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1.  Quantitative assessment of overall inflammatory bowel disease activity using labelled leucocytes: a direct comparison between indium-111 and technetium-99m HMPAO methods. 
Gut  1995;37(5):679-683.
The ideal imaging method in inflammatory bowel disease would reliably detect inflammation, identify the correct intestinal location, and assess the severity of the disease. The aim of this study was to compare scintigraphic methods of quantifying overall disease activity using both indium-111 (111In) and technetium-99M (99mTc) HMPAO labelled leucocyte scans. The four day faecal excretion of 111In was measured after 111In scintigraphy in 24 patients known to have inflammatory bowel disease. The same patients also underwent 99mTc HMPAO scanning. The scans were performed 10 days or less apart with no changes in treatment between scans. Bowel activity on the 99mTc HMPAO scans was assessed using a computer based method (scan score) and a visual grading method in a further 54 99mTc HMPAO. The results showed a close correlation between inflammatory activity defined by faecal 111In excretion and the scan score generated from the computer analysis of the 99mTc HMPAO image (Spearman rank correlation: rs = 0.78; p < 0.001). Accurate information to localise inflammatory activity could be obtained by simple visual assessment of both types of scan images, although image quality was superior with 99mTc HMPAO. Qualification of disease activity from 99mTc HMPAO images by visual grading was associated with a large variability, only 69% of scans had similar scores when graded by three observers. Computer generated image analysis was more reproducible. In conclusion, in inflammatory bowel disease 99mTc HMPAO scintigraphy and faecal 111In excretion correlated well. Either method can quantify and localise the inflammation. As 99mTc HMPAO scanning provides a quicker result, with a lower radiation dose, and avoids faecal collection, it may be the preferred method.
PMCID: PMC1382874  PMID: 8549945
2.  A comparative study of perfusion CT and 99mTc-HMPAO SPECT measurement to assess cerebrovascular reserve capacity in patients with internal carotid artery occlusion 
Background and purpose
Patients with internal carotid artery (ICA) occlusion can demonstrate impaired cerebral vascular reserve (CVR). The detection of CVR using single photon emission CT (SPECT) is nowadays widely accepted as a predictor in the diagnostic pathway in patients considered for cerebral revascularization. Recently perfusion CT (PCT) gained widely acceptance in stroke imaging The present study was aimed at comparing the results of perfusion CT (PCT) and 99mTc-HMPAO SPECT with acetazolamide challenge in patients with ICA occlusion.
13 patients were included in the prospective evaluation. Both PCT and 99mTc-HMPAO SPECT were performed before and after the administration of acetazolamide. In detail, regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), adapted time to peak (Tmax) and mean transit times (MTT) were compared with SPECT data.
99mTc-HMPAO SPECT demonstrated an impairment of CVR in six patients. A preserved CVR was present in seven patients. All patients with impaired CVR proven by SPECT had a delayed MTT (mean +2.98 s) and a delayed Tmax (mean + 5.9 s), (both p < 0.005 compared with the non occluded side). 66% of patients with impaired CVR in SPECT showed a complete correlation of Tmax measurements in PCT with a high positive predictive value (PPV: 88.8%).
The prospective study demonstrated a highly significant correlation of perfusion parameters as' detected by 99mTc-HMPAO SPECT and the Tmax as detected by PCT in patients with ICA occlusion. Therefore this easy-to-perform technique seems to be an adequate method for the evaluation of cerebral perfusion in patients with ICA occlusion.
PMCID: PMC3351805  PMID: 22027641
cerebral vascular reserve; perfusion CT; SPECT; internal carotid artery occlusion
3.  Imaging of perfusion, angiogenesis, and tissue elasticity after stroke 
Blood flow interruption in a cerebral artery causes brain ischemia and induces dramatic changes of perfusion and metabolism in the corresponding territory. We performed in parallel positron emission tomography (PET) with [15O]H2O, single photon emission computed tomography (SPECT) with [99mTc]hexamethylpropylene-amino-oxime ([99mTc]HMPAO) and ultrasonic ultrafast shear wave imaging (SWI) during, immediately after, and 1, 2, 4, and 7 days after middle cerebral artery occlusion (MCAO) in rats. Positron emission tomography and SPECT showed initial hypoperfusion followed by recovery at immediate reperfusion, hypoperfusion at day 1, and hyperperfusion at days 4 to 7. Hyperperfusion interested the whole brain, including nonischemic areas. Immunohistochemical analysis indicated active angiogenesis at days 2 to 7, strongly suggestive that hyperperfusion was supported by an increase in microvessel density in both brain hemispheres after ischemia. The SWI detected elastic changes of cerebral tissue in the ischemic area as early as day 1 after MCAO appearing as a softening of cerebral tissue whose local internal elasticity decreased continuously from day 1 to 7. Taken together, these results suggest that hyperperfusion after cerebral ischemia is due to formation of neovessels, and indicate that brain softening is an early and continuous process. The SWI is a promising novel imaging method for monitoring the evolution of cerebral ischemia over time in animals.
PMCID: PMC3421095  PMID: 22491156
middle cerebral artery occlusion; PET; shear wave imaging; SPECT; stroke; ultrasound
4.  Brain perfusion abnormalities in Alzheimer's disease: comparison between patients with focal temporal lobe dysfunction and patients with diffuse cognitive impairment 
OBJECTIVES—Patients with Alzheimer's disease (AD) showing a selective impairment of episodic and semantic memory have recently been classified as affected by focal temporal lobe dysfunction (FTLD) and considered as a distinct subgroup of patients affected by a particular form of AD. The aim was to compare the cerebral perfusion of patients with AD with FTLD and patients with AD with the more typical profile of diffuse cognitive impairment (dAD).
METHODS—Ten patients with AD with FTLD, 14 patients with AD with dAD, and 12 normal controls were studied. All the 24 patients with AD underwent a complete neuropsychological assessment. SPECT examination with [99mTc]-HMPAO, using a four head brain dedicated tomograph, was performed in patients and controls. Tracer uptake was quantified in 27 regions of interest (ROIs), including lateral and mesial temporal areas. Mean counts in the 27 ROIs of controls, patients with FTLD and those with dAD were compared using an ANOVA for repeated measures with Bonferroni's correction. A logistic regression analysis, followed by a receiver operating characteristic (ROC) analysis, was also applied to select SPECT patterns which significantly differentiated patients with FTLD and those with dAD.
RESULTS—Two scintigraphic patterns of abnormalities, shaping a double dissociation between the FTLD and dAD groups, emerged: a bilateral mesial temporal hypoperfusion, characteristic of FTLD and a posterior parietal (and temporal parietal) hypoperfusion characteristic of patients with dAD.
CONCLUSIONS—These scintigraphic findings provide further support to the hypothesis that FTLD is not a mere stage but a distinct anatomoclinical form of AD. The combination of neuropsychological tests and [99mTc]-HMPAO SPECT may be very useful in identifying patients with FTLD from the wider group of patients with dAD. This issue is particularly worthwhile, as there is increasing evidence that patients with FTLD have a slower rate of cognitive decline.

PMCID: PMC1763484  PMID: 11118243
5.  Increased uptake of 99mTc-HMPAO in necrotic brain tumors. 
Journal of Korean Medical Science  1998;13(5):529-532.
99mTc complex of hexamethylpropylene amine oxime (99mTc-HMPAO), which has been used as a tracer for regional cerebral blood flow (rCBF), has been shown to localize in primary brain tumors with wide spectrum of its uptake. The causes of the wide spectrum of tumor uptake, however, has not been understood in detail. We performed autoradiographic study with this agent to get further knowledge about HMPAO distribution in 10 cases of transplanted rat gliomas. Eight cases of rat gliomas without tumor necrosis, showed decreased uptake of 99mTc-HMPAO in the autoradiography (average tumor/normal (T/N) uptake ratio: 0.75, range: 0.40-0.90). On the other hand, two cases with tumor necrosis revealed increased uptakes of this agent in central necrotic area. T/N uptake ratios of these two cases were 1.23 and 1.42, respectively. In addition, three patients with histologically proven glioblastoma with tumor necrosis were studied after administration of 20mCi 99mTc-HMPAO. Two out of three patients showed higher uptake of 99mTc-HMPAO in tumor necrotic area than the contralateral area. Our findings suggest that the necrotic area of brain tumor may retain 99mTc-HMPAO and causes an increased uptake.
PMCID: PMC3054513  PMID: 9811184
6.  HMPAO SPECT in Parkinson's disease before and after levodopa: correlation with dopaminergic responsiveness. 
Regional cerebral perfusion was evaluated by SPECT with technetium 99m hexamethylpropyleneamine oxime (99mTc HMPAO) as a tracer in 21 patients presenting with Parkinson's disease and in 11 normal controls. In the parkinsonian patients, scans were performed both off treatment, and after levodopa, and clinical dopaminergic responsiveness was evaluated. Uptake of HMPAO by the basal ganglia was significantly decreased in the parkinsonian subjects, compared with normal controls. This reduction was seen in both responders (n = 14) and non-responders (n = 7) to dopaminergic treatment. Uptake of HMPAO by the basal ganglia rose after treatment with levodopa, but the change was similar in both responders and non-responders. By contrast a striking difference in cortical HMPAO uptake was found between responders and non-responders, with significantly lower uptake in the medial temporal and posterior parietal cortex in the non-responders. This reduction was symmetrical. Basal ganglia perfusion assessed by this technique is unlikely to be of use in the diagnosis of Parkinson's disease that is responsive to dopaminergic treatment. The presence of extensive cortical involvement on a baseline scan correlates with a lack of dopaminergic responsiveness, however, and this may be useful diagnostically.
PMCID: PMC1072446  PMID: 8126501
7.  Diagnosis of bone infection by complementary role of technetium-99m MDP and technetium-99m hexamethylpropylene-amineoxime-leukocytes 
Valuate complementary role of 99mTc-MDP bone scan and 99mTechnetium hexamethylpropylene-amineoxime (99mTc-HMPAO) labeled leukocyte scintigraphy in diagnosis of bone infection.
Patients and Methods:
Ninety one sites suspected to have bone infection were divided in to two groups: Group I 49 sites with current endo-prothesis; and group II 42 sites with no prosthesis. All patients were subjected to serial images of 99mTc-HMPAO labeled leukocyte (99mTc-white blood cells (WBCs)), triple phase bone scan (99mTc-MDP) and plain X-ray, in addition to clinical and bacteriological assessment, together with follow-up.
The overall sensitivity (Sn) was found to be 34.9%, 95.4%, and 86% for plain X-ray, 99mTc-MDP, and 99mTc-WBCs respectively. Concerning specificity (Sp) was found to be 47.9%, 45.8%, and 91.7% respectively for the three imaging modalities. 99mTc-WBCs showed better Sn, Sp, and accuracy in group I (95%, 93.1% and 93.9%, respectively) compared to 40%, 41.4%, and 40.8% for plain X-ray and 90%, 62%, and 73.5% respectively for 99mTc-MDP. On the other hand, 99mTc-MDP proved to have best Sn 100% versus 78.3% and 30.4% for 99mTc-WBCs and plain X-ray respectively. Yet, Sp and accuracy was found to best for 99mTc-WBCs (89.5% and 83.3% respectively) compared to 57.9% and 42.9% for plain X-ray and 21.1% and 64.3% for 99mTc-MDP.
Combined imaging with 99mTc-WBCs and 99mTc-MDP proved to be effective in early detection of bone infection in the presence or absence of prosthesis.
PMCID: PMC3728737  PMID: 23919069
Bone infection; prosthesis; triple phase bone scan; 99mTechnetium hexamethylpropylene-amineoxime-leukocyte
8.  α4β2 nicotinic receptor status in Alzheimer's disease using 123I‐5IA‐85380 single‐photon‐emission computed tomography 
Loss of the α4β2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease.
To investigate in vivo changes in this receptor using single‐photon‐emission CT (SPECT) with 123I‐5‐iodo‐3‐[2(S)‐2‐azetidinylmethoxy] pyridine (5IA‐85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the α4β2 receptor.
32 non‐smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I‐5IA‐85380 and perfusion (99mTc‐hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation.
Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I‐5IA‐85380 and 99mTc‐HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.
Using 123I‐5IA‐85380 SPECT we found changes consistent with significant reductions in the nicotinic α4β2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.
PMCID: PMC2077777  PMID: 17135460
9.  Functional imaging studies of cognition using 99mTc-HMPAO SPECT: empirical validation using the n-back working memory paradigm 
Functional activation protocols are widely applied for the study of brain-cognition relations. Only few take advantage of the intrinsic characteristics of SPECT, particularly those allowing cognitive assessment outside of the camera, in settings close to the standard clinical or laboratory ones. The purpose of the study was to assess the feasibility of a split-dose activation protocol with 99mTc-HMPAO using low irradiation dose.
Materials and methods
A two-scans protocol was applied to 12 healthy young volunteers using 270 MBq of 99mTc-HMPAO per scan, with each image associated to a particular experimental condition of the verbal n-back working memory task (0-back, 2-back). Subtraction method was used to identify regional brain activity related to the task.
Voxel-wise statistical analysis showed left lateralized activity associated with the 2-back task, compared to the 0-back task. Activated regions, mainly prefrontal and parietal, were similar to those observed in previous fMRI and 15O-PET studies.
The results support the use of 99mTc-HMPAO SPECT for the investigation of brain-cognition relations and demonstrate the feasibility of optimal quality images despite low radiopharmaceutical doses. The findings also acknowledge the use of HMPAO as a radioligand to capture neuro-energetic modulations linked to cognitive activity. They encourage extending the application of the described activation protocol to clinical populations.
PMCID: PMC2755766  PMID: 18231790
99mTc-HMPAO SPECT; Brain imaging; Activation study; Working memory; Protocol validation
10.  A clinical role for 99mTc-HMPAO SPECT in the investigation of dementia? 
OBJECTIVES—To provide the clinician with a guide to the clinical utility of 99mTc-HMPAO single photon emission computed tomography (SPECT) and to the interpretation of specific test results in the differential diagnosis of dementia.
METHODS—Three hundred and sixty three patients with dementia were studied prospectively for a median three (range 1-6) years and classified into disease groups on the basis of established clinical criteria. The degree to which different patterns of cerebral blood flow (CBF) abnormality found on 99mTc-HMPAO SPECT imaging at the time of initial patient presentation modified clinical diagnoses was determined by calculating the likelihood ratios for pairwise disease group comparisons. The optimal clinical usage of 99mTc-HMPAO SPECT was determined by calculating the percentage of significant test results for each pairwise disease group comparison.
RESULTS—Bilateral posterior CBF abnormality was found to significantly increase the odds of a patient having Alzheimer's disease as opposed to vascular dementia or frontotemporal dementia. Bilateral anterior CBF abnormality significantly increased the odds of a patient having frontotemporal dementia as opposed to Alzheimer's disease, vascular dementia, or Lewy body disease. "Patchy" CBF changes significantly increased the odds of a patient having vascular dementia as opposed to Alzheimer's disease. Unilateral anterior, unilateral anterior plus unilateral posterior, and generalised CBF abnormality failed to contribute to the differentiation of any of these forms of dementia.
CONCLUSIONS—99mTc-HMPAO SPECT was found to be most useful in distinguishing Alzheimer's disease from vascular dementia and fronto temporal dementia, and least useful in differentiating between Alzheimer's disease and Lewy body disease, and between vascular dementia, frontotemporal dementia, and progressive aphasia. It is suggested that CBF SPECT should be used selectively and as an adjunct to clinical evaluation and CT.

PMCID: PMC2169991  PMID: 9527139
11.  Differences at brain SPECT between depressed females with and without adult ADHD and healthy controls: etiological considerations 
Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression.
Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and 99mTc-HMPAO SPECT. Controls for 99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences.
The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions (Brodmann areas 8, 9, 10, 32) in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales.
The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal 99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. 99mTc-HMPAO uptake mechanisms are discussed.
PMCID: PMC2753339  PMID: 19723308
12.  99mTc-Hexamethyl Propyleneamine Oxime Brain Perfusion Single Photon Emission Computed Tomography in Characterization of Dementia: An Initial Experience in Indian Clinical Practice 
World Journal of Nuclear Medicine  2014;13(2):120-127.
There is a growing health burden in developing countries due to recent trends of increasing incidence of neurodegenerative diseases. To reduce the healthcare cost and effective management of dementia illness, early diagnosis, accurate differentiation and their progression assessment is becoming crucially important. We are utilizing 99mTc-d, l-hexamethyl propyleneamine oxime (HMPAO) brain perfusion single photon emission computed tomography (SPECT) to characterize dementia on the basis of perfusion patterns and observed significant improvement in their management. Eleven patients (median age of 60 years range of 53-83 years) with clinical suspicion of dementia underwent 99mTc-HMPAO brain perfusion SPECT. SPECT-computed tomography acquisition done, data are reconstructed, reviewed in three view and further processed in “neurogam” to get voxel based analysis and the comparison with age based normal database and surface mapping. Final diagnosis was done with clinical correlation. Four patients are diagnosed as Alzheimer's disease, two as frontotemporal dementia, one as dementia of Lewy bodies, two as vascular dementia and two as pseudodementia. All imaging findings are well-correlated with clinical background. Brain perfusion SPECT with HMPAO was very helpful to us in characterizing the patients of dementia by its perfusion pattern.
PMCID: PMC4150154  PMID: 25191127
Brain perfusion; dementia; hexamethyl propyleneamine oxime; single photon emission computed tomography
13.  Role of Multimodal Evaluation of Cerebral Hemodynamics in Selecting Patients with Symptomatic Carotid or Middle Cerebral Artery Steno-occlusive Disease for Revascularization 
The circle of Willis provides collateral pathways to perfuse the affected vascular territories in patients with severe stenoocclusive disease of major arteries. The collateral perfusion may become insufficient in certain physiological circumstances due to failed vasodilatory reserve and intracranial steal phenomenon, so-called ‘Reversed-Robinhood syndrome’. We evaluated cerebral hemodynamics and vasodilatory reserve in patients with symptomatic distal internal carotid (ICA) or middle cerebral artery (MCA) severe steno-occlusive disease.
Diagnostic transcranial Doppler (TCD) and TCD-monitoring with voluntary breath-holding according to a standard scanning protocol were performed in patients with severe ICA or MCA steno-occlusive disease. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. Patients with exhausted vasomotor reactivity and intracranial steal phenomenon during breath-holding were further evaluated by 99technetiumm-hexamethyl propylene amine oxime single photon emission computed tomography (HMPAO-SPECT) with acetazolamide challenge.
Sixteen patients (age 27–74 years, 11 men) fulfilled our TCD criteria for exhausted vasomotor reactivity and intracranial steal phenomenon during the standard vasomotor testing by breath holding. Acetazolamide-challenged HMPAO-SPECT demonstrated significant hypoperfusion in 12 patients in affected arterial territories, suggestive of failed vasodilatory reserve. A breath-holding index of ≤0.3 on TCD was associated with an abnormal HMPAO-SPECT with acetazolamide challenge. TCD findings of a breath holding index of ≤0.3 and intracranial steal during the procedure were determinants of a significant abnormality on HMPAO-SPECT with acetazolamide challenge.
Multimodal evaluation of cerebral hemodynamics in symptomatic patients with severe steno-occlusive disease of the ICA or MCA is helpful in the identification and quantification of failed vasodilatory reserve. This approach may be useful in selecting patients for possible revascularization procedures.
PMCID: PMC3317325  PMID: 22518232
Transcranial Doppler; cerebrovascular reserve; acetazolamide challenge; single photon emission computed tomography; revascularization
14.  Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram 
BMC Psychiatry  2004;4:30.
Several studies have now examined the effects of selective serotonin reuptake inhibitor (SSRI) treatment on brain function in a variety of anxiety disorders including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). Regional changes in cerebral perfusion following SSRI treatment have been shown for all three disorders. The orbitofrontal cortex (OFC) (OCD), caudate (OCD), medial pre-frontal/cingulate (OCD, SAD, PTSD), temporal (OCD, SAD, PTSD) and, thalamic regions (OCD, SAD) are some of those implicated. Some data also suggests that higher perfusion pre-treatment in the anterior cingulate (PTSD), OFC, caudate (OCD) and antero-lateral temporal region (SAD) predicts subsequent treatment response. This paper further examines the notion of overlap in the neurocircuitry of treatment and indeed treatment response across anxiety disorders with SSRI treatment.
Single photon emission computed tomography (SPECT) using Tc-99 m HMPAO to assess brain perfusion was performed on subjects with OCD, PTSD, and SAD before and after 8 weeks (SAD) and 12 weeks (OCD and PTSD) treatment with the SSRI citalopram. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs non-responders) in the combined group of subjects.
Citalopram treatment resulted in significant deactivation (p = 0.001) for the entire group in the superior (t = 4.78) and anterior (t = 4.04) cingulate, right thalamus (t = 4.66) and left hippocampus (t = 3.96). Deactivation (p = 0.001) within the left precentral (t = 4.26), right mid-frontal (t = 4.03), right inferior frontal (t = 3.99), left prefrontal (3.81) and right precuneus (t= 3.85) was more marked in treatment responders. No pattern of baseline activation distinguished responders from non-responders to subsequent pharmacotherapy.
Although each of the anxiety disorders may be mediated by different neurocircuits, there is some overlap in the functional neuro-anatomy of their response to SSRI treatment. The current data are consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, are innervated by serotonergic neurons, and changes in their activity during serotonergic pharmacotherapy seem crucial.
PMCID: PMC529251  PMID: 15482603
15.  Concurrent Activation of the Somatosensory Forebrain and Deactivation of Periaqueductal Grey Associated With Diabetes-Induced Neuropathic Pain 
Experimental neurology  2007;208(2):305-313.
We combined behavioral testing with brain imaging using 99mTc-HMPAO (Amersham Health), to identify CNS structures reflecting alterations in pain perception in the streptozotocin (STZ) model of Type 1 diabetes. We induced diabetic hyperglycemia (blood glucose >300 mg/dl) by injecting male Sprague-Dawley rats with STZ (45 mg/kg i.p.). Four weeks after STZ, diabetic rats exhibited behaviors indicative of neuropathic pain (hypersensitivity thermal stimuli) and this hypersensitivity persisted for up to six weeks. Imaging data in STZ-diabetic rats revealed significant increases in the activation of brain regions involved in pain processing after six weeks duration of diabetes. These regions included secondary somatosensory cortex, ventrobasal thalamic nuclei and the basolateral amygdala. In contrast, the activation in habenular nuclei and the midbrain periaqueductal gray were markedly decreased in STZ rats. These data suggest that pain in diabetic neuropathy may be due in part to hyperactivity in somatosensory structures coupled with a concurrent deactivation of structures mediating antinociception.
PMCID: PMC2180394  PMID: 17936273
16.  Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with 99mTc- and 123I-labelled probes 
The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of 123I- and 99mTc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake.
A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D2 receptor ligand [123I]IBZM and the cerebral perfusion tracer [99mTc]HMPAO (1.2–0.4 MBq/g body weight) in healthy mice. The fatty acid [123I]IPPA (0.94 ± 0.05 MBq/g body weight) and the perfusion tracer [99mTc]sestamibi (3.8 ± 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP3 receptor.
In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [123I]IBZM and of cardiac [99mTc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [123I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [99mTc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [123I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight.
Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of 123I- and 99mTc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-009-1142-9) contains supplementary material, which is available to authorized users.
PMCID: PMC2724637  PMID: 19421750
Brain; Heart; [123I]IBZM; Mice; Multi-pinhole SPECT; [99mTc]sestamibi
17.  Regional differences in cerebral perfusion associated with the α-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder 
Neurobiologic studies have suggested that dysregulation of central noradrenergic systems may be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD), and it has been hypothesized that genetic changes in the norepinephrine pathways might contribute to dysfunction of the prefrontal cortex circuits in ADHD. We previously reported decreased cerebral blood flow in the right lateral prefrontal cortex and both orbitofrontal cortices in children with ADHD. Genetic investigations have shown that the α-2A-adrenergic receptor gene (ADRA2A) is associated with ADHD. Our aim was to examine whether the presence of a risk allele of the ADRA2A MspI polymorphism is associated with differences in regional cerebral blood flow in boys with ADHD.
We recruited 21 Korean boys with ADHD (mean age 9.9, standard deviation [SD] 2.7 yr) and 11 age- and sex-matched controls (mean age 10.6 [SD 2.1] yr). Each participant underwent technetium-99m-hexamethylpropylene amine oxime (99mTc-HMPAO) single-photon emission computed tomography. We performed image analyses with voxel-wise t statistics using SPM2.
We found regional hypoperfusion in the prefrontal regions, including the right orbitofrontal and right medial gyri, and the bilateral putamen and cerebellum in boys with ADHD relative to controls (p < 0.0005, uncorrected for multiple comparisons). Boys with ADHD who carried the C allele (n = 13) at the ADRA2A MspI polymorphism had reduced perfusion in the bilateral orbitofrontal regions compared with those without the C allele (n = 8) (p < 0.0005, uncorrected for multiple comparisons).
This study was limited by the small sample size, and we did not obtain genetic data from the controls.
Our findings suggest that regional differences in cerebral perfusion in the orbitofrontal cortex represent an intermediate neuroimaging phenotype associated with the ADRA2A MspI polymorphism; these data support the validity of the noradrenergic hypothesis regarding the pathophysiology of ADHD.
PMCID: PMC2928286  PMID: 20731965
18.  Cardiac ventricular dimensions predict cognitive decline and cerebral blood flow abnormalities in aging men 
BMC Geriatrics  2013;13:45.
The aims of this study are to examine possible associations between left cardiac ventricular measures in sixth decade and cognitive performance, both cross sectionally and longitudinally, and to examine if left cardiac ventricular measures could predict future changes in cerebral blood flow (CBF).
211 elderly men from a cohort of the population study “Men born in 1914” completed M-mode echocardiography and a cognitive test battery at age 68. The cognitive test battery was repeated at age 81. CBF was estimated with 99mTc-HMPAO SPECT in 72 survivors at age 83. Cognitive performance at baseline and at 1st follow up and CBF at 1st follow up were analysed in relation to left ventricular internal dimension in diastole (LVIDd mm/m2) and fractional shortening (FS).
Subjects with enlarged LVIDd at age 68 had poorer results on verbal and speed-performance tests at baseline and on verbal and visuo-spatial tests 14 years later on. Low FS was associated with decreased results on visuo-spatial tests at baseline. There was an inverse relationship between LVIDd and both verbal and spatial ability at the baseline and after 14 years of follow-up. Normotensive men with lower FS had also decreased CBF in a majority of brain areas 14 years later.
Mild echocardiographic abnormalities in 68 ys.-old men, as increased LVIDd and lower FS, are associated with lower cognitive test results and may predict cognitive decline and silent cerebral perfusion abnormalities 14 years later.
PMCID: PMC3660177  PMID: 23672300
Aging; Cerebrovascular circulation; Cohort study; Cognition; Hypertension; Left ventricular dimension
19.  Radiolabelled lymphocyte migration in rheumatoid synovitis. 
OBJECTIVES--To study the ability of technetium-99m hexamethyl propylene amineoxime (HMPAO) labelled lymphocyte scintigraphy to quantify synovial inflammation, and to analyse the kinetics of lymphocyte retention in the joints of patients with rheumatoid arthritis (RA). METHODS--After isolation of the lymphocytes, the cells were radiolabelled in vitro with 250 MBq 99mTc-HMPAO. The scans were performed 30 minutes, three hours and 20 hours after injection. RESULTS--An increase of the scintigram signal obtained at 20 hours was associated with a high joint swelling and joint pain score (F test = 3.07, p < 0.002), but not with the radiological score. A positive joint scintigram was predictive of active synovitis. Although the scintigram variation over time did not reach statistical significance, the kinetics of the scintigram signal tended to differ according to the disease duration: in early RA, active arthritis could be clearly imaged as early as 30 minutes, increased at three hours and the signal intensity persisted at 20 hours. In contrast, in long standing disease, the affected joints were imaged at 30 minutes, persisted unchanged at three hours, and the scintigram score decreased significantly at 20 hours. CONCLUSIONS--The study shows that 99mTc-HMPAO joint scintigraphy may be used to detect and to localise active rheumatoid arthritis.
PMCID: PMC1005510  PMID: 7880120
20.  Depressive symptoms, atherosclerotic burden and cerebral blood flow disturbances in a cohort of octogenarian men from a general population 
BMC Psychiatry  2013;13:347.
The aim of this study was to examine in elderly men a relationship between depressive symptoms, peripheral vascular disease and cerebral blood flow (CBF).
Population-based cohort study started with an examination of 809 men at age 55, followed by the first (age 68ys) and second follow up (age 82ys). 128 survivors were examined at age 82 with 99mTc-HMPAO-SPECT to estimate CBF, Zung-Self-Rating-Depression Scale (ZSDS), and Ankle-Brachial Index (ABI). Analysis was performed on men free from stroke and dementia which defined the final study population to 120 subjects.
ZSDS in the whole cohort ranged from 0.26 to 0.71 (reference 0.25-1.0). As the frequency of depressive symptoms was low, the case group (n = 31) was defined by ZSDS index above 75th percentile (≥0.48), comprising 9 subjects with mild depression (ZSDS 0.55-0.71) and 22 subjects at 88th percentile and above of the normal range (ZSDS index 0.48-0.54). Cases were more often current smokers at age 68 (44% vs. 24%; p = .02) and had lower systolic blood presure (SBP), lower social and physical activity, and suffered from fatigue, nausea, freezing and leg edema at age 82. Within the case group, ZSDS-index correlated negatively with CBF in subcortical area (r = -.42*), left and right thalamus (r = -.40*, r = -.46**), and right basal nuclei (r = -.35*). ZSDS-index correlated also with ABI at age 82 (right leg r = -.40*; left leg r = -.37*), and with Δ between ABI at age 82 and 68 (right r = -.36*; left r = -.46**). Despite decreasing SBP from age 68 to 82, adjusted multiple regression analysis showed in the case group that higher SBP determined CBF changes in the frontal and parietal areas, independently of ZSDS index, Δ ABI, and smoking.
In this population-based cohort of octogenarian men free from stroke or dementia, a proportion of subjects with depressive symptoms was low. Still, men with borderline or mild depression scores had lower social and physical activity, persistent smoking habit, worse peripheral circulation in legs, and cerebral perfusion changes in basal nuclei, thalamus and subcortical white matter. Regional CBF decline could be partly mediated by higher SBP.
PMCID: PMC3878789  PMID: 24369109
Vascular depression; Elderly; Subcortical; Cerebral blood flow; Ankle-brachial index
21.  Single photon emission computed tomography perfusion differences in mild cognitive impairment 
To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI).
Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc‐HMPAO. Clinical outcome after a 5‐year follow‐up period was heterogeneous.
Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer's disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer's disease within the follow‐up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer's disease were also included for purposes of comparison. The group of patients with Alzheimer's disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion.
These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.
PMCID: PMC2117661  PMID: 17056633
22.  High resolution SPECT with [99mTc]-d,l-HMPAO in normal pressure hydrocephalus before and after shunt operation. 
Cranial CT and high resolution measurements of regional cerebral blood flow (rCBF) with brain dedicated single photon emission computer tomography (SPECT) and [99mTc]-d,l-hexamethylpropyleneamine oxime ([99mTc]-d,l-HMPAO) were performed before and after shunt operation in 14 consecutive patients with dementia and normal pressure hydrocephalus (NPH). When compared with a control group of 14 age matched healthy volunteers, the group of NPH patients was characterised by an enlarged subcortical low-flow region, significantly reduced rCBF and enhanced side-to-side asymmetry of rCBF in the central white matter, and enhanced side-to-side asymmetry in the inferior and mid-temporal cortex. Global CBF was normal. Shunt operation reduced the mean area of the ventricles on CT and of the subcortical low-flow region on SPECT. Global CBF was unchanged. All 14 patients had an abnormal pre-shunt rCBF pattern with enlargement of the subcortical low flow region, focal cortical blood flow deficits, or both. Shunt operation improved the clinical status in 11 patients, and the area of the subcortical low flow region correctly classified 3/3 unimproved and 10/11 improved patients. Shunt operation normalised or reduced the area of the subcortical low flow region in nine of 10 patients. It is concluded that SPECT with [99mTc]-d,l-HMPAO is a useful supplement in the diagnosis of NPH versus normal ageing, and that SPECT may help to identify patients not likely to benefit clinically from surgery.
PMCID: PMC489616  PMID: 8509780
23.  In vivo molecular imaging of atherosclerotic lesions in ApoE-/- mice using VCAM-1-specific, 99mTc-labeled peptidic sequences 
Journal of Nuclear Medicine  2013;54(8):1442-1449.
Vascular Cell Adhesion Molecule-1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the technetium-labeled HMC-I derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in WHHL rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. In order to improve the target-to-background ratio, twenty derivatives of B2702p (B2702p1 to B2702p20) were synthesized using the ALA-scan methodology. We hypothesized that technetium-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis.
A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in ApoE−/− mice was used (n = 82). 99mTc-B2702p and 99mTc-B2702p1 to 99mTc-B2702p20 were injected intravenously to anesthetized animals 3 weeks following the ligation. Whole-body planar image acquisition was performed for 3 hrs. Single Photon Emission Computed Tomography (SPECT) imaging of 6 additionnal ligated ApoE−/− mice was also performed with 99mTc-B2702p1. The animals were then euthanized and the biodistribution of 99mTc-labeled peptides was evaluated by gamma-well counting of excised organs. The expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology.
A robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation whereas no VCAM-1 expression was detected in the contralateral carotid. Among all evaluated peptides, 99mTc-B2702p1 exhibited the most favourable properties. By gamma-well counting, there was a significant 2.0-fold increase in 99mTc-B2702p1 left-to-right carotid artery activity ratio (2.6±0.6) and a 3.4-fold increase in left carotid-to-blood activity ratio (1.4±0.4) in comparison to 99mTc-B2702p (1.3±0.2 and 0.4±0.1, respectively, P<0.05 for both comparisons). Similarly, planar images quantification indicated a higher left-to-right carotid activity ratio in 99mTc-B2702p1 than in 99mTc-B2702p injected mice (1.2±0.1 vs. 1.0±0.0, respectively, P<0.05). Finally, a significantly higher 99mTc-B2702p1 activity in the left than in the right carotid was observed by SPECT imaging (33.3±5.8 vs. 25.1±5.3 cpm/mm2/ID, respectively, P<0.05).
99mTc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.
PMCID: PMC3886675  PMID: 23719858
Amino Acid Sequence; Animals; Apolipoproteins E; deficiency; Female; Kinetics; Mice; Molecular Imaging; methods; Peptide Fragments; chemistry; diagnostic use; pharmacokinetics; Plaque, Atherosclerotic; diagnosis; metabolism; radionuclide imaging; Technetium; diagnostic use; Tomography, Emission-Computed, Single-Photon; Vascular Cell Adhesion Molecule-1; chemistry; metabolism; VCAM-1; molecular imaging; vulnerable atherosclerotic plaque
24.  Heterogeneity of neocortical cerebral blood flow deficits in dementia of the Alzheimer type: a [99mTc]-d,l-HMPAO SPECT study. 
Regional cerebral blood flow (rCBF) was measured with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable Alzheimer's disease and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. The aim was to analyse the topography of rCBF deficits in individual patients. In the group of patients with Alzheimer's disease as a whole, global CBF was reduced, but a factorial analysis of variance did not show disproportionate reduction of rCBF in any brain region. A parametric analysis of the rCBF data in individual patients was carried out with reference to normal values for internal rCBF ratios and to 13 different abnormal rCBF patterns. These theoretical patterns were predefined by showing significant hypoperfusion in at least one, or in any relevant combination of two, three, or four, of four major brain regions (a left and right frontal and a left and right posterior region). All patients with Alzheimer's disease and none of the control subjects had an abnormal rCBF pattern. Eleven of the 13 different patterns were seen in the patients. Frontal changes were seen in 19 (76%) of the patients, more often than previously reported. No single Alzheimer's disease pattern could be derived from our data. The number of regions with hypoperfusion, but not the presence of frontal changes, correlated significantly with the duration of disease. It is concluded that a clinical diagnosis of probable Alzheimer's disease is associated with heterogeneous patterns of rCBF deficits as measured with SPECT and [99mTc]-d,l-HMPAO. This heterogeneity may reflect different stages of the disease or cognitive subtypes and help explain published discrepancies concerning the topography of hypoperfusion in Alzheimer's disease. An analysis of individual rCBF data may add important information in the investigation of diseases with heterogeneous effects on the brain.
PMCID: PMC1072816  PMID: 8158175
25.  Technetium-99m hexamethyl propylene amine oxime granulocyte scintigraphy in Crohn's disease: diagnostic and clinical relevance. 
Gut  1993;34(10):1364-1369.
Scintigraphy with autologous granulocytes labelled by technetium-99m hexamethyl, propylene amine oxime (99mTc-HMPAO) was performed in 103 Crohn's disease patients and 52 healthy controls. In 31 patients endoscopic and histologic activity was compared with scan activity index. In the 98 patients with a positive scan, the extent of Crohn's disease, assessed by scintigraphy, was compared with that evaluated by small bowel x ray or colonoscopy with biopsies. In 48 patients, Crohn's disease activity index, activity index, simple index, erythrocyte sedimentation rate, C-reactive protein were correlated with the scan results. In 16 patients the five parameters and scan were repeated after treatment with methyl-prednisolone (10 cases), enteral nutrition (3), and 5-acetylsalicylic acid (3). The results showed that 99mTc-HMPAO granulocyte scan had a 95% sensitivity and 100% specificity to detect active inflammation; it correctly showed an abscess or a fistula in all the 24 cases found. The correlation between histological inflammatory activity and scan activity index was highly significant (r = 0.85; p < 0.01), less significant (r = 0.65; p < 0.01) between endoscopy and scan activity index. The evaluation for the extent of Crohn's disease by scan was completely correct in the small bowel (100%) and 93% correct in the large bowel. No correlation was seen between the three clinical activity parameters and scanning; in more than 80% of the cases in remission on the basis of a clinical or laboratory index, scintigraphy remained positive. Medical treatment was effective on the clinical indices but not on the active inflammation in the ileum, whereas it led to a negative scan in 5/11 cases in the large intestine. Scintigraphy with 99mTc-HMPAO granulocyte plays an important part in Crohn's disease for the diagnosis of complications, for activity and assessment of the extent, and for the treatment results evaluation.
PMCID: PMC1374542  PMID: 8244102

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