Molecular Imaging (PET and SPECT) for Children with Hypoxic-ischemic-encephalopathy and Cerebral Palsy before and after cell therapy.

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Toshinobu Nakatake, Makoto Nabetani, Nanae Yutaka, Kaho Suzuki, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1491013/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Glucose metabolism has been the focus of research in order to understand pathological conditions associated with diseases such as neonatal hypoxic-ischemic-encephalopathy (HIE), cerebral palsy (CP) and cerebral infarction. [Objective] To evaluate the use of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy, and to propose future perspectives on the use of those modalities for assessment of brain function in children with these conditions. [Methods] PubMed search for studies using PET or SPECT scans for HIE and CP in children. [Results] We identified 18 PET and 17 SPECT studies that have been performed in cases under age of 19 over the past three decades (1991–2021). Six papers on PET use consisted of one with human umbilical cord derived mesenchymal stromal cells, one mobilized peripheral blood mononuclear cells, three autologous bone marrow mononuclear cells and one allogeneic umbilical cord blood. 4/6 papers reported that PET-CT scan revealed increased glucose metabolism and 1/6 showed no significant change in glucose metabolism after cell therapy. One article on SPECT reported that 2/5 cases had improvement of cerebral perfusion in the thalamus after treatment. [Discussion] SPECT in the first few weeks of life is useful and more sensitive than MRI in predicting major neurological disability. SPECT is not appropriate for neonates because of the risk of radiation, improvement of other clinical test equipment. PET studies reported high glucose metabolism in the early neonatal periods in children with mild to moderate HIE, but not in the most severe cases, including those neonates that died. We suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT. [Conclusion] PET might be a good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely. PET SPECT Cerebral palsy HIE Cell therapy 1. Introduction Hypoxic-ischemic-encephalopathy (HIE) is one of the most common neonatal conditions and may lead to severe motor difficulties and cerebral palsy (CP). Magnetic resonance imaging (MRI) studies have been valuable to evaluate the severity of HIE and helped in determining the severity of HIE; (1) mild - involving cortex lesions, (2) moderate - that include the basal ganglia and the thalamus in addition to cortex lesions, and (3) severe - include additional lesions. We reported in 2018 a correlation between MRI and neurological sequelae in some patients with HIE 1) .(Shinomoto) However, our clinical experience is that there is frequently some noticeable mismatch between MRI findings and neurological sequelae. Single-photon emission computed tomography (SPECT) and Positron Emission Tomography (PET) studies have been performed to evaluate the extent of HIE and/or CP for several decades, based on the fact that damage to cerebral blood flow and glucose metabolism is one of the most important reasons for HIE and CP 2) . (Volpe) Furthermore, evidence suggest the effectiveness of stem cell therapy for improvement in patients with CP, 3) (Nabetani) that was not associated with paracrine, immune-regulatory, or angiogenesis. Studies of cell therapy for CP reported significant increase of glucose metabolism, as shown on PET studies 4,5,6) (Gu,Sharma,Min). 2. Objective The purpose of this review was to evaluate the value of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy, based on a literature search from 1991 to 2021 and to propose future perspectives on the use of those modalities for assessment of brain function in children with these conditions. We conducted a PubMed (MEDLINE) search for studies using PET or SPECT, that included the terms HIE, CP and Encephalopathy, in human subjects under the age of 19 years, in English and Japanese. We found a total of 18 papers related to the use of PET and 17 to the use of SPECT. 3. Results SPECT Six studies included patients with HIE, four reported low cerebral perfusion in the basal ganglia in patients with HIE 7) (Iwaibara 2010), and low cerebral perfusion in the lentiform nucleus and thalamus in half (3/6) of the patients with severe HIE. Tranquart et al. reported low corpus striatum-to-cerebellum activity ratio in cerebral perfusion 8) , Kapucu et al. reported low striatal-to-occipital cortex ratio in cerebral perfusion 8) and Oshima et al. reported low cerebral perfusion in the entire brain 9) . Three studies reported cerebral perfusion of parasagittal lesions 9–11) (Oshima 1993) (Konishi, 1994) (Shah 2001). Konishi et al. reported low cerebral perfusion of a wide area of the brain, except in the basal ganglia, brain stem and the sensory cortex, in three cases with HIE that suffered severe neurological prognosis, despite no remarkable MRI abnormality 10) . Oshima et al. reported low cerebral perfusion in the parasagittal region in cases with mild HIE 9) . Shah reported low cerebral perfusion of parasagittal lesions in 5/12 cases 11) . (Table 1 ) Table 1 SPECT studies on neonatal HIE and CP during 1991–2020 SPECT Objects n 1990(livanainen) 16) pediatric patients with various neurological diagnosis 60 1993 (M Oshima) 9) HIE 11 123I-IMP Diffuse↓, Parasagital↓ 1994 (C H Kao) 16) CP; perinatal asphyxia with MR and involved limbs 13 99mTc-ECD motor cortex ↓, Occipital lobe ↓ 1994 (Y Konishi) 10) HIE; 41–44 post-conceptional weeks 10 123I-IMP Diffuse without somatosensory ↓, BG↓, brainstem ↓ 1995(Yamada) 12) CP; ATE 12 123I-IMP Thalamus ↓corpus striatum ↓orbitofrontal ↓pericentral gyrus areas ↓prefrontal ↓medial temporal areas ↓ 1996(Sztriha L) 45) CP (7 five with porencephalic cyst), stroke (2), HHES (3), TBI (2) 14 99mTc-ECD 1998(Lee) 13) CP; SD(35) SQ (11), spastic HEMI(2) ATE(2), mixed(1) 51 99mTc-ECD temporal lobe 53% ↓, BG ↓, Thalamus ↓, cerebellum ↓, extratemporal cortex ↓ 1998(Kapucu) 8) HIE; mild (6), moderate (10), severe (4) 20 123I-IBZM ST/OC(striatal to occipital cortex)↓ 2000(Yim) 14) CP; bilateral spastic 36 99mTc-ECD Thalamus or cerebellar cortex ↓ 2001(Valkama) 19) VLBW; birth weight < 1,500 g, gestation age < 34 weeks 34 99mTc-ECD cerebellar cortex 2001(Tranquart) 46) HIE 39.2w 12 123I-IMP Striatum/cerebellum activity ratios ↓ 2001 (S Shah) 11) HIE; Sanart 2–3 24 99mTc-ECD Parasagital↓ 2006(Okumura) 15) CP; ATE due to kernicterus 3 SPECT all hypoperfusion BG related to cortical area ↓ 2010(Klaus Borch) 18) Premature babies; 26-32W 13 99mTc-ECD Periventriclular 2010 (Iwaibara) 7) HIE; Sanart 2–3 13 99mTc-ECD lentiform nucleus ↓ Thalamus ↓ 2012(Lee) 21) CP; SQ(11), HEMI(6), SD(3) 20 The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP. 2016(Rana) 17) CP; Spastic(91%), Asphyxia(69.6%) White matter change including PVL(73.2%) 56 99mTc-ECD cortex↓, sub cortex↓ Seven papers included patients with CP, and five reported low cerebral perfusion in the thalamus area. Yamada et al. reported low cerebral perfusion in the cortex and corpus striatum, in addition to the thalamus 12) . Lee et al. reported low cerebral perfusion of the cortex, basal ganglia and cerebellum, in addition to the thalamus 13) . Yim et al. reported low cerebral perfusion in the cerebellum in addition to the thalamus 14) . Okumura reported low cerebral perfusion of the basal ganglia connecting to the cortex 15) . Kao reported low cerebral perfusion of occipital lesions in cases with visual disturbances and relevant cortical area in children with spastic quadiplesia 16) . Rana reported low cerebral perfusion of the cortex and a subcortex lesion 17) . (Table 1 ) Two articles provided information on neonates that were born with very low birth weight (VLBW); Borch reported that 13 VLBW cases with Periventricular Leukomalacia (PVL) had low cerebral blood flow in periventricular white matter lesions 18) . Valkama reported low cerebral blood flow of the cortex, thalamus and cerebellum 19) .(Table 1 ) In 1990 Iivanainen reported that SPECT was useful for the diagnosis of degenerative brain diseases (82%) 20) , And that it was more sensitive than Electroencephalogram (EEG), CT and MRI. (Iivanainen 1990). Konishi reported that SPECT is better than other tests if done during the first week of life 10) . Shah reported that the relationship between findings in a SPECT exam and neurological sequelae at three months of age had a positive predictive value of 75% (brain ultrasonography (USG) 60%) and negative predictive value of 100%༈USG 76%༉ 11) . Okumura suggested that SPECT might be useful in cases of kernicterus when no remarkable findings can be demonstrated on an MRI scan 15) . However, two studies suggested that SPECT might not be the most appropriate test for neonatal HIE because of limited image resolution and risk of exposure to radiation. Indeed, there have been no reports of SPECT studies with neonates since 2016 with one exception – for the study of epilepsy 10,19) . Of interest, SPECT was useful in one study to demonstrate cerebral perfusion in children with CP after stem cell therapy 21) . Diverse neurological domains improved in five patients (25%) as assessed by developmental evaluation tools as well as by fractional anisotropy values in brain MRI-diffusion tensor imaging (DTI). The neurologic improvement was significant in patients with diplegia or hemiplegia rather than quadriplegia. The procedure was generally well-tolerated, although five patients experienced temporary nausea, hemoglobinuria, or urticaria during the intravenous infusion of the autologous umbilical cord blood (UCB) transfusion. They concluded that autologous UCB infusion is safe and feasible, and has yielded potential benefits in children with CP accompanied with improvement cerebral perfusion 21) . PET A total of 18 studies were reviewed to assess the benefit of PET for assessment of glucose matabolism. Fourteen studies used Fludeoxyglucose (18F) PET, two assessed GABA-A receptor binding using 18F PET 22–23) and two other groups reported cerebral blood flow 24–25) (Table 2 ). Table 2 PET studies on neonatal HIE and CP during 1991–2020 PET Result 1991 (Kerrigan JF) 31) SQ, SD, HEMI, Ate 23 18F-FDG-PET Cortex↓ (SD), BG↓, Thalamus↓ ༈Ate༉ 1993(Suhonen-Polvi) 47) HIE 14 18F-FDG-PET Sensorimotor cortex↓ cases with delayed development; subcortical lesion ↓, Thalamus ↓, cerebellum ↓, brainstem↓(neonatal period and 3 mo) 1995 (M Blennow) 26) HIE 6 18F-FDG-PET Prefrontal Cortex3/6↑, BG3/6↑, 1995 (Kucukali I) 24) SD 3 Germanium68/gallium68 PET using 15O Whole brain 1995(H Suhonen-Polvi) 27) HIE and hypoglycemia 9 18F-FDG-PET 1996 (Azzarelli B) 28) HIE 12 18F-FDG-PET most severe HIE; BG↓ Thalamus↓ brainstem↓ 1997 (Rosenbaum) 25) HIE 26 CBF with cesium fluoride scintilation detectors PET 2006 (Wong VC) CP 4 18F-FDG-PET body acupuncture brain glucose metabolism showed a > 10% increase in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture 2007 (Batista CE) 29) CP (Ate) 1 18F-FDG-PET severe cases; BG↓, Thalamus↓, early days after HIE; Transient BG↑ (Ate) 2007 (Lee JD) 21) SD due to PVL 30 cerebral GABAr PET by 18F-Fluoroflumazenil 2013 (Park HJ) 23) HEMI (human?) 6 18F-Fluoroflumazenil-PET 2013 (Sharma A) 34) CP and MR 1 PET-CT Six months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning. 2013 (Min K) 6) CP 96 18F-FDG-PET Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. 2015 (Sharma A) 35) CP 1 PET 2015 (Sharma A) 5) CP 40 PET Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. 2017 (Rah WJ) 33) CP 57 18F-FDG-PET The administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo. 2020 (Fowler EG) 30) Spastic CP 9 18F-FDG-PET Cortex↓, cerebellar↑ in children with less SVMC 2020 (Gu J) 4) CP 39 18F-FDG-PET 9 patients received treatments and completed the scheduled assessments. No significant difference was shown between the 2 groups in AE incidence.Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation. For those using Fludeoxyglucose (18F) PET, four studies investigated cases with HIE, of whom three reported glucose metabolism of the basal ganglia and the thalamus. Blennow reported that none of those with low glucose metabolism and half (3/6) of those with high glucose metabolism in the basal ganglia region at two and a half days after birth 26) .(M Blennow,1995) Suhonen-Polvi et al. reported low glucose metabolism in the cortex, basal ganglia and thalamus in cases with neurological sequaela during the first week of life and three months of life. The repeated PET study showed that the uptake of FDG was markedly high and increased in all brain sections of infants with normal development (n = 11), whereas those with delayed development (n = 4) had significantly lower values (P < or = 0.005). 27) . (Suhonen-Polvi H 1995) Azzarelli reported low glucose metabolism of the brain stem region in addition to basal ganglia and thalamus, in severe cases in which 10/12 infants died at the age of 2 to 12 weeks 28) . (Azzarelli B, 1996) When it comes to children with CP, 2/3 papers reported cases with spastic diplegia with low glucose metabolism of the cortex 29–30) .(Batista CE 2007)(Fowler EG 2020) Two papers reported children with athetoid CP (“dyskinetic cerebral palsy”) who were found to have low glucose metabolism in the basal ganglia 29,31) .(Kerrigan JF 1991)(Batista CE,2007) Batista reported that neonates with athetoid CP with transient high glucose metabolism in the basal ganglia 29) .(Batista CE,2007) Human umbilical cord derived mesenchymal stromal cell (UC-MSC) therapies for individuals with CP showed improvement in motor function and increase in glucose metabolism by PET-CT scan 4) (Gu et al. 2020). Virginia et al. reported that the brain glucose metabolism was more than 10% higher in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture in CP using PET 32) . Cell therapy Recently, PET and SPECT have been used for the investigation of the effectiveness of cell therapies. We identified six clinical studies for CP from 18 articles on PET and one from 17 articles who studied on SPECT since 2013.(Table 3 ) PET and SPECT were performed before and after cell therapies for cases with cerebral palsy. Six articles on PET consist of one by human umbilical cord derived mesenchymal stromal cells(hUC-MSC) 4) , one mobilized peripheral blood mononuclear cells (mPBMCs) 33) , three autologous bone marrow mononuclear cells (BMMNCs) 5, 34–35) , one allogeneic umbilical cord blood 6) . Four of six paper reported that PET-CT scan showed much increase of glucose metabolism and one of six no significant change of glucose metabolism after cell therapy. One article on SPECT reported that two from five cases showed improvement of cerebral perfusion in the thalamus by SPECT after autologous cord blood treatment 13) . Most studies were performed using intrathecal (IT) (n = 3) and intravenous (IV)(n = 4) injection. Administration was once in 6 studies and four times in one study. As with adverse events, allogeneic UCB with rhEPO showed ten serious adverse events that required the hospitalization of nine patients among the 105 recruited participants. A 25-month-old female died after allogeneic UCB with rhEPO at 14 weeks post-treatment. (Table 3 ) Table 3 References related to change of PET or SPECT score for neonatal HIE and CP after cell therapy Reference Number Disease N Route Cell Type Cell number Results Adverse events PET 2013(Sharma) 35) CP and MR 1 IT Auto BMMNC 1 × 1 × 106 CD34 + cells Six months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning. None reported PET 2013 (Min ) 6) CP 96 IV alloUCB with rhEPO 1 × 3 × 107/kg total nucleated cells (TNCs) Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. Ten serious adverse events that required hospitalization of nine patients were reported among the 105 recruited participants; similar between the three groups. The death of a 25-month-old female in the pUCB group at 14 weeks post-treatment. She was quadriplegic with spasticity from profound hypoxia with involvement of the central gray matter and brainstem. She had severe motor impairment and was unable to control her head. She was medically stable post-treatment with continuous neurological improvement up until the 3-month follow-up evaluation. During routine seizure follow-up, she was found to be neurologically stable. The same day she died during sleep with no apparent cause, and determined not to be related to the treatment. PET 2015(Sharma) 35) CP 1 IT Auto BMMNCs 1 × 3.3 × 107 total nucleated cells (TNCs) On repeating the Functional Independence Measure (FIM), the score increased from 90 to 113. A repeat PET-CT scan of the brain six months after intervention showed progression of the mean standard deviation values towards normalization which correlated to the functional changes. At one year, all clinical improvements have remained. None reported PET 2015(Sharma) 5) CP 40 IT BMMNCs 1 × 10.23 × 106 CD34 + cells Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. At the time of the procedure, there were no complications recorded. During the hospital stay, a few patients did show minor procedure related adverse events-15% a spinal headache, 7.5% nausea, 30% vomiting, 12.5% pain at the site of injection, and 2.5% diarrhea. These events were self-limiting and relieved within one-week using medication. The only major adverse event noted related to cell transplantation was seizures - in 2 patients. PET 2017 (Rah) 33) CP 57 IV mPBMCs 1st 4.63 ± 2.88 × 108/kg 2nd 6.20 ± 1.94× 108/kg TNCs, 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo. Transient hemoglobinuria (n = 3) and abdominal pain (n = 1) were reported during the mPBMC infusion, and these were resolved with supportive treatments. PET 2020 (Gu) 4) CP 39 IV hUC-MSCs 1 × 4.6 ± 0.50 × 107 MSC cells 9 patients received treatments and completed the scheduled assessments. Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation. No significant difference between hUC-MSC and control in AE incidence. Serious adverse events were not observed. Upper respiratory infections were reported most frequently (52.6%). Diarrhea (31.6%) fever (36.8%) with a high incidence. SPECT 2012 (Lee) 21) CP 20 IV Auto UCB 1 × 5.5 ± 3.8 (0.6 ~ 15.65) × 107 TNCs The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP. Infusion was generally well-tolerated, even without premedication, although 3 patients experienced temporary nausea and hemoglobinuria, and 2 patients experienced hemoglobinuria and urticaria, but these were easily controlled with peniramine or intravenous hydration. 4. Discussion Perinatal complications may result in severe motor disability with a prevalence of 1–2 per 1000 live births in developed countries causing significant burden of illness and necessitating extensive multidisciplinary care 36) . (Jacobs S. 2007) Despite large body of research over the last three decades, no clinically meaningful interventions are offered in order to repair damage to the areas of the brain that were found responsible for control of muscle coordination and movement 37) . (J Pediatrics. 2004 Aug; 145(2):S42-4 Use of SPECT imaging studies among neonates (0–7 days of life) with moderate to severe HIE suggest low cerebral perfusion of the thalamus and basal ganglia regions, despite seeing no such discoveries on MRI scan. Similarly, SPECT findings are associated with low cerebral perfusion of cortex area while none are seen on MRI. Our prior study 7) (Iwaibara 2010), as well as other published studies, reported that SPECT was a useful modality to identify low cerebral perfusion of the thalamus or orbitofrontal area compared to MRI. SPECT was also shown to be useful to diagnose HIE and CP. Further evidence suggests that SPECT in the first few weeks of life is useful and more sensitive than MRI in predicting major neurological disability. However, because of the risk of radiation, improvements in MR angiography and high cost of SPECT, it is not popular for all neonates. Indeed, there have been no reports of the use of SPECT for evaluation of neonatal diseases such as HIE or CP since 2016, except those evaluating epilepsy. Ultrasonography, MR Spectroscopy or MR angiography, having no risk of exposure to radiation, were the preferred modality. 38–40) .(Groenendaal 2016, Aida 2021,O Tierradentro-García 2021) Glucose metabolism has been the focus of identifying the pathology associated with cerebral ischemic disease in neonatal HIE, CP and cerebral infarction 41) .(Nabetani) PET studies reported high glucose metabolism in the early neonatal periods in children with mild to moderate HIE, but not in the most severe cases, including those neonates that perished. Nonetheless, studies using SPECT reported that cases with severe HIE reported to have low cerebral perfusion. It is possible that the brain may keep sufficient glucose metabolism despite reduced cerebral perfusion. The mechanism of MSCs to improve glucose metabolism might lead to therapeutic potential for individuals CP. We reported that the importance of glucose for neural activity in hippocampal slices of immature and adult rats during deprivation of oxygen and/or glucose 41) .(Nabetani 1995). We evaluated the relationship between neural activity and energy levels in neonatal brain. During episodes of hypoxia and glucose deprivation, adenosine triphosphate (ATP) levels of noted to be preserved in neonates, compared to adult brains. This suggests that energy consumption of the immature brain is smaller than that in the adult brain. During glucose deprivation, neural activity of neonatal rats ceased rapidly although the level of ATP is preserved at high levels. This suggests that glucose plays an important role in the preservation of neural activity in addition to its major function as an energy substrate in neonatal brains 41) .(Nabetani 1995) Lactate has been shown to be important in maintaining neural function as an energy substrate and energy transporter. We previously reported the possibility of lactate preserving neural function of the adult brain and that glucose metabolites such as lactate and OHBA(beta-hydroxybutyrate) are available for both neural activity as well as maintaining the levels of high-energy phosphates in the tissue slice of neonatal rats 42–43) . (Saitoh 1994) (Wada 1997) In this study, some article have reported that glucose metabolism improved in clinical experiences for a case with CP after stem cell therapy, evaluated by PET, as well as cerebral perfusion by SPECT. UCB (umbilical cord blood) and peripheral blood mononuclear cells infusion therapy for patients with CP improved brain glucose metabolism. Six months following Autologous BM Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning 6) . (Min et al. 2013) Rah et al. reported that the administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. Close to half (42.6%) of patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. The results showed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans and no significant differences in such changes between the mPBMC and placebo 33) . (Rah et al. 2017 ). Sharma et al. reported that autologous bone marrow mononuclear cells therapies for patients with CP also showed improvement of motor function and glucose metabolism. At six months of age, 95% of patients showed improvement. PET-CT scan done in six patients showed metabolic improvements in areas of the brain correlating to clinical improvements 5) .(Sharma et al. 2015 ) The improvement of glucose metabolism might be caused by improvement of GAP junction-mediated cell-cell interaction. In 2020, Kikuchi-Taura et al. reported that angiogenesis is activated by bone marrow mononuclear cells via gap junction–mediated cell–cell interaction and that cell–cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells and improvement of glucose uptake. Transplanted BM-MNCs transferred small molecules to endothelial cells via gap junction followed by activated Hif-1α and suppressed autophagy at endothelial cells 44) .(Kikuchi-Taura et al. 2020 ). We suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT. 5. Conclusion PET might be a good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely. Abbreviations CP Cerebral palsy HIE hypoxic–ischemic encephalopathy MSCs mesenchymal stromal cells BM bone marrow BM-MNCs bone marrow mononuclear cells UC-MSCs umbilical cord derived-MSCs PVL periventricular leukomalacia UCB umbilical cord blood BM-MSCs BM–derived mesenchymal stromal cells mPBMCs mobilized peripheral blood mononuclear cells ATP adenosine triphosphate OHBA beta-hydroxybutyrate IVH intraventricular hemorrhage ASD autism spectrum disorder IT intrathecal IV intravenous PET positron emission topography SPECT Single Photon Emission Computed Tomography G-CSF Granulocyte Colony Stimulating Factor rhEPO Recombinant human erythropoietin USG Ultrasonography DTI diffusion tensor imaging Declarations Funding: We have no fund support for this study. Conflicts of Interest: The authors declare no conflict of interest. References T Shinomoto , M Nabetani , K Kobata , A Mima , N Yutaka , H Sano. The utility of neonatal MRI for prediction of outcome with neonatal Hypoxic-Ischemic Encephalopathy. Nihon-shusanki-sinseijigakkaishi(Jpn) 2018, 54(1): 55-59 Joseph j Volpe, P Herscovitch, Jeffrey M Perlman, Katherine L Kreusser, Marcus E Raiche. Positron Emission Tomography in the Asphyxiated Term Newborn: Parasagittal Impairment of Cerebral Blood Flow. Ann Neurol 1985 17:287-296 Makoto Nabetani, et al. Preventing Brain Damage from Hypoxic–Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells. Am J Perinatology 2021, Apr 14 Gu J, Huang L, Zhang C, Wang Y, Zhang R, Tu Z, Wang H, Zhou X, Xiao Z, Liu Z, Hu X, Ke Z, Wang D, Liu L. Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial. Stem Cell Res Ther. 2020 Feb 3;11(1):43. Sharma A, Sane H, Gokulchandran N, Kulkarni P, Gandhi S, Sundaram J, Paranjape A, Shetty A, Bhagwanani K, Biju H, Badhe P. A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier. Stem Cells Int. 2015;2015:905874. doi: 10.1155/2015/905874. Epub 2015 Feb 18. Min K, Song J, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK, Kim SS, Kim M. Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells. 2013 Mar;31(3):581-91. Iwaibara T, Ri S, Nabetani M, et al. Studies of quantitative SPECT on bilateral basal ganglia and thalamic lesions (BGTL) in hypoxic ischemic encephalopathy (HIE). Hot Topics in the neonatology John Wiley & Sons: Washington DC 2010. Kapucu LO, Atalay Y, van Royen E. et al. D2 receptor imaging with iodine-123-iodobenzamide brain SPECT in infants with hypoxic-ischemic brain injury. J Nucl Med 1998 Oct;39(10):1703-7. Oshima M, Suzuki C, Sasaki J, Kitoh O, Yasukochi H. Evaluation of newborns with brain disease using 123I-IMP SPECT. Kaku Igaku 1993 Jul;30(7):727-33. Konishi Y, Kuriyama M, Mori I, Fujii Y, Konishi K, Sudo M, Ishii Y. Assessment of local cerebral blood flow in neonates with N-isopropyl-P-[123I]iodoamphetamine and single photon emission computed tomography. Brain Dev 1994 Nov-Dec;16(6):450-3. doi: 10.1016/0387-7604(94)90006-x. Shah S, Fernandez AR. Chirla D. Role of brain SPECT in neonates with hypoxic ischemic encephalopathy and its correlation with neurodevelopmental outcome. Indian Pediatr. 2001 Jul;38(7):705-13. Yamada K, Tsuzura S, Matsuda H. Brain MRI and single photon emission computed tomography in severe athetotic cerebral palsy: a comparative study with mental and motor disorders. No To Hattatsu 1995, Jul;27(4):269-75. Lee JD, Kim DI, Ryu YH, Whang GJ, Park CI, Kim DG. Technetium-99m-ECD brain SPECT in cerebral palsy: comparison with MRI. J Nucl Med 1998, Apr;39(4):619-23. Yim SY, Lee IY, Park CH, Kim OH. A qualitative analysis of brain SPECT for prognostication of gross motor development in children with cerebral palsy. Clin Nucl Med 2000 Apr;25(4):268-72. doi: 10.1097/00003072-200004000-00006. Okumura A, Hayakawa F, Maruyama K, Kubota T, Kato K, Watanabe K. Single photon emission computed tomography and serial MRI in preterm infants with kernicterus. Brain Dev. 2006 Jul;28(6):348-52. doi: 10.1016/j.braindev.2005.11.004. Epub 2006 Feb 14. Kao CH, Wang SJ, Yeh SH. The relationship among the quantitative perfusion-defect indices in Tc-99m HMPAO brain SPECT, IQ test, and involved extremities in children with cerebral palsy due to perinatal asphyxia. Clin Nucl Med 1994 Apr;19(4):309-13. doi: 10.1097/00003072-199404000-00007. Rana KS, Narwal V, Chauhan L, Singh G, Sharma M, Chauhan S. Structural and Perfusion Abnormalities of Brain on MRI and Technetium-99m-ECD SPECT in Children With Cerebral Palsy: A Comparative Study. J Child Neurology 2016, Apr;31(5):589-92. Børch Klaus, Lou HC, Greisen G. Cerebral white matter blood flow and arterial blood pressure in preterm infants. Acta Paediatr 2010 Oct;99(10):1489-92. doi: 10.1111/j.1651-2227.2010.01856.x. Valkama AM, Ahonen A, Vainionp滑 L, Torniainen P, Lanning P, Koivisto M. Brain single photon emission computed tomography at term age for predicting cerebral palsy after preterm birth. Biol Neonate 2001 Jan;79(1):27-33. doi: 10.1159/000047062. M Iivanainen 1 , J Launes, H Pihko, P Nikkinen, L Lindroth. Single-photon emission computed tomography of brain perfusion: analysis of 60 paediatric cases. Dev Med Child Neurol 1990 Jan;32(1):63-8. doi: 10.1111/j.1469-8749.1990.tb08468.x. Lee YH, Choi KV, Moon JH, Jun HJ, Kang HR, Oh SI, Kim HS, Um JS, Kim MJ, Choi YY, Lee YJ, Kim HJ, Lee JH, Son SM, Choi SJ, Oh W, Yang YS. Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. J Translat Med 2012, Mar 23;10:58. doi: 10.1186/1479-5876-10-58. Lee JD, Park HJ, Park ES, Kim DG, Rha DW, Kim EY, Kim DI, Kim JJ, Yun M, Ryu YH, Lee J, Jeong JM, Lee DS, Lee MC, Park CI. Assessment of regional GABA(A) receptor binding using 18F-fluoroflumazenil positron emission tomography in spastic type cerebral palsy. Neuroimage. 2007 Jan 1;34(1):19-25. Park HJ, Kim CH, Park ES, Park B, Oh SR, Oh MK, Park CI, Lee JD. Increased GABA-A receptor binding and reduced connectivity at the motor cortex in children with hemiplegic cerebral palsy: a multimodal investigation using 18F-fluoroflumazenil PET, immunohistochemistry, and MR imaging. J Nucl Med. 2013 Aug;54(8):1263-9 Kucukali I, De Reuck J, Decoo D, Strijckmans K, Goethals P, Lemahieu I. Positron emission tomography in spastic diplegia. Clin Neurol Neurosurg. 1995 Feb;97(1):28-31. Rosenbaum JL, Almli CR, Yundt KD, Altman DI, Powers WJ. Higher neonatal cerebral blood flow correlates with worse childhood neurologic outcome. Neurology 1997 Oct;49(4):1035-41. M Blennow 1 , M Ingvar, H Lagercrantz, S Stone-Elander, L Eriksson, H Forssberg, K Ericson, O Flodmark. Early [18F]FDG positron emission tomography in infants with hypoxic-ischaemic encephalopathy shows hypermetabolism during the postasphyctic period. Acta Paediatr 1995 Nov;84(11):1289-95. H Suhonen-Polvi 1 , U Ruotsalainen, A Kinnala, J Bergman, M Haaparanta, M Ter郭, P M akel a, O Solin, U Wegelius. FDG-PET in early infancy: simplified quantification methods to measure cerebral glucose utilization J Nucl Med. 1995 Jul;36(7):1249-54. Azzarelli B, Caldemeyer KS, Phillips JP, DeMyer WE. Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study. Pediatr Neurol. 1996 Feb;14(2):108-16. Batista CE, Chugani HT, Shankaran S.et al. Transient hypermetabolism of the basal ganglia following perinatal hypoxia. Pediatr Neurol. 2007 May;36(5):330-3. Fowler EG, Oppenheim WL, Greenberg MB, Staudt LA, Joshi SH, Silverman DHS. Brain Metabolism During A Lower Extremity Voluntary Movement Task in Children With Spastic Cerebral Palsy. Front Hum Neurosci. 2020 May 25;14:159. Kerrigan JF, Chugani HT, Phelps ME. Regional cerebral glucose metabolism in clinical subtypes of cerebral palsy. Pediatr Neurol. 1991 Nov-Dec;7(6):415-25. Virginia C N Wong , Jie-Guang Sun, David W C Yeung. Pilot study of positron emission tomography (PET) brain glucose metabolism to assess the efficacy of tongue and body acupuncture in cerebral palsy. J Child Neurol. 2006 Jun;21(6):456-62. Rah WJ, Lee YH, Moon JH, Jun HJ, Kang HR, Koh H, Eom HJ, Lee JY, Lee YJ, Kim JY, Choi YY, Park K, Kim MJ, Kim SH. Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study. J Transl Med. 2017 Jan 21;15(1):16. Sharma A, Sane H, Paranjape A, Gokulchandran N, Kulkarni P, Nagrajan A, Badhe P. Positron emission tomography-computer tomography scan used as a monitoring tool following cellular therapy in cerebral palsy and mental retardation-a case report. Case Rep Neurol Med. 2013;2013:141983. Sharma A, Sane H, Kulkarni P, D'sa M, Gokulchandran N, Badhe P. Improved Quality of Life in A Case of Cerebral Palsy after Bone Marrow Mononuclear Cell Transplantation. Cell J. 2015 Summer;17(2):389-94. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;(04):CD003311 Murray Goldstein, The treatment of cerebral palsy: What we know, what we don't know. J of Pediatrics 2004 Aug;145(2 Suppl):S42-6. doi: 10.1016/j.jpeds.2004.05.022. Floris Groenendaal, Linda S de Vries, Fifty years of brain imaging in neonatal encephalopathy following perinatal asphyxia Pediatr Res. 2017 Jan;81(1-2):150-155. doi: 10.1038/pr.2016.195. Epub 2016 Sep 27. Noriko Aida, 1H-MR Spectroscopy of the Early Developmental Brain, Neonatal Encephalopathies, and Neurometabolic Disorders. Magn Reson Med Sci. 2021 Aug 21. doi: 10.2463/mrms.rev.2021-0055. Luis Octavio Tierradentro-García , Sandra Saade-Lemus, Colbey Freeman, Matthew Kirschen, Hao Huang, Arastoo Vossough, Misun Hwang. Cerebral Blood Flow of the Neonatal Brain after Hypoxic-Ischemic Injury. Am J Perinatol . 2021 Jul 5. doi: 10.1055/s-0041-1731278. M Nabetani et al. Neural activity and the levels of high energy phosphates during deprivation of oxygen and/or glucose in hippocampal slices of immature and adult rats. Int J of Developmental Neurosci 1995 Feb;13(1):3-12 Saitoh, M.; Okada, Y.; Nabetani, M., Effect of mannose, fructose and lactate on the preservation of synaptic potentials in hippocampal slices. Neurosci letters 1994, 171, (1-2), 125-8. Wada, H.; Okada, Y.; Nabetani, M.; Nakamura, H., The effects of lactate and beta-hydroxybutyrate on the energy metabolism and neural activity of hippocampal slices from adult and immature rat. Brain research. Developmental brain research 1997, 101, (1-2), 1-7. Kikuchi-Taura A, Okinaka Y, Takeuchi Y, et al. Bone marrow mononuclear cells activate angiogenesis via GAP junction-mediated cell-cell interaction. Stroke 2020, 51(04):1279–1289 Sztriha L, al Suhaili AR, Prais V, Nork M. Regional cerebral blood perfusion in children with hemiplegia: A SPECT study. Neuropediatrics 1996 Aug;27(4):178-83. doi: 10.1055/s-2007-973783. Tranquart F, Saliba E, Barantin L, Lanneau M, Simmer L, Guilloteau D, Baulieu JL. D2 receptor imaging in neonates using I-123 iodobenzamide brain SPECT. Clin Nucl Med 2001 Jan;26(1):36-40. doi: 10.1097/00003072-200101000-00009. Suhonen-Polvi H, Kero P, Korvenranta H, Ruotsalainen U, Haaparanta M, Bergman J, Simell O, Wegelius U. Repeated fluorodeoxyglucose positron emission tomography of the brain in infants with suspected hypoxic-ischaemic brain injury. Eur J Nucl Med. 1993 Sep;20(9):759-65. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1491013","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":99848388,"identity":"15e77d34-f118-479d-b8a1-4bf4f952681b","order_by":0,"name":"Toshinobu Nakatake","email":"","orcid":"","institution":"Yodogawa Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toshinobu","middleName":"","lastName":"Nakatake","suffix":""},{"id":99848389,"identity":"ab969708-5299-4e3c-a2f6-dde797875df4","order_by":1,"name":"Makoto Nabetani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYFACHgbGj38keNjYG4AcAwvitDBLNtjI8fEcAGmRIE4LA29DmrGcRAKIR4QWc/azBx9I7jic2Cb5/OqGHwUSDPzt3Ql4tVj25CUbFJ4BapHOKbvZA3SYxJmzG/BqMTiQYyYhwQbWknaDB6jFQCKXgJbzb8x/8IC0SJ5Ju/mHKC03cswYeNvSjNkk2I/dJs6WG++SpSXO2Mix8eSw3ZYxkOAh7JfzuQc/fqiQ4JFvP/7s5ps/NnL87b34tSABHgMwSaxyEGB/QIrqUTAKRsEoGEEAANwBR2HXYG9bAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9762-0438","institution":"Yodogawa Christian Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Nabetani","suffix":""},{"id":99848390,"identity":"99416ed8-24e8-498d-afd0-5b98dcd9629d","order_by":2,"name":"Nanae Yutaka","email":"","orcid":"","institution":"Yodogawa Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nanae","middleName":"","lastName":"Yutaka","suffix":""},{"id":99848391,"identity":"92bb4c5f-66b1-46d1-a55b-e04090489d17","order_by":3,"name":"Kaho Suzuki","email":"","orcid":"","institution":"Yodogawa Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kaho","middleName":"","lastName":"Suzuki","suffix":""},{"id":99848392,"identity":"2b60ff14-19b8-4e52-a099-3b818c376007","order_by":4,"name":"Ryoichi Hazama","email":"","orcid":"","institution":"Yodogawa Christian Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryoichi","middleName":"","lastName":"Hazama","suffix":""},{"id":99848393,"identity":"48eb7a2c-6a22-4a07-a67a-2b96fa2ca87e","order_by":5,"name":"Satoshi Ohnishi","email":"","orcid":"","institution":"Osaka Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu Igakuka","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Ohnishi","suffix":""},{"id":99848394,"identity":"b092484c-1ec9-48e0-b090-861e9705d54c","order_by":6,"name":"Takashi Hamazaki","email":"","orcid":"","institution":"Osaka Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu Igakuka","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Hamazaki","suffix":""},{"id":99848395,"identity":"7de1c6ef-3ce7-4336-9cdb-ece0fbadf6e9","order_by":7,"name":"Haruo Shintaku","email":"","orcid":"","institution":"Osaka Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu Igakuka","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haruo","middleName":"","lastName":"Shintaku","suffix":""},{"id":99848396,"identity":"3dc28c34-6742-4773-8e3f-f9f98285b719","order_by":8,"name":"Ran D Goldman","email":"","orcid":"","institution":"British Columbia Children's Hospital: BC Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ran","middleName":"D","lastName":"Goldman","suffix":""}],"badges":[],"createdAt":"2022-03-26 04:02:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1491013/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1491013/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20734805,"identity":"53a89836-6bb2-4ee1-83cb-c77ae60c18a1","added_by":"auto","created_at":"2022-04-25 15:05:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":344425,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1491013/v1/9377b595-b545-4741-8fdf-8f663527782c.pdf"},{"id":20734804,"identity":"d9401657-b7e1-47ff-8002-aafcc93a56c4","added_by":"auto","created_at":"2022-04-25 15:05:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":344425,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1491013/v1/c5f8cc6a-5f55-4fdc-a426-b18fa25f56b4.pdf"}],"financialInterests":"","formattedTitle":"Molecular Imaging (PET and SPECT) for Children with Hypoxic-ischemic-encephalopathy and Cerebral Palsy before and after cell therapy.","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHypoxic-ischemic-encephalopathy (HIE) is one of the most common neonatal conditions and may lead to severe motor difficulties and cerebral palsy (CP). Magnetic resonance imaging (MRI) studies have been valuable to evaluate the severity of HIE and helped in determining the severity of HIE; (1) mild - involving cortex lesions, (2) moderate - that include the basal ganglia and the thalamus in addition to cortex lesions, and (3) severe - include additional lesions.\u003c/p\u003e \u003cp\u003eWe reported in 2018 a correlation between MRI and neurological sequelae in some patients with HIE \u003csup\u003e1)\u003c/sup\u003e.(Shinomoto) However, our clinical experience is that there is frequently some noticeable mismatch between MRI findings and neurological sequelae.\u003c/p\u003e \u003cp\u003eSingle-photon emission computed tomography (SPECT) and Positron Emission Tomography (PET) studies have been performed to evaluate the extent of HIE and/or CP for several decades, based on the fact that damage to cerebral blood flow and glucose metabolism is one of the most important reasons for HIE and CP\u003csup\u003e2)\u003c/sup\u003e. (Volpe)\u003c/p\u003e \u003cp\u003eFurthermore, evidence suggest the effectiveness of stem cell therapy for improvement in patients with CP, \u003csup\u003e3)\u003c/sup\u003e (Nabetani) that was not associated with paracrine, immune-regulatory, or angiogenesis. Studies of cell therapy for CP reported significant increase of glucose metabolism, as shown on PET studies\u003csup\u003e4,5,6)\u003c/sup\u003e (Gu,Sharma,Min).\u003c/p\u003e"},{"header":"2. Objective","content":"\u003cp\u003eThe purpose of this review was to evaluate the value of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy, based on a literature search from 1991 to 2021 and to propose future perspectives on the use of those modalities for assessment of brain function in children with these conditions.\u003c/p\u003e \u003cp\u003eWe conducted a PubMed (MEDLINE) search for studies using PET or SPECT, that included the terms HIE, CP and Encephalopathy, in human subjects under the age of 19 years, in English and Japanese. We found a total of 18 papers related to the use of PET and 17 to the use of SPECT.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003cb\u003eSPECT\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSix studies included patients with HIE, four reported low cerebral perfusion in the basal ganglia in patients with HIE \u003csup\u003e7)\u003c/sup\u003e (Iwaibara 2010), and low cerebral perfusion in the lentiform nucleus and thalamus in half (3/6) of the patients with severe HIE. Tranquart et al. reported low corpus striatum-to-cerebellum activity ratio in cerebral perfusion\u003csup\u003e8)\u003c/sup\u003e, Kapucu et al. reported low striatal-to-occipital cortex ratio in cerebral perfusion\u003csup\u003e8)\u003c/sup\u003e and Oshima et al. reported low cerebral perfusion in the entire brain\u003csup\u003e9)\u003c/sup\u003e. Three studies reported cerebral perfusion of parasagittal lesions\u003csup\u003e9\u0026ndash;11)\u003c/sup\u003e (Oshima 1993) (Konishi, 1994) (Shah 2001). Konishi et al. reported low cerebral perfusion of a wide area of the brain, except in the basal ganglia, brain stem and the sensory cortex, in three cases with HIE that suffered severe neurological prognosis, despite no remarkable MRI abnormality\u003csup\u003e10)\u003c/sup\u003e. Oshima et al. reported low cerebral perfusion in the parasagittal region in cases with mild HIE\u003csup\u003e9)\u003c/sup\u003e. Shah reported low cerebral perfusion of parasagittal lesions in 5/12 cases\u003csup\u003e11)\u003c/sup\u003e. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSPECT studies on neonatal HIE and CP during 1991\u0026ndash;2020\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSPECT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eObjects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1990(livanainen)\u003csup\u003e16)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epediatric patients with various neurological diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1993 (M Oshima)\u003csup\u003e9)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123I-IMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiffuse\u0026darr;, Parasagital\u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1994 (C H Kao)\u003csup\u003e16)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; perinatal asphyxia with MR and involved limbs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emotor cortex \u0026darr;, Occipital lobe \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1994 (Y Konishi) \u003csup\u003e10)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE; 41\u0026ndash;44 post-conceptional weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123I-IMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiffuse without somatosensory \u0026darr;, BG\u0026darr;, brainstem \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1995(Yamada)\u003csup\u003e12)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; ATE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123I-IMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThalamus \u0026darr;corpus striatum \u0026darr;orbitofrontal \u0026darr;pericentral gyrus areas \u0026darr;prefrontal \u0026darr;medial temporal areas \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1996(Sztriha L)\u003csup\u003e45)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP (7 five with porencephalic cyst), stroke (2), HHES (3), TBI (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1998(Lee) \u003csup\u003e13)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; SD(35) SQ (11), spastic HEMI(2) ATE(2), mixed(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003etemporal lobe 53% \u0026darr;, BG \u0026darr;, Thalamus \u0026darr;, cerebellum \u0026darr;, extratemporal cortex \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1998(Kapucu) \u003csup\u003e8)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE; mild (6), moderate (10), severe (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123I-IBZM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eST/OC(striatal to occipital cortex)\u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2000(Yim) \u003csup\u003e14)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; bilateral spastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThalamus or cerebellar cortex \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2001(Valkama)\u003csup\u003e19)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVLBW; birth weight\u0026thinsp;\u0026lt;\u0026thinsp;1,500 g, gestation age\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecerebellar cortex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2001(Tranquart) \u003csup\u003e46)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE 39.2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123I-IMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStriatum/cerebellum \u003c/p\u003e \u003cp\u003eactivity ratios \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2001 (S Shah)\u003csup\u003e11)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE; Sanart 2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eParasagital\u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2006(Okumura)\u003csup\u003e15)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; ATE due to kernicterus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSPECT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eall hypoperfusion\u003c/p\u003e \u003cp\u003eBG related to cortical area \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2010(Klaus Borch)\u003csup\u003e18)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePremature babies; 26-32W\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePeriventriclular\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2010 (Iwaibara) \u003csup\u003e7)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE; Sanart 2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elentiform nucleus \u0026darr; Thalamus \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2012(Lee)\u003csup\u003e21)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; SQ(11), HEMI(6), SD(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016(Rana)\u003csup\u003e17)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP; Spastic(91%), Asphyxia(69.6%) White matter change including PVL(73.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99mTc-ECD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecortex\u0026darr;, sub cortex\u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSeven papers included patients with CP, and five reported low cerebral perfusion in the thalamus area. Yamada et al. reported low cerebral perfusion in the cortex and corpus striatum, in addition to the thalamus\u003csup\u003e12)\u003c/sup\u003e. Lee et al. reported low cerebral perfusion of the cortex, basal ganglia and cerebellum, in addition to the thalamus\u003csup\u003e13)\u003c/sup\u003e. Yim et al. reported low cerebral perfusion in the cerebellum in addition to the thalamus\u003csup\u003e14)\u003c/sup\u003e. Okumura reported low cerebral perfusion of the basal ganglia connecting to the cortex\u003csup\u003e15)\u003c/sup\u003e. Kao reported low cerebral perfusion of occipital lesions in cases with visual disturbances and relevant cortical area in children with spastic quadiplesia\u003csup\u003e16)\u003c/sup\u003e. Rana reported low cerebral perfusion of the cortex and a subcortex lesion\u003csup\u003e17)\u003c/sup\u003e. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTwo articles provided information on neonates that were born with very low birth weight (VLBW); Borch reported that 13 VLBW cases with Periventricular Leukomalacia (PVL) had low cerebral blood flow in periventricular white matter lesions\u003csup\u003e18)\u003c/sup\u003e. Valkama reported low cerebral blood flow of the cortex, thalamus and cerebellum\u003csup\u003e19)\u003c/sup\u003e.(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn 1990 Iivanainen reported that SPECT was useful for the diagnosis of degenerative brain diseases (82%) \u003csup\u003e20)\u003c/sup\u003e, And that it was more sensitive than Electroencephalogram (EEG), CT and MRI. (Iivanainen 1990). Konishi reported that SPECT is better than other tests if done during the first week of life\u003csup\u003e10)\u003c/sup\u003e. Shah reported that the relationship between findings in a SPECT exam and neurological sequelae at three months of age had a positive predictive value of 75% (brain ultrasonography (USG) 60%) and negative predictive value of 100%༈USG 76%༉\u003csup\u003e11)\u003c/sup\u003e. Okumura suggested that SPECT might be useful in cases of kernicterus when no remarkable findings can be demonstrated on an MRI scan\u003csup\u003e15)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, two studies suggested that SPECT might not be the most appropriate test for neonatal HIE because of limited image resolution and risk of exposure to radiation. Indeed, there have been no reports of SPECT studies with neonates since 2016 with one exception \u0026ndash; for the study of epilepsy\u003csup\u003e10,19)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOf interest, SPECT was useful in one study to demonstrate cerebral perfusion in children with CP after stem cell therapy\u003csup\u003e21)\u003c/sup\u003e. Diverse neurological domains improved in five patients (25%) as assessed by developmental evaluation tools as well as by fractional anisotropy values in brain MRI-diffusion tensor imaging (DTI). The neurologic improvement was significant in patients with diplegia or hemiplegia rather than quadriplegia. The procedure was generally well-tolerated, although five patients experienced temporary nausea, hemoglobinuria, or urticaria during the intravenous infusion of the autologous umbilical cord blood (UCB) transfusion. They concluded that autologous UCB infusion is safe and feasible, and has yielded potential benefits in children with CP accompanied with improvement cerebral perfusion\u003csup\u003e21)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePET\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA total of 18 studies were reviewed to assess the benefit of PET for assessment of glucose matabolism. Fourteen studies used Fludeoxyglucose (18F) PET, two assessed GABA-A receptor binding using 18F PET \u003csup\u003e22\u0026ndash;23)\u003c/sup\u003e and two other groups reported cerebral blood flow\u003csup\u003e24\u0026ndash;25)\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePET studies on neonatal HIE and CP during 1991\u0026ndash;2020\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResult\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1991 (Kerrigan JF)\u003csup\u003e31)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSQ, SD, HEMI, Ate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCortex\u0026darr; (SD), BG\u0026darr;, Thalamus\u0026darr; ༈Ate༉\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1993(Suhonen-Polvi) \u003csup\u003e47)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSensorimotor cortex\u0026darr; cases with delayed development; subcortical lesion \u0026darr;, Thalamus \u0026darr;, cerebellum \u0026darr;, brainstem\u0026darr;(neonatal period and 3 mo)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1995 (M Blennow)\u003csup\u003e26)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrefrontal Cortex3/6\u0026uarr;, BG3/6\u0026uarr;,\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1995 (Kucukali I)\u003csup\u003e24)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGermanium68/gallium68 PET using 15O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWhole brain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1995(H Suhonen-Polvi) \u003csup\u003e27)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE and hypoglycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1996 (Azzarelli B)\u003csup\u003e28)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emost severe HIE; BG\u0026darr; Thalamus\u0026darr; brainstem\u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1997 (Rosenbaum)\u003csup\u003e25)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCBF with cesium fluoride scintilation detectors PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2006 (Wong VC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET body acupuncture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ebrain glucose metabolism showed a\u0026thinsp;\u0026gt;\u0026thinsp;10% increase in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2007 (Batista CE) \u003csup\u003e29)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP (Ate)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esevere cases; BG\u0026darr;, Thalamus\u0026darr;, early days after HIE; Transient BG\u0026uarr; (Ate)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2007 (Lee JD)\u003csup\u003e21)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSD due to PVL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecerebral GABAr PET by 18F-Fluoroflumazenil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013 (Park HJ) \u003csup\u003e23)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHEMI (human?)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-Fluoroflumazenil-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013 (Sharma A) \u003csup\u003e34)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP and MR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePET-CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSix months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013 (Min K)\u003csup\u003e6)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCompared with the EPO (n\u0026thinsp;=\u0026thinsp;33) and Control (n\u0026thinsp;=\u0026thinsp;32) groups, the pUCB (n\u0026thinsp;=\u0026thinsp;31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015 (Sharma A) \u003csup\u003e35)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015 (Sharma A) \u003csup\u003e5)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOverall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017 (Rah WJ) \u003csup\u003e33)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020 (Fowler EG)\u003csup\u003e30)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpastic CP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCortex\u0026darr;, cerebellar\u0026uarr; in children with less SVMC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020 (Gu J)\u003csup\u003e4)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18F-FDG-PET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 patients received treatments and completed the scheduled assessments. No significant difference was shown between the 2 groups in AE incidence.Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor those using Fludeoxyglucose (18F) PET, four studies investigated cases with HIE, of whom three reported glucose metabolism of the basal ganglia and the thalamus. Blennow reported that none of those with low glucose metabolism and half (3/6) of those with high glucose metabolism in the basal ganglia region at two and a half days after birth\u003csup\u003e26)\u003c/sup\u003e.(M Blennow,1995) Suhonen-Polvi et al. reported low glucose metabolism in the cortex, basal ganglia and thalamus in cases with neurological sequaela during the first week of life and three months of life. The repeated PET study showed that the uptake of FDG was markedly high and increased in all brain sections of infants with normal development (n\u0026thinsp;=\u0026thinsp;11), whereas those with delayed development (n\u0026thinsp;=\u0026thinsp;4) had significantly lower values (P\u0026thinsp;\u0026lt;\u0026thinsp;or =\u0026thinsp;0.005). \u003csup\u003e27)\u003c/sup\u003e. (Suhonen-Polvi H 1995) Azzarelli reported low glucose metabolism of the brain stem region in addition to basal ganglia and thalamus, in severe cases in which 10/12 infants died at the age of 2 to 12 weeks\u003csup\u003e28)\u003c/sup\u003e. (Azzarelli B, 1996)\u003c/p\u003e \u003cp\u003eWhen it comes to children with CP, 2/3 papers reported cases with spastic diplegia with low glucose metabolism of the cortex\u003csup\u003e29\u0026ndash;30)\u003c/sup\u003e.(Batista CE 2007)(Fowler EG 2020) Two papers reported children with athetoid CP (\u0026ldquo;dyskinetic cerebral palsy\u0026rdquo;) who were found to have low glucose metabolism in the basal ganglia\u003csup\u003e29,31)\u003c/sup\u003e.(Kerrigan JF 1991)(Batista CE,2007) Batista reported that neonates with athetoid CP with transient high glucose metabolism in the basal ganglia \u003csup\u003e29)\u003c/sup\u003e.(Batista CE,2007) Human umbilical cord derived mesenchymal stromal cell (UC-MSC) therapies for individuals with CP showed improvement in motor function and increase in glucose metabolism by PET-CT scan\u003csup\u003e4)\u003c/sup\u003e (Gu et al. 2020).\u003c/p\u003e \u003cp\u003eVirginia et al. reported that the brain glucose metabolism was more than 10% higher in the frontal, parietal, temporal, and occipital cortices and cerebellum after a short course of tongue and body acupuncture in CP using PET\u003csup\u003e32)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCell therapy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRecently, PET and SPECT have been used for the investigation of the effectiveness of cell therapies. We identified six clinical studies for CP from 18 articles on PET and one from 17 articles who studied on SPECT since 2013.(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) PET and SPECT were performed before and after cell therapies for cases with cerebral palsy. Six articles on PET consist of one by human umbilical cord derived mesenchymal stromal cells(hUC-MSC)\u003csup\u003e4)\u003c/sup\u003e, one mobilized peripheral blood mononuclear cells (mPBMCs) \u003csup\u003e33)\u003c/sup\u003e, three autologous bone marrow mononuclear cells (BMMNCs) \u003csup\u003e5, 34\u0026ndash;35)\u003c/sup\u003e, one allogeneic umbilical cord blood\u003csup\u003e6)\u003c/sup\u003e. Four of six paper reported that PET-CT scan showed much increase of glucose metabolism and one of six no significant change of glucose metabolism after cell therapy. One article on SPECT reported that two from five cases showed improvement of cerebral perfusion in the thalamus by SPECT after autologous cord blood treatment\u003csup\u003e13)\u003c/sup\u003e. Most studies were performed using intrathecal (IT) (n\u0026thinsp;=\u0026thinsp;3) and intravenous (IV)(n\u0026thinsp;=\u0026thinsp;4) injection. Administration was once in 6 studies and four times in one study. As with adverse events, allogeneic UCB with rhEPO showed ten serious adverse events that required the hospitalization of nine patients among the 105 recruited participants. A 25-month-old female died after allogeneic UCB with rhEPO at 14 weeks post-treatment. (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReferences related to change of PET or SPECT score for neonatal HIE and CP after cell therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference Number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRoute\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCell number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2013(Sharma)\u003csup\u003e35)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP and MR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAuto\u003c/p\u003e \u003cp\u003eBMMNC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 1 \u0026times; 106 CD34\u0026thinsp;+\u0026thinsp;cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSix months following Autologous Bone Marrow Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone reported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2013 (Min )\u003csup\u003e6)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ealloUCB with rhEPO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 3 \u0026times; 107/kg total nucleated cells (TNCs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCompared with the EPO (n\u0026thinsp;=\u0026thinsp;33) and Control (n\u0026thinsp;=\u0026thinsp;32) groups, the pUCB (n\u0026thinsp;=\u0026thinsp;31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTen serious adverse events that required hospitalization of nine patients were reported among the 105 recruited participants; similar between the three groups. The death of a 25-month-old female in the pUCB group at 14 weeks post-treatment. She was quadriplegic with spasticity from profound hypoxia with involvement of the central gray matter and brainstem. She had severe motor impairment and was unable to control her head. She was medically stable post-treatment with continuous neurological improvement up until the 3-month follow-up evaluation. During routine seizure follow-up, she was found to be neurologically stable. The same day she died during sleep with no apparent cause, and determined not to be related to the treatment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2015(Sharma) \u003csup\u003e35)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAuto\u003c/p\u003e \u003cp\u003eBMMNCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 3.3 \u0026times; 107 total nucleated cells (TNCs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOn repeating the Functional Independence Measure (FIM), the score increased from 90 to 113. A repeat PET-CT scan of the brain six months after intervention showed progression of the mean standard deviation values towards normalization which correlated to the functional changes. At one year, all clinical improvements have remained.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNone reported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2015(Sharma) \u003csup\u003e5)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBMMNCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 10.23 \u0026times; 106 CD34\u0026thinsp;+\u0026thinsp;cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOverall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAt the time of the procedure, there were no complications recorded. During the hospital stay, a few patients did show minor procedure related adverse events-15% a spinal headache, 7.5% nausea, 30% vomiting, 12.5% pain at the site of injection, and 2.5% diarrhea. These events were self-limiting and relieved within one-week using medication. The only major adverse event noted related to cell transplantation was seizures - in 2 patients.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2017 (Rah)\u003csup\u003e33)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emPBMCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1st 4.63\u0026thinsp;\u0026plusmn;\u0026thinsp;2.88 \u0026times; 108/kg 2nd 6.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94\u0026times; 108/kg TNCs,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTransient hemoglobinuria (n\u0026thinsp;=\u0026thinsp;3) and abdominal pain (n\u0026thinsp;=\u0026thinsp;1) were reported during the mPBMC infusion, and these were resolved with supportive treatments.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePET\u003c/p\u003e \u003cp\u003e2020 (Gu)\u003csup\u003e4)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehUC-MSCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50 \u0026times; 107 MSC cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9 patients received treatments and completed the scheduled assessments. Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo significant difference between hUC-MSC and control in AE incidence. Serious adverse events were not observed. Upper respiratory infections were reported most frequently (52.6%). Diarrhea (31.6%) fever (36.8%) with a high incidence.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSPECT\u003c/p\u003e \u003cp\u003e2012 (Lee) \u003csup\u003e21)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAuto\u003c/p\u003e \u003cp\u003eUCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 \u0026times; 5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 (0.6\u0026thinsp;~\u0026thinsp;15.65) \u0026times; 107 TNCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eThe neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eInfusion was generally well-tolerated, even without premedication, although 3 patients experienced temporary nausea and hemoglobinuria, and 2 patients experienced hemoglobinuria and urticaria, but these were easily controlled with peniramine or intravenous hydration.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003ePerinatal complications may result in severe motor disability with a prevalence of 1\u0026ndash;2 per 1000 live births in developed countries causing significant burden of illness and necessitating extensive multidisciplinary care\u003csup\u003e36)\u003c/sup\u003e. (Jacobs S. 2007)\u003c/p\u003e \u003cp\u003eDespite large body of research over the last three decades, no clinically meaningful interventions are offered in order to repair damage to the areas of the brain that were found responsible for control of muscle coordination and movement\u003csup\u003e37)\u003c/sup\u003e. (J Pediatrics. 2004 Aug; 145(2):S42-4\u003c/p\u003e \u003cp\u003eUse of SPECT imaging studies among neonates (0\u0026ndash;7 days of life) with moderate to severe HIE suggest low cerebral perfusion of the thalamus and basal ganglia regions, despite seeing no such discoveries on MRI scan. Similarly, SPECT findings are associated with low cerebral perfusion of cortex area while none are seen on MRI. Our prior study\u003csup\u003e7)\u003c/sup\u003e (Iwaibara 2010), as well as other published studies, reported that SPECT was a useful modality to identify low cerebral perfusion of the thalamus or orbitofrontal area compared to MRI. SPECT was also shown to be useful to diagnose HIE and CP. Further evidence suggests that SPECT in the first few weeks of life is useful and more sensitive than MRI in predicting major neurological disability. However, because of the risk of radiation, improvements in MR angiography and high cost of SPECT, it is not popular for all neonates. Indeed, there have been no reports of the use of SPECT for evaluation of neonatal diseases such as HIE or CP since 2016, except those evaluating epilepsy. Ultrasonography, MR Spectroscopy or MR angiography, having no risk of exposure to radiation, were the preferred modality. \u003csup\u003e38\u0026ndash;40)\u003c/sup\u003e.(Groenendaal 2016, Aida 2021,O Tierradentro-Garc\u0026iacute;a 2021)\u003c/p\u003e \u003cp\u003eGlucose metabolism has been the focus of identifying the pathology associated with cerebral ischemic disease in neonatal HIE, CP and cerebral infarction\u003csup\u003e41)\u003c/sup\u003e.(Nabetani) PET studies reported high glucose metabolism in the early neonatal periods in children with mild to moderate HIE, but not in the most severe cases, including those neonates that perished. Nonetheless, studies using SPECT reported that cases with severe HIE reported to have low cerebral perfusion. It is possible that the brain may keep sufficient glucose metabolism despite reduced cerebral perfusion. The mechanism of MSCs to improve glucose metabolism might lead to therapeutic potential for individuals CP.\u003c/p\u003e \u003cp\u003eWe reported that the importance of glucose for neural activity in hippocampal slices of immature and adult rats during deprivation of oxygen and/or glucose\u003csup\u003e41)\u003c/sup\u003e.(Nabetani 1995). We evaluated the relationship between neural activity and energy levels in neonatal brain. During episodes of hypoxia and glucose deprivation, adenosine triphosphate (ATP) levels of noted to be preserved in neonates, compared to adult brains. This suggests that energy consumption of the immature brain is smaller than that in the adult brain. During glucose deprivation, neural activity of neonatal rats ceased rapidly although the level of ATP is preserved at high levels. This suggests that glucose plays an important role in the preservation of neural activity in addition to its major function as an energy substrate in neonatal brains\u003csup\u003e41)\u003c/sup\u003e.(Nabetani 1995)\u003c/p\u003e \u003cp\u003eLactate has been shown to be important in maintaining neural function as an energy substrate and energy transporter. We previously reported the possibility of lactate preserving neural function of the adult brain and that glucose metabolites such as lactate and OHBA(beta-hydroxybutyrate) are available for both neural activity as well as maintaining the levels of high-energy phosphates in the tissue slice of neonatal rats\u003csup\u003e42\u0026ndash;43)\u003c/sup\u003e. (Saitoh 1994) (Wada 1997)\u003c/p\u003e \u003cp\u003eIn this study, some article have reported that glucose metabolism improved in clinical experiences for a case with CP after stem cell therapy, evaluated by PET, as well as cerebral perfusion by SPECT. UCB (umbilical cord blood) and peripheral blood mononuclear cells infusion therapy for patients with CP improved brain glucose metabolism. Six months following Autologous BM Derived MNCs therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning\u003csup\u003e6)\u003c/sup\u003e. (Min et al. 2013) Rah et al. reported that the administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. Close to half (42.6%) of patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. The results showed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans and no significant differences in such changes between the mPBMC and placebo\u003csup\u003e33)\u003c/sup\u003e. (Rah et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Sharma et al. reported that autologous bone marrow mononuclear cells therapies for patients with CP also showed improvement of motor function and glucose metabolism. At six months of age, 95% of patients showed improvement. PET-CT scan done in six patients showed metabolic improvements in areas of the brain correlating to clinical improvements\u003csup\u003e5)\u003c/sup\u003e.(Sharma et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) The improvement of glucose metabolism might be caused by improvement of GAP junction-mediated cell-cell interaction. In 2020, Kikuchi-Taura et al. reported that angiogenesis is activated by bone marrow mononuclear cells via gap junction\u0026ndash;mediated cell\u0026ndash;cell interaction and that cell\u0026ndash;cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells and improvement of glucose uptake. Transplanted BM-MNCs transferred small molecules to endothelial cells via gap junction followed by activated Hif-1α and suppressed autophagy at endothelial cells\u003csup\u003e44)\u003c/sup\u003e.(Kikuchi-Taura et al. \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). We suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003ePET might be a good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cerebral palsy\u003c/p\u003e\n\u003cp\u003eHIE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hypoxic\u0026ndash;ischemic encephalopathy\u003c/p\u003e\n\u003cp\u003eMSCs\u0026nbsp; \u0026nbsp; \u0026nbsp;mesenchymal stromal cells\u003c/p\u003e\n\u003cp\u003eBM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; bone marrow\u003c/p\u003e\n\u003cp\u003eBM-MNCs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;bone marrow mononuclear cells\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUC-MSCs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;umbilical cord derived-MSCs\u003c/p\u003e\n\u003cp\u003ePVL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; periventricular leukomalacia\u003c/p\u003e\n\u003cp\u003eUCB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; umbilical cord blood\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBM-MSCs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;BM\u0026ndash;derived mesenchymal stromal cells\u003c/p\u003e\n\u003cp\u003emPBMCs\u0026nbsp; mobilized peripheral blood mononuclear cells\u003c/p\u003e\n\u003cp\u003eATP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; adenosine triphosphate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOHBA\u0026nbsp; \u0026nbsp;\u0026nbsp; beta-hydroxybutyrate\u003c/p\u003e\n\u003cp\u003eIVH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; intraventricular hemorrhage\u003c/p\u003e\n\u003cp\u003eASD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; autism spectrum disorder\u003c/p\u003e\n\u003cp\u003eIT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; intrathecal\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; intravenous\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePET\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; positron emission topography\u003c/p\u003e\n\u003cp\u003eSPECT \u0026nbsp;Single Photon Emission Computed Tomography\u003c/p\u003e\n\u003cp\u003eG-CSF\u0026nbsp;\u0026nbsp;Granulocyte Colony Stimulating Factor\u003c/p\u003e\n\u003cp\u003erhEPO \u0026nbsp;Recombinant human erythropoietin\u003c/p\u003e\n\u003cp\u003eUSG \u0026nbsp; \u0026nbsp;Ultrasonography\u003c/p\u003e\n\u003cp\u003eDTI \u0026nbsp; \u0026nbsp; diffusion tensor imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: We have no fund support for this study.\u003c/p\u003e\n\u003cp\u003eConflicts of Interest: The authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eT Shinomoto , M Nabetani , K Kobata , A Mima , N Yutaka , H Sano. The utility of neonatal MRI for prediction of outcome with neonatal Hypoxic-Ischemic Encephalopathy. Nihon-shusanki-sinseijigakkaishi(Jpn) 2018, 54(1): 55-59\u003c/li\u003e\n\u003cli\u003eJoseph j Volpe, P Herscovitch, Jeffrey M Perlman, Katherine L Kreusser, Marcus E Raiche. Positron Emission Tomography in the Asphyxiated Term Newborn: Parasagittal Impairment of Cerebral Blood Flow. Ann Neurol 1985 17:287-296\u003c/li\u003e\n\u003cli\u003eMakoto Nabetani, et al. Preventing Brain Damage from Hypoxic\u0026ndash;Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells. Am J Perinatology 2021, Apr 14\u003c/li\u003e\n\u003cli\u003eGu J, Huang L, Zhang C, Wang Y, Zhang R, Tu Z, Wang H, Zhou X, Xiao Z, Liu Z, Hu X, Ke Z, Wang D, Liu L. Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial. Stem Cell Res Ther. 2020 Feb 3;11(1):43.\u003c/li\u003e\n\u003cli\u003eSharma A, Sane H, Gokulchandran N, Kulkarni P, Gandhi S, Sundaram J, Paranjape A, Shetty A, Bhagwanani K, Biju H, Badhe P. A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier. Stem Cells Int. 2015;2015:905874. doi: 10.1155/2015/905874. Epub 2015 Feb 18.\u003c/li\u003e\n\u003cli\u003eMin K, Song J, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK, Kim SS, Kim M. Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells. 2013 Mar;31(3):581-91.\u003c/li\u003e\n\u003cli\u003eIwaibara T, Ri S, Nabetani M, et al. Studies of quantitative SPECT on bilateral basal ganglia and thalamic lesions (BGTL) in hypoxic ischemic encephalopathy (HIE). Hot Topics in the neonatology John Wiley \u0026amp; Sons: Washington DC 2010.\u003c/li\u003e\n\u003cli\u003eKapucu LO, Atalay Y, van Royen E. et al. D2 receptor imaging with iodine-123-iodobenzamide brain SPECT in infants with hypoxic-ischemic brain injury. J Nucl Med 1998 Oct;39(10):1703-7.\u003c/li\u003e\n\u003cli\u003eOshima M, Suzuki C, Sasaki J, Kitoh O, Yasukochi H. Evaluation of newborns with brain disease using 123I-IMP SPECT. Kaku Igaku 1993 Jul;30(7):727-33.\u003c/li\u003e\n\u003cli\u003eKonishi Y, Kuriyama M, Mori I, Fujii Y, Konishi K, Sudo M, Ishii Y. Assessment of local cerebral blood flow in neonates with N-isopropyl-P-[123I]iodoamphetamine and single photon emission computed tomography. Brain Dev 1994 Nov-Dec;16(6):450-3. doi: 10.1016/0387-7604(94)90006-x.\u003c/li\u003e\n\u003cli\u003eShah S, Fernandez AR. Chirla D. Role of brain SPECT in neonates with hypoxic ischemic encephalopathy and its correlation with neurodevelopmental outcome. Indian Pediatr. 2001 Jul;38(7):705-13.\u003c/li\u003e\n\u003cli\u003eYamada K, Tsuzura S, Matsuda H. Brain MRI and single photon emission computed tomography in severe athetotic cerebral palsy: a comparative study with mental and motor disorders. No To Hattatsu 1995, Jul;27(4):269-75.\u003c/li\u003e\n\u003cli\u003eLee JD, Kim DI, Ryu YH, Whang GJ, Park CI, Kim DG. Technetium-99m-ECD brain SPECT in cerebral palsy: comparison with MRI. J Nucl Med 1998, Apr;39(4):619-23.\u003c/li\u003e\n\u003cli\u003eYim SY, Lee IY, Park CH, Kim OH. A qualitative analysis of brain SPECT for prognostication of gross motor development in children with cerebral palsy. Clin Nucl Med 2000 Apr;25(4):268-72. doi: 10.1097/00003072-200004000-00006.\u003c/li\u003e\n\u003cli\u003eOkumura A, Hayakawa F, Maruyama K, Kubota T, Kato K, Watanabe K. Single photon emission computed tomography and serial MRI in preterm infants with kernicterus. Brain Dev. 2006 Jul;28(6):348-52. doi: 10.1016/j.braindev.2005.11.004. Epub 2006 Feb 14.\u003c/li\u003e\n\u003cli\u003eKao CH, Wang SJ, Yeh SH. The relationship among the quantitative perfusion-defect indices in Tc-99m HMPAO brain SPECT, IQ test, and involved extremities in children with cerebral palsy due to perinatal asphyxia. Clin Nucl Med 1994 Apr;19(4):309-13. doi: 10.1097/00003072-199404000-00007.\u003c/li\u003e\n\u003cli\u003eRana KS, Narwal V, Chauhan L, Singh G, Sharma M, Chauhan S. Structural and Perfusion Abnormalities of Brain on MRI and Technetium-99m-ECD SPECT in Children With Cerebral Palsy: A Comparative Study. J Child Neurology 2016, Apr;31(5):589-92. \u003c/li\u003e\n\u003cli\u003eB\u0026oslash;rch Klaus, Lou HC, Greisen G. Cerebral white matter blood flow and arterial blood pressure in preterm infants. Acta Paediatr 2010 Oct;99(10):1489-92. doi: 10.1111/j.1651-2227.2010.01856.x. \u003c/li\u003e\n\u003cli\u003eValkama AM, Ahonen A, Vainionp滑 L, Torniainen P, Lanning P, Koivisto M. Brain single photon emission computed tomography at term age for predicting cerebral palsy after preterm birth. Biol Neonate 2001 Jan;79(1):27-33. doi: 10.1159/000047062.\u003c/li\u003e\n\u003cli\u003eM Iivanainen 1 , J Launes, H Pihko, P Nikkinen, L Lindroth. Single-photon emission computed tomography of brain perfusion: analysis of 60 paediatric cases. Dev Med Child Neurol 1990 Jan;32(1):63-8. doi: 10.1111/j.1469-8749.1990.tb08468.x.\u003c/li\u003e\n\u003cli\u003eLee YH, Choi KV, Moon JH, Jun HJ, Kang HR, Oh SI, Kim HS, Um JS, Kim MJ, Choi YY, Lee YJ, Kim HJ, Lee JH, Son SM, Choi SJ, Oh W, Yang YS. Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. J Translat Med 2012, Mar 23;10:58. doi: 10.1186/1479-5876-10-58.\u003c/li\u003e\n\u003cli\u003eLee JD, Park HJ, Park ES, Kim DG, Rha DW, Kim EY, Kim DI, Kim JJ, Yun M, Ryu YH, Lee J, Jeong JM, Lee DS, Lee MC, Park CI. Assessment of regional GABA(A) receptor binding using 18F-fluoroflumazenil positron emission tomography in spastic type cerebral palsy. Neuroimage. 2007 Jan 1;34(1):19-25.\u003c/li\u003e\n\u003cli\u003ePark HJ, Kim CH, Park ES, Park B, Oh SR, Oh MK, Park CI, Lee JD. Increased GABA-A receptor binding and reduced connectivity at the motor cortex in children with hemiplegic cerebral palsy: a multimodal investigation using 18F-fluoroflumazenil PET, immunohistochemistry, and MR imaging. J Nucl Med. 2013 Aug;54(8):1263-9\u003c/li\u003e\n\u003cli\u003eKucukali I, De Reuck J, Decoo D, Strijckmans K, Goethals P, Lemahieu I. Positron emission tomography in spastic diplegia. Clin Neurol Neurosurg. 1995 Feb;97(1):28-31.\u003c/li\u003e\n\u003cli\u003eRosenbaum JL, Almli CR, Yundt KD, Altman DI, Powers WJ. Higher neonatal cerebral blood flow correlates with worse childhood neurologic outcome. Neurology 1997 Oct;49(4):1035-41.\u003c/li\u003e\n\u003cli\u003eM Blennow 1 , M Ingvar, H Lagercrantz, S Stone-Elander, L Eriksson, H Forssberg, K Ericson, O Flodmark. Early [18F]FDG positron emission tomography in infants with hypoxic-ischaemic encephalopathy shows hypermetabolism during the postasphyctic period. Acta Paediatr 1995 Nov;84(11):1289-95.\u003c/li\u003e\n\u003cli\u003eH Suhonen-Polvi 1 , U Ruotsalainen, A Kinnala, J Bergman, M Haaparanta, M Ter郭, P M akel a, O Solin, U Wegelius. FDG-PET in early infancy: simplified quantification methods to measure cerebral glucose utilization J Nucl Med. 1995 Jul;36(7):1249-54.\u003c/li\u003e\n\u003cli\u003eAzzarelli B, Caldemeyer KS, Phillips JP, DeMyer WE. Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study. Pediatr Neurol. 1996 Feb;14(2):108-16.\u003c/li\u003e\n\u003cli\u003eBatista CE, Chugani HT, Shankaran S.et al. Transient hypermetabolism of the basal ganglia following perinatal hypoxia. Pediatr Neurol. 2007 May;36(5):330-3.\u003c/li\u003e\n\u003cli\u003eFowler EG, Oppenheim WL, Greenberg MB, Staudt LA, Joshi SH, Silverman DHS. Brain Metabolism During A Lower Extremity Voluntary Movement Task in Children With Spastic Cerebral Palsy. Front Hum Neurosci. 2020 May 25;14:159.\u003c/li\u003e\n\u003cli\u003eKerrigan JF, Chugani HT, Phelps ME. Regional cerebral glucose metabolism in clinical subtypes of cerebral palsy. Pediatr Neurol. 1991 Nov-Dec;7(6):415-25.\u003c/li\u003e\n\u003cli\u003eVirginia C N Wong , Jie-Guang Sun, David W C Yeung. Pilot study of positron emission tomography (PET) brain glucose metabolism to assess the efficacy of tongue and body acupuncture in cerebral palsy. J Child Neurol. 2006 Jun;21(6):456-62.\u003c/li\u003e\n\u003cli\u003eRah WJ, Lee YH, Moon JH, Jun HJ, Kang HR, Koh H, Eom HJ, Lee JY, Lee YJ, Kim JY, Choi YY, Park K, Kim MJ, Kim SH. Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study. J Transl Med. 2017 Jan 21;15(1):16.\u003c/li\u003e\n\u003cli\u003eSharma A, Sane H, Paranjape A, Gokulchandran N, Kulkarni P, Nagrajan A, Badhe P. Positron emission tomography-computer tomography scan used as a monitoring tool following cellular therapy in cerebral palsy and mental retardation-a case report. Case Rep Neurol Med. 2013;2013:141983.\u003c/li\u003e\n\u003cli\u003eSharma A, Sane H, Kulkarni P, D\u0026apos;sa M, Gokulchandran N, Badhe P. Improved Quality of Life in A Case of Cerebral Palsy after Bone Marrow Mononuclear Cell Transplantation. Cell J. 2015 Summer;17(2):389-94.\u003c/li\u003e\n\u003cli\u003eJacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;(04):CD003311\u003c/li\u003e\n\u003cli\u003eMurray Goldstein, The treatment of cerebral palsy: What we know, what we don\u0026apos;t know. J of Pediatrics 2004 Aug;145(2 Suppl):S42-6. doi: 10.1016/j.jpeds.2004.05.022.\u003c/li\u003e\n\u003cli\u003eFloris Groenendaal, Linda S de Vries, Fifty years of brain imaging in neonatal encephalopathy following perinatal asphyxia Pediatr Res. 2017 Jan;81(1-2):150-155. doi: 10.1038/pr.2016.195. Epub 2016 Sep 27.\u003c/li\u003e\n\u003cli\u003eNoriko Aida, 1H-MR Spectroscopy of the Early Developmental Brain, Neonatal Encephalopathies, and Neurometabolic Disorders. Magn Reson Med Sci. 2021 Aug 21. doi: 10.2463/mrms.rev.2021-0055. \u003c/li\u003e\n\u003cli\u003eLuis Octavio Tierradentro-Garc\u0026iacute;a , Sandra Saade-Lemus, Colbey Freeman, Matthew Kirschen, Hao Huang, Arastoo Vossough, Misun Hwang. Cerebral Blood Flow of the Neonatal Brain after Hypoxic-Ischemic Injury. Am J Perinatol . 2021 Jul 5. doi: 10.1055/s-0041-1731278. \u003c/li\u003e\n\u003cli\u003eM Nabetani et al. Neural activity and the levels of high energy phosphates during deprivation of oxygen and/or glucose in hippocampal slices of immature and adult rats. Int J of Developmental Neurosci 1995 Feb;13(1):3-12\u003c/li\u003e\n\u003cli\u003eSaitoh, M.; Okada, Y.; Nabetani, M., Effect of mannose, fructose and lactate on the preservation of synaptic potentials in hippocampal slices. Neurosci letters 1994, 171, (1-2), 125-8.\u003c/li\u003e\n\u003cli\u003eWada, H.; Okada, Y.; Nabetani, M.; Nakamura, H., The effects of lactate and beta-hydroxybutyrate on the energy metabolism and neural activity of hippocampal slices from adult and immature rat. Brain research. Developmental brain research 1997, 101, (1-2), 1-7.\u003c/li\u003e\n\u003cli\u003eKikuchi-Taura A, Okinaka Y, Takeuchi Y, et al. Bone marrow mononuclear cells activate angiogenesis via GAP junction-mediated cell-cell interaction. Stroke 2020, 51(04):1279\u0026ndash;1289\u003c/li\u003e\n\u003cli\u003eSztriha L, al Suhaili AR, Prais V, Nork M. Regional cerebral blood perfusion in children with hemiplegia: A SPECT study. Neuropediatrics 1996 Aug;27(4):178-83. doi: 10.1055/s-2007-973783.\u003c/li\u003e\n\u003cli\u003eTranquart F, Saliba E, Barantin L, Lanneau M, Simmer L, Guilloteau D, Baulieu JL. D2 receptor imaging in neonates using I-123 iodobenzamide brain SPECT. Clin Nucl Med 2001 Jan;26(1):36-40. doi: 10.1097/00003072-200101000-00009.\u003c/li\u003e\n\u003cli\u003eSuhonen-Polvi H, Kero P, Korvenranta H, Ruotsalainen U, Haaparanta M, Bergman J, Simell O, Wegelius U. Repeated fluorodeoxyglucose positron emission tomography of the brain in infants with suspected hypoxic-ischaemic brain injury. Eur J Nucl Med. 1993 Sep;20(9):759-65. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PET, SPECT, Cerebral palsy, HIE, Cell therapy","lastPublishedDoi":"10.21203/rs.3.rs-1491013/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1491013/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGlucose metabolism has been the focus of research in order to understand pathological conditions associated with diseases such as neonatal hypoxic-ischemic-encephalopathy (HIE), cerebral palsy (CP) and cerebral infarction.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e[Objective]\u003c/strong\u003e To evaluate the use of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy, and to propose future perspectives on the use of those modalities for assessment of brain function in children with these conditions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e[Methods]\u003c/strong\u003e PubMed search for studies using PET or SPECT scans for HIE and CP in children.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e[Results]\u003c/strong\u003e We identified 18 PET and 17 SPECT studies that have been performed in cases under age of 19 over the past three decades (1991–2021). Six papers on PET use consisted of one with human umbilical cord derived mesenchymal stromal cells, one mobilized peripheral blood mononuclear cells, three autologous bone marrow mononuclear cells and one allogeneic umbilical cord blood. 4/6 papers reported that PET-CT scan revealed increased glucose metabolism and 1/6 showed no significant change in glucose metabolism after cell therapy. One article on SPECT reported that 2/5 cases had improvement of cerebral perfusion in the thalamus after treatment.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e[Discussion]\u003c/strong\u003e SPECT in the first few weeks of life is useful and more sensitive than MRI in predicting major neurological disability. SPECT is not appropriate for neonates because of the risk of radiation, improvement of other clinical test equipment. PET studies reported high glucose metabolism in the early neonatal periods in children with mild to moderate HIE, but not in the most severe cases, including those neonates that died.\u003c/p\u003e\u003cp\u003eWe suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e[Conclusion] \u003c/strong\u003ePET might be a good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely.\u003c/p\u003e","manuscriptTitle":"Molecular Imaging (PET and SPECT) for Children with Hypoxic-ischemic-encephalopathy and Cerebral Palsy before and after cell therapy.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-25 15:05:41","doi":"10.21203/rs.3.rs-1491013/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82379f75-5de8-413a-87e1-05f1923255b3","owner":[],"postedDate":"April 25th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-04-25T15:05:43+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-25 15:05:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1491013","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1491013","identity":"rs-1491013","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}