Test-retest reliability of (11)C-ORM-13070 in PET imaging of α2C-adrenoceptors in vivo in the human brain.

PURPOSE: α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes. METHODS: PET imaging with the specific α2C-adrenoceptor antagonist tracer [(11)C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. RESULTS: The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [(11)C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. CONCLUSION: The results of this study support the use of [(11)C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios.

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 (11)C-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.

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.

1-11C-methyl-4-piperidinyl-N-butyrate radiation dosimetry in humans by dynamic organ-specific evaluation.

UNLABELLED: 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-[(11)C]-Methyl-4-piperidinyl-N-butyrate ((11)C-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 (11)C-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 (11)C-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 (11)C-MP4B. Brain input was derived from our previous studies on 18 healthy control subjects and 10 patients with Alzheimer's 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 (11)C 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 microSv/MBq. CONCLUSION: (11)C-MP4B causes less radiation burden than previously studied (11)C-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.

Adenosine A2A receptors in secondary progressive multiple sclerosis: a [(11)C]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 magnetic 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.

Cholinergic activity correlates with reserve proxies in Alzheimer's disease.

The clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain "reserve capacity." A possible association between the cholinergic system and reserve is suggested by preclinical observations that the cholinergic system allows cortical plasticity and by clinical observations of variable responses to cholinergic treatments depending on the patient's educational level. The aim of this study was to investigate the association of reserve proxies, that is, education and occupation, with acetylcholinesterase (AChE) activity, measured voxelwise by [(11)C]-MP4A and positron emission tomography (PET), in 9 healthy controls (HC), 7 patients with early probable AD, and 9 subjects with mild cognitive impairment (MCI) at the time of PET imaging, who progressed to AD at follow-up (prodromal AD). The analysis of prodromal and early AD showed positive correlations between education and AChE activity in the hippocampus, bilaterally, and between occupation and AChE activity in the right posterior cingulate gyrus. The significant correlation between AChE activity in structures belonging to the memory network and reserve proxies suggests that the brain reserve in AD is associated with a preserved/stimulated cholinergic neurotransmission.

[11C]-MP4A PET cholinergic measurements in amnestic mild cognitive impairment, probable Alzheimer's disease, and dementia with Lewy bodies: a Bayesian method and voxel-based analysis.

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.