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1.  99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events 
PLoS ONE  2014;9(3):e92729.
Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4−) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4− required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4−–mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.
PMCID: PMC3963936  PMID: 24663284
2.  No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT 
EJNMMI Research  2013;3:39.
Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers.
A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor.
There was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers.
Our results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.
PMCID: PMC3671201  PMID: 23688063
Tobacco smoking; Non-smoking; SPECT; [123I]FP-CIT (DaTSCAN); Dopamine transporter
3.  Normalisation to Blood Activity Is Required for the Accurate Quantification of Na/I Symporter Ectopic Expression by SPECT/CT in Individual Subjects 
PLoS ONE  2012;7(3):e34086.
The utilisation of the Na/I symporter (NIS) and associated radiotracers as a reporter system for imaging gene expression is now reaching the clinical setting in cancer gene therapy applications. However, a formal assessment of the methodology in terms of normalisation of the data still remains to be performed, particularly in the context of the assessment of activities in individual subjects in longitudinal studies. In this context, we administered to mice a recombinant, replication-incompetent adenovirus encoding rat NIS, or a human colorectal carcinoma cell line (HT29) encoding mouse NIS. We used 99mTc pertechnetate as a radiotracer for SPECT/CT imaging to determine the pattern of ectopic NIS expression in longitudinal kinetic studies. Some animals of the cohort were culled and NIS expression was measured by quantitative RT-PCR and immunohistochemistry. The radioactive content of some liver biopsies was also measured ex vivo. Our results show that in longitudinal studies involving datasets taken from individual mice, the presentation of non-normalised data (activity expressed as %ID/g or %ID/cc) leads to ‘noisy’, and sometimes incoherent, results. This variability is due to the fact that the blood pertechnetate concentration can vary up to three-fold from day to day. Normalisation of these data with blood activities corrects for these inconsistencies. We advocate that, blood pertechnetate activity should be determined and used to normalise the activity measured in the organ/region of interest that expresses NIS ectopically. Considering that NIS imaging has already reached the clinical setting in the context of cancer gene therapy, this normalisation may be essential in order to obtain accurate and predictive information in future longitudinal clinical studies in biotherapy.
PMCID: PMC3309932  PMID: 22470517
4.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Patients were recruited from 40 European centres.
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
PMCID: PMC3330257  PMID: 22318660

Results 1-4 (4)