Molecular Imaging (PET and SPECT) for Children with Hypoxic-Ischemic-Encephalopathy and Cerebral Palsy Before and After Cell Therapy

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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; CT: Computed Tomography; G-CSF: Granulocyte Colony Stimulating Factor; rhEPO: recombinant human Erythropoietin; USG: Ultrasonography; DTI: Diffusion Tensor Imaging

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 (Shinomoto T, et al., 2018).

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 (Volpe JJ, et al., 1985).

Furthermore, evidence suggest the effectiveness of stem cell therapy for improvement in patients with CP (Nabetani M, et al., 2021) 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 (Gu J, et al., 2020; Sharma A, et al., 2015; Min K, et al., 2013).

Materials and Methods

The purpose of this study 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.

Results

Single Photon Emission Computed Tomography (SPECT)

Six studies included patients with HIE, four reported low cerebral perfusion in the basal ganglia in patients with HIE (Iwaibara T, et al., 2010), and low cerebral perfusion in the lentiform nucleus and thalamus in half (3/6) of the patients with severe HIE. Tranquart F, et al. reported low corpus striatum-to-cerebellum activity ratio in cerebral perfusion (Tranquart F, et al., 2001). Kapucu LO, et al. reported low striatal-to-occipital cortex ratio in cerebral perfusion (Kapucu LO, et al., 1998) and Oshima M, et al. reported low cerebral perfusion in the entire brain (Oshima M, et al., 1993). Three studies reported cerebral perfusion of parasagittal lesions (OshimaM, et al., 1993; Konishi Y, et al., 1994; Shah S, et al., 2001). Konishi Y, 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 (Konishi Y, et al., 1994). Oshima M, et al. reported low cerebral perfusion in the parasagittal region in cases with mild HIE (Oshima M, et al., 1993). Shah reported low cerebral perfusion of parasagittal lesions in 5/12 cases (Shah S, et al., 2001) (Table 1).

Table 1: SPECT studies on neonatal HIE and CP during 1991-2020

Seven papers included patients with CP, and five reported low cerebral perfusion in the thalamus area. Yamada K, et al. reported low cerebral perfusion in the cortex and corpus striatum, in addition to the thalamus (Yamada K, et al., 1995). Lee JD, et al. reported low cerebral perfusion of the cortex, basal ganglia and cerebellum, in addition to the thalamus (Lee JD, et al., 1998). Yim SY, et al. reported low cerebral perfusion in the cerebellum in addition to the thalamus (Yim SY, et al., 2000). Okumura A, et al. reported low cerebral perfusion of the basal ganglia connecting to the cortex (Okumura A, et al., 2006). Kao CH, et al. reported low cerebral perfusion of occipital lesions in cases with visual disturbances and relevant cortical area in children with spastic quadiplesia (Kao CH, et al., 1994). Rana KS, et al. has reported low cerebral perfusion of the cortex and a sub- cortex lesion (Rana KS, et al., 2016) (Table 1).

Two articles provided information on neonates that were born with Very Low Birth Weight (VLBW). Borch K, et al. reported that 13 VLBW cases with Periventricular Leukomalacia (PVL) had low cerebral blood flow in periventricular white matter lesions (Borch K, et al., 2010). Valkama AM, et al. reported low cerebral blood flow of the cortex, thalamus and cerebel- lum (Valkama AM, et al., 2001) (Table 1).

Iivanainen M, et al. reported that SPECT was useful for the diagnosis of degenerative brain diseases (82%) (Iivanainen M, et al., 1990) and it was more sensitive than Electroencephalogram (EEG), CT and MRI. Konishi Y, et al. reported that SPECT is better than other tests if done during the first week of life (Konishi Y, et al., 1994). Shah S, et al. 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 Ultra- sonography (USG) 60%) and negative predictive value of 100% (USG 76%) (Shah S, et al., 2001). Okumura A, et al. suggested that SPECT might be useful in cases of kernicterus when no remarkable findings can be dem- onstrated on an MRI scan (Okumura A, et al., 2006).

However, two studies suggested that SPECT might not be the most appro- priate test for neonatal HIE because of limited image resolution and risk of exposure to radiation. Indeed, there have been no reports of SPECT stud- ies with neonates since 2016 with one exception-for the study of epilepsy (Konishi Y, et al., 1994; Valkama AM, et al., 2001).

Of interest, SPECT was useful in one study to demonstrate cerebral per- fusion in children with CP after stem cell therapy (Lee YH, et al., 2012). 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 improve- ment 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 dur- ing the Intravenous (IV) 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 accom- panied with improvement cerebral perfusion (Lee YH, et al., 2012).

Positron Emission Topography (PET)

A total of 18 studies were reviewed to assess the benefit of PET for assess- ment of glucose matabolism. Fourteen studies used Fludeoxyglucose (18F) PET, two assessed GABA-A receptor binding using 18F PET (Lee JD, et al., 2007; Park HJ, et al., 2013) and two other groups reported cerebral blood flow (Kücükali I, et al., 1995; Rosenbaum JL, et al., 1997) (Table 2).

Table 2: PET studies on neonatal HIE and CP during 1991-2020

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 M, et al. 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 (Blennow M, et al., 1995). Suhonen-Polvi H, et al. reported low glucose metabolism in the cortex, basal ganglia and thalamus in cases with neurological sequaela dur- ing the first week of life and three months of life. The repeated PET study showed that the uptake of Fludeoxyglucose (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 val- ues (P ≤ 0.005) (Suhonen-Polvi H, et al., 1995). Azzarelli B, et al. reported low glucose metabolism of the brain stem region in addition to basal gan- glia and thalamus, in severe cases in which 10/12 infants died at the age of 2 to 12 weeks (Azzarelli B, et al., 1996).

When it comes to children with CP, 2/3 papers reported cases with spastic diplegia with low glucose metabolism of the cortex (Batista CE, et al., 2007; Fowler EG, et al., 2020). Two papers reported children with athetoid CP (“dyskinetic Cerebral Palsy”) who were found to have low glucose metab- olism in the basal ganglia (Batista CE, et al., 2007; Kerrigan JF, et al., 1991). Batista CE, et al. reported that neonates with athetoid CP with transient high glucose metabolism in the basal ganglia (Batista CE, et al., 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 (Gu J, et al., 2020).

Wong VC, 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 (Wong VC, et al., 2006).

Cell therapy

Recently, PET and SPECT have been used for the investigation of the ef- fectiveness 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 ther- apies for cases with Cerebral Palsy. Six articles on PET consist of one by human Umbilical Cord derived Mesenchymal Stromal Cells (hUC-MSC) (Gu J, et al., 2020), one mobilized Peripheral Blood Mononuclear Cells (mPBMCs) (Rah WJ, et al., 2017), three autologous Bone Marrow Mono- nuclear Cells (BM-MNCs) (Sharma A, et al., 2015; Sharma A, et al., 2013; Sharma A, et al., 2015), one allogeneic Umbilical Cord Blood (Min K, et al., 2013). Four of six paper reported that PET-CT scan showed much in- crease of glucose metabolism and one of six no significant change of glu- cose 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 (Lee JD, et al., 1998). 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

Discussion

Perinatal complications may result in severe motor disability with a preva- lence of 1-2 per 1000 live births in developed countries causing significant burden of illness and necessitating extensive multidisciplinary care (Jacobs SE, et al., 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 (Goldstein M, 2004).

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 (Iwaibara T, et al., 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 (Groenendaal F, et al., 2017; Aida N, 2022; Tierradentro-García LO, et al., 2021).

Glucose metabolism has been the focus of identifying the pathology as- sociated with cerebral ischemic disease in neonatal HIE, CP and cerebral infarction (Nabetani M, et al., 1995). PET studies reported that high glu- cose metabolisms 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.

Glucose metabolism has been the focus of identifying the pathology as- sociated with cerebral ischemic disease in neonatal HIE, CP and cerebral infarction (Nabetani M, et al., 1995). PET studies reported that high glu- cose metabolisms 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.

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 (Saitoh M, et al., 1994; Wada H, et al., 1997).

In this study, some article have reported that glucose metabolism improved in clinical experiences for a case with CP after stem cell therapy, evaluat- ed by PET, as well as cerebral perfusion by SPECT. UCB (Umbilical Cord Blood) and peripheral blood mononuclear cells infusion therapy for pa- tients 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 Intelligence Quotient (IQ), social behavior, speech, balance and daily functioning (Min K, ., 2013). Rah WJ, 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 (Rah WJ, et al., 2017). Sharma A, 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 (Sharma A, et al., 2015). The improvement of glucose metabolism might be caused by improvement of gap junction-mediated cell-cell interaction. In 2020, Kikuchi-Taura A, 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 Hypoxia-Inducible Factor 1-alpha (HIF-1α) and suppressed autophagy at endothelial cells (Kikuchi-Taura A, et al., 2020). We suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT (Sztriha L, et al., 1996; Suhonen-Polvi H, et al., 1993).

Conclusion

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 metabolisms in the early neonatal period of 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. PET might be good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely.

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