Structural and neurochemical evaluation of the brain and pons in patients with Wilson’s disease

Purpose  

The aim of this study was to examine the structural-neurochemical abnormalities of the frontal white matter (FWM), deep gray matter nuclei, and pons in patients with Wilson’s disease (WD) using proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI).     

Dopamine transporter imaging and the effects of deep brain stimulation in patients with Parkinson’s disease

Purpose Single-photon emission computed tomography (SPECT) with [¹²³I]FP-CIT is a marker for loss of presynaptic dopamine transporters in the striatum in Parkinson’s disease (PD). We used [¹²³I]FP-CIT SPECT in order to evaluate binding to the dopamine transporter before and after neurosurgical treatment with bilateral stimulation in the subthalamic nucleus (STN). Methods Thirty-five patients with levodopa-responsive PD were examined with [¹²³I]FP-CIT SPECT pre-operatively (baseline scan: mean 3 months before surgery), and 3 and 12 months after surgery. Results Pre-operatively, all patients already had substantial signs of severe nigrostriatal neuronal loss as determined from the [¹²³I]FP-CIT SPECT scans. One year after surgery the specific [¹²³I]FP-CIT binding to the striatum was significantly reduced by 10.3% compared with the pre-operative baseline scan. The mean time span from the baseline scan before surgery to the follow-up scan 1 year after surgery was 16.2 months. Hence, the rate of reduction equals a mean annual reduction of 7.7%. A comparable control group of patients with PD who did not undergo surgery was also examined longitudinally. In this group the specific binding of [¹²³I]FP-CIT was reduced by 6.7% per year. Conclusion The specific binding of [¹²³I]FP-CIT was reduced equally in the STN-stimulated patients and a group of non-operated PD patients with advanced disease. Our study does not support the notion that electrode implantation and STN stimulation exert a neuroprotective effect by themselves.     

Non-invasive grading of primary brain tumours: Results of a comparative study between SPET with123I-α-methyl tyrosine and PET with18F-deoxyglucose

Use of iodine-123--methyl tyrosine (¹²³I-IMT) allows investigation of the amino acid transport rate in gliomas. It was the aim of this study to compare the value of measurement of glucose metabolism with that of measurement of¹²³I-IMT uptake for the non-invasive grading of brain tumours. The study population comprised 23 patients with histopathologically proven primary brain tumours; 14 had high-grade gliomas, and nine low-grade brain neoplasms. Glucose metabolism was studied using an ECAT EXACT 47 positron emission tomography (PET) camera and fluorine-18 fluorodeoxyglucose (¹⁸F-FDG);¹²³I-IMT uptake was measured with the triple-headed single-photon emission tomography (SPET) camera, MULTISPECT 3.¹⁸F-FDG and¹²³I-IMT uptake was quantified as ratios between the uptake by the tumour and contralateral regions of reference. Glucose metabolism and amino acid uptake of the brain tumours correlated significantly (r=0.71,P <0.001). Assuming discrimination thresholds between high-grade and low-grade tumours of 0.8 for¹⁸F-FDG uptake and 1.8 for¹²³I-IMT uptake, the accuracy values of¹⁸F-FDG PET and¹²³I-IMT SPET for differentiating between high-grade and low-grade tumours were 21/23 (91%) and 19/23 (83%), respectively. The difference in diagnostic performance was not significant on receiver operating characteristic analysis (P >0.4). It is concluded that there is no major difference between the PET investigation of glucose metabolism and the less expensive SPET measurement of amino acid uptake in terms of their accuracy in evaluating the malignancy grade of primary brain tumours. This encourages the performance of further studies to analyse the potential impact of¹²³I-IMT SPET on the therapeutic management of patients with brain tumours.     

Validation of cardiac 123I-MIBG scintigraphy in patients with Parkinson’s disease who were diagnosed with dopamine PET

Purpose  

The aim of this study was to evaluate the diagnostic potential of cardiac ¹²³I-labelled metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy in idiopathic Parkinson’s disease (PD). The diagnosis was confirmed by positron emission tomography (PET) imaging with ¹¹C-labelled 2β-carbomethoxy-3β-(4-fluorophenyl)-tropane (¹¹C-CFT) and ¹¹C-raclopride (together designated as dopamine PET).     

Apparent diffusion coefficient vale of the brain in patients with Gaucher’s disease type II and type III

Introduction  

The aim of this work is to assess the usefulness of apparent diffusion coefficient (ADC) value of the brain for diagnosis of patients with Gaucher’s disease type II and type III.     

Detection and appearance of intraparenchymal haematomas of the brain at 1.5 T with spin-echo, FLAIR and GE sequences: poor relationship to the age of the haematoma

The specific appearance of blood related to time at T1- and T2-weighted spin-echo (SE) sequences is generally accepted; thus, these sequences are classically used for estimating the age of haematomas. Magnetic resonance imaging at 1.5 T, including T1- and T2-weighted SE fluid-attenuated inversion recovery (FLAIR) and T2*-weighted gradient-echo (GE) sequences, was performed on 82 intraparenchymal haematomas (IPHs) and 15 haemorrhagic infarcts (HIs) in order to analyse the appearance at different stages and with different sequences, and to investigate how reliably the age of hematomas can be estimated. The IPHs had been previously detected by CT, were spontaneous (n=72) or traumatic (n=10) in origin and were of different sizes (2 mm to 7 cm) and ages (from 7.5 h to 4 years after acute haemorrhagic event). The age of the lesion was calculated from the moment when clinical symptoms started or the traumatic event occurred. The 15 patients with HIs were patients with ischaemic stroke in whom there was either a suspicion of haemorrhagic transformation on CT, or haemorrhage was detected as an additional finding on MR performed for other indications. Patients with conditions that could affect the SI of blood, such as anticoagulant therapy or severe anaemia, were excluded. The signal intensity pattern of the lesions was analysed and related to their ages without prior knowledge of the clinical data. All lesions were detected with T2*-weighted GE. T1-weighted SE missed 13 haematomas and T2-weighted SE and FLAIR sequences missed five. Haemorrhagic transformation was missed in three infarcts by T1-, T2-weighted SE and FLAIR. The signal pattern on FLAIR was identical to that on T2-weighted SE. For all sequences, a wide variety of signal patterns, without a clear relationship to the age of the haematomas, was observed. There was a poor relationship between the real MR appearance of IPHs and the theoretical appearance on SE sequences. T2*-weighted GE was effective for detecting small bleedings but was not useful for estimating the age of a lesion. The FLAIR does not provide any more information than T2-weighted SE.This work was presented at the XXVIII ESNR congress, in Istanbul, Turkey, September 2003     

Imaging of dopamine transporters and D<Subscript>2</Subscript> receptors in patients with Parkinson’s disease and multiple system atrophy

Purpose The aim of this study was to ascertain whether combined presynaptic and postsynaptic dopaminergic single-photon emission computed tomography (SPECT) scanning is useful for differentiation between patients with idiopathic Parkinsons disease (IPD), patients with multiple system atrophy of the striatonigral type (MSA) and healthy subjects.Methods SPECT measurements of the dopamine transporter (DAT) were done with ¹²³I--CIT, while for determination of the dopamine D₂-like receptors (D₂), ¹²³I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight patients with MSA and 11 healthy age-matched control subjects.Results Putaminal DAT binding was reduced to 32% of control values in IPD and to 19% of control values in MSA . Significantly higher striatal asymmetry in DAT binding was found in MSA than in controls, but IPD patients had significantly higher asymmetry than MSA patients. Striatal D₂ binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D₂ binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account.Conclusion Patients with reduced striatal ¹²³I--CIT binding and a side-to-side difference greater than 15% are likely to suffer from IPD. Patients with reduced striatal ¹²³I--CIT binding and a side-to-side difference of between 5% and 15% are more likely to have MSA. ¹²³I-epidepride SPECT measurements may add further diagnostic information, since the ratio between DAT and D₂ receptor binding is significantly higher in IPD than in MSA.     

Where have we got to with neuroreceptor mapping of the human brain?

In the past two decades, tritiated radioligand receptor binding, a tool commonly used to investigate the site of action of drugs in laboratory animals, has provided a vast body of information on neuropharmacology and neurobiology. Several neurological and psychiatric diseases have been related to neurotransmitter and receptor disorders. In order to study ligand interactions with receptors in vivo in humans, new tracers capable of carrying a-emitting radionuclide to the receptor have been designed. Emission computerized tomography (ECT) techniques such as positron (PET) or single photon emission tomography (SPET) allow monitoring of the time-course of regional tissue concentration of these radiolabelled ligands. PET and SPET each have their inherent advantages and drawbacks. The cyclotron-based technology of PET is a demanding and expensive technique that, to date, is still mainly reserved for research purposes. It is hoped that once the scientific basis of a physiopathological study is established using PET, diagnostic information might be provided by the more readily available SPET technology. The purpose of this article is to review the current state of receptor-binding-emitting radioligands and to present the clinical potential of these new kinds of radiopharmaceuticals in clinical investigation.     

Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline

Purpose

In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD.

Methods

This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [¹¹C]-_L-deprenyl-D₂ radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6–15 days.

Results

At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an E_max of ～80–90 % across brain regions of interest and in an EC₅₀ of 1–2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition.

Conclusions

This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.

     

Kinetics of the uptake and distribution of the dopamine D(2,3) agonist (R)-N-[1-(11)C]n-propylnorapomorphine in brain of healthy and MPTP-treated Göttingen miniature pigs

The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized G?ttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.     

The effect of levodopa therapy on dopamine transporter SPECT imaging with 123I-FP-CIT in patients with Parkinson’s disease

Purpose The aim of this study was to evaluate, by means of ¹²³I-FP-CIT SPECT, the effect of chronic treatment with levodopa on striatal dopamine transporter (DAT) in patients with Parkinsons disease.Methods Fifteen patients under stable levodopa/carbidopa monotherapy were imaged twice: at baseline on medication and after at least 20 days of treatment wash-out. DAT levels were assessed from SPECT imaging for the entire striatum, the right and left striatum, the right and left putamen and the right and left caudate, as a ratio of regional brain activities using the formula: (striatal region of interest–occipital)/occipital.Results During levodopa wash-out, despite a worsening in patients clinical disability (H&Y mean stage 2.53±0.58 versus 1.73±0.45 on therapy, p<0.001), striatal ¹²³I-FP-CIT levels were not significantly different from those at baseline in any of the brain regions examined.Conclusion The results of this study suggest that levodopa does not affect ¹²³I-FP-CIT brain imaging and confirm that it is not necessary to withdraw this medication to measure DAT levels with SPECT.     

Differential kinetics of [123I]β-CIT binding to dopamine and serotonin transporters

Iodine-123-labelled 3-(4-iodophenyl)tropane-2-carboxylic acid ([¹²³I]-CIT) labels both the dopamine transporter (DAT) and the serotonin transporter (5-HTT) and this ligand is able to clarify pathological changes in both dopaminergic and serotonergic systems. However, the differential kinetics of -CIT binding to DAT and 5-HTT has not been clarified fully. In this study we examined time-activity curves of [¹²³I]-CIT in individual regions in the rat brain. Using cerebellum as the reference region,k ₃ andk ₄ values were estimated by a two-compartment kinetic analysis. In the striatum, the kinetics was slowest among all brain areas. In this area specific binding reached its peak 4 h after the injection. In the hypothalamus, specific binding reached its peak 1 h after the injection and its amount did not change until 4 h after the injection. In the occipital cortex, the binding and washout of the ligand were fastest among all brain regions. Estimatedk ₃ values were 0.040±0.003 in the striatum, 0.019±0.002 in the hypothalamus and 0.082±0.011 in the occipital cortex (min^–t, mean ±SD). Estimatedk ₄ values were 0.0034±0.0005 in the striatum, 0.0071±0.0009 in the hypothalamus and 0.083±0.013 in the occipital cortex (min^–1, mean ±SD). Therefore binding kinetics of [¹²³I]-CIT in the region rich in DAT is apparently different from that in the region rich in 5-HTT. These results will provide fundamental data to image both DAT and 5-HTT in one series of examinations with [¹²³I]-CIT.     

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine—an in vivo imaging study with a dedicated small animal SPECT

Purpose This study assessed [¹²³I]iodobenzamide binding to the rat dopamine D₂ receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT.Methods Subsequent to baseline quantifications of D₂ receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D₂ receptors and dopamine transporters, respectively.Results Striatal baseline equilibrium ratios (V₃) of [¹²³I]iodobenzamide binding were 1.42±0.31 (mean±SD). After pre-treatment with haloperidol and methylphenidate, V₃ values decreased to 0.54±0.46 (p<0.0001) and 0.98±0.48 (p=0.009), respectively.Conclusion The decrease in [¹²³I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D₂ receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [¹²³I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [¹²³I]iodobenzamide binding to D₂ receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.     

Proton MR Spectroscopy of the brain in children with neuronopathic Gaucher’s disease

Objective

To assess the clinical usefulness of proton magnetic resonance spectroscopy (¹H-MRS) in children with neuronopathic Gaucher’s disease (NGD).

Methods

A prospective study was conducted upon 21 consecutive children with acute (n?=?7) and chronic (n?=?14) forms of NGD (13 boys, 8 girls; mean age 37 months) and for a control group (n?=?15). All patients and controls underwent ¹H-MRS of frontal white matter. The choline/creatine (Ch/Cr) and N-acetyl aspartate (NAA)/Cr ratios were calculated. A modified severity scoring tool (m-SST) of NGD was calculated and genotyping was performed for all patients. Metabolic ratios were correlated with clinical types, m-SST and genotyping.

Results

There was a significant difference in Ch/Cr (P?=?0.001) between patients with NGD and the control group. Lipid peak was detected in 15 patients with NGD. Patients with acute NGD revealed higher m-SST (P?=?0.001) and Ch/Cr (P?=?0.001) compared with the chronic form. Patients with homozygous gene mutation (L444P/L444P) had significantly higher m-SST (P?=?0.001) and Ch/Cr (P?=?0.013) than those with the heterozygous gene mutation (L444P/other). The Ch/Cr was negatively correlated with m-SST (r?=??0.682; P?=?0.001)

Conclusion

¹H-MRS can be used to detect brain abnormalities in children with NGD and Ch/Cr is well correlated with m-SST and genotyping.

Key Points

? Proton magnetic resonance spectroscopy offers important information in some paediatric neurological conditions. ? Significantly different choline/creatine ratios were found between neuronopathic Gaucher’s disease and controls. ? Lipid peak helps with the diagnosis of neuronopathic Gaucher’s disease. ? Ch/Cr correlated with the modified severity scoring tool of Gaucher’s disease.     

Evaluation of the effects of chemotherapy on brain glucose metabolism in children with Hodgkin’s lymphoma

Annals of Nuclear Medicine - Chemobrain is a recently proposed pathological entity. 18F-FDG PET/CT can show objective abnormalities to explain brain disorders caused by chemotherapy, although no...     

Cranial CT with 64-, 16-, 4- and single-slice CT systems–comparison of image quality and posterior fossa artifacts in routine brain imaging with standard protocols

Posterior fossa artifacts constitute a characteristic limitation of cranial CT. To identify practical benefits and drawbacks of newer CT systems with reduced collimation in routine cranial imaging, we aimed to investigate image quality, posterior fossa artifacts and parenchymal delineation in non-enhanced CT (NECT) with 1-, 4-, 16- and 64-slice scanners using standard scan protocols. We prospectively enrolled 25 consecutive patients undergoing NECT on a 64-slice CT. Three groups with 25 patients having undergone NECT on 1-, 4- and 16-slice CT machines were matched regarding age and sex. Standard routine CT parameters were used on each CT system with helical acquisition in the posterior fossa; the parameters varied regarding collimation and radiation dose. Three blinded readers independently assessed the cases regarding image quality, infra- and supratentorial artifacts and delineation of brain parenchymal structures on a five-point ordinal scale. Reading orders were randomized. A proportional odds model that accounted for the correlated nature of the data was fit using generalized estimating equations. Posterior fossa artifacts were significantly reduced, and the delineation of infratentorial brain structures was significantly improved with the thinner collimation used for the newer CT systems (p<0.001). No significant differences were observed for midbrain structures (p>0.5). The thinner collimation available on modern CT systems leads to reduced posterior fossa artifacts and to a better delineation of brain parenchyma in the posterior fossa.     

Are there adaptive changes in the human brain of patients with Parkinson’s disease treated with long-term deep brain stimulation of the subthalamic nucleus? A 4-year follow-up study with regional cerebral blood flow SPECT

Purpose The aim of this follow-up study was to assess persistent motor and regional cerebral blood flow (rCBF) changes in patients with Parkinson’s disease (PD) treated with high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN). Methods Ten PD patients with STN-DBS underwent three rCBF SPECT studies at rest, once preoperatively in the off-drug condition (T₀), and twice postoperatively in the off-drug/off-stimulation conditions at 5 ± 2 (T₁) and 42 ± 7 months (T₂). Patients were assessed using the UPDRS, H&Y and S&E scales. SPM was used to investigate baseline rCBF changes from the preoperative condition to the postoperative conditions and the relationship between rCBF and UPDRS scores used as covariate of interest. Results Parkinsonian patients showed a clinical improvement which was significant only on follow-up at 42 months. The main effect of treatment from T₀ to T₁ was to produce baseline rCBF increases in the pre-supplementary motor area (pre-SMA), premotor cortex and somatosensory association cortex. From T₁ to T₂ a further baseline rCBF increase was detected in the pre-SMA (p < 0.0001). A correlation was detected between the slight improvement in motor scores and the rCBF increase in the pre-SMA (p < 0.0001), which is known to play a crucial role in clinical progression. Conclusion Our study suggests the presence of adaptive functional changes in the human brain of PD patients treated with long-term STN-DBS. Such adaptive processes seem to occur in the pre-SMA and to play only a slightly beneficial role in terms of functional compensation of motor impairment.     

Molecular nature of mutations induced by irradiation with repeated low doses of X‐rays in spleen,liver, brain and testis of lacZ‐transgenic mice

Purpose: To investigate the molecular characteristics of mutations induced by repeated low doses of X‐rays in spleen, liver, brain and testis of mice.

Materials and methods: Muta^? mice, which harbour the lacZ gene contained in the lambda genome, were irradiated with 0.15?Gy every Monday, Wednesday and Friday for 6 months starting at 10 weeks of age for a total of 78 times. Four months after the last irradiation, DNAs were isolated from the four different tissues and the mutant frequencies of lacZ were determined. Next, the nucleotide sequences of the mutant lacZ genes were determined and compared with that of the wild‐type to identify the molecular changes in the mutants. The frequencies of different types of mutations were compared with those found in age‐matched non‐irradiated mice. They were also compared with those found in mice irradiated with a single high dose.

Results: The repeated low‐dose irradiation resulted in slight increases in the mutant frequency in the four kinds of tissues. The spleen, liver and brain in repeatedly irradiated mice showed higher frequencies of deletion type mutations than those of non‐irradiated mice. In testis, however, the level of the increase was modest and not statistically significant. Complex type mutations were observed only in irradiated tissues. The characteristics observed in somatic tissues were similar to those induced by a single high dose of irradiation.

Conclusions: The results suggest that the mechanism of mutation induction in vivo is similar between low‐ and high‐dose irradiation in spleen, liver and brain. The low induction of deletion mutations in testis with low‐dose irradiation suggests that spermatogonial cells have a unique DNA repair system against low‐dose radiation‐induced damage.