approach and the DOSE method, we simulated whole-body data acquisition methods used in 11C dosimetry studies with our fixed-bed data. Results: The organs with the highest radiation-absorbed doses were the liver, urinary bladder, kidneys (renal cortex), upper large intestine, trabecular bone, salivary glands, and heart wall. Up to 60% of the injected dose was excreted via the urinary pathway, and the clearance was relatively rapid, as 30% of the radioactivity was excreted within 60 min after injection. With a 2-h voiding interval the effective dose was 4.2 μSv/MBq. Conclusion: 11C-MP4B causes less radiation burden than previously studied 11C-labeled PET tracers. No intolerably high absorbed doses were observed in critical organs. With 740 MBq of injected radioactivity, the radiation burden is equivalent to 3.11 mSv. This would allow multiple PET examinations per year to be performed on the same subject. The DOSE method and the simulated whole-body imaging approach produced similar results.

Parametric Binding Images of the TSPO Ligand 18F-DPA-714

18F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. Methods: Ninety-minute dynamic 18F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input–based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images. Results: Plasma-input Logan analysis (r2 = 0.99; slope, 0.88) and spectral analysis (r2 = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r2 = 0.83; slope, 0.95) and reference Logan analysis (r2 = 0.88; slope, 1.01) correlated well with nonlinear regression–based estimates. Conclusion: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.

Brain Cholinergic Function and Response to Rivastigmine in Patients With Chronic Sequels of Traumatic Brain Injury: A PET Study.

Objective: To investigate quantitative positron emission tomography (PET) findings and to study whether the cholinergic function differs between respondents to cholinergic medication versus nonrespondents. Setting: Outpatient clinic and university PET imaging center. Participants: We studied 17 subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication. Design: Cholinergic function was assessed with [methyl-11C] N-methylpiperidyl-4-acetate-PET (11C-MP4A-PET), which reflects the activity of the acetylcholinesterase (AChE) enzyme. The subjects were PET scanned twice: without medication and after a 4-week treatment with rivastigmine 1.5 mg twice a day. Measures: Regional cerebral AChE activity was measured with PET. Results: At baseline Statistical Parametric Mapping analyses showed significantly lower AChE activity in respondents bilaterally in the frontal cortex as compared with nonrespondents. Region of interest (ROI) analysis revealed that the difference was most pronounced in the lateral frontal cortex (−9.4%, P = .034) and anterior cingulate (−6.0%, P = .049). After rivastigmine treatment, AChE activity was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them. Conclusion: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury.

Human subject with unexpected biodistribution of [11C]PK11195

[N-Methyl11 C](R)-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinoline carboxamide [ 11 C]PK11195 is a widely used radiopharmaceutical for in vivo assessment of translocator protein 18 kDa (TSPO) activity using positron emission tomography. Here we present an interesting case of unusual distribution of [ 11 C]PK11195, that is a lack of uptake in tissues known for high expression of the TSPO.