Neuroimaging for optimization of stem cell therapy in Parkinson's disease

Figures & data

Table 1. Neuroimaging instruments, types of imaging, biomarkers and biological & clinical correlates in PD.

Imaging instrument	Type of imaging (PET tracer, MRI sequences)	Biomarker	Biological and clinical correlations
PET	^18F-DOPA, l-[beta-^11C]-DOPA	Dopamine decarboxylase Amino acid transporter	Dopamine synthesis in dopaminergic presynaptic terminals Tumorigenicity/inflammation
	^11C-DTBZ	VMAT2	Dopaminergic presynaptic VMAT2 function
	^11C-CFT, ^11C-PE2I, ^11C-dMP	Dopamine transporter	Dopaminergic presynaptic DAT function
	^11C-SCH23390	Dopamine D1 receptor	Postsynaptic D1 receptor availability
	^11C-Raclopride	Dopamine D2 receptor (+ D3 receptor)	Postsynaptic D2 receptor availability, often used for assessing endogenous dopamine release by combining with methylphenidate administration
	^11C-PHNO	Dopamine D3 receptor (+ D2 receptor)	Postsynaptic D3 receptor availability
	^11C-DASB	Serotonin transporter (SERT)	Presynaptic SERT binding, excessive binding in the graft potentially associated with formation of dyskinesia
	^11C-PK11195	TSPO	Microglial activation, associated with inflammatory reaction
	^11C-Ketoprofen methyl ester	Cyclooxygenase 1	Activated microglia and macrophages, associated with inflammatory reaction
	^18F-FLT	Thymidine kinase 1	Thymidine-rich tumor formation
	^18F-FDG	Glucose metabolism	Neural activity (PD-related network abnormality), tumor formation, inflammation
	^15O-H2O	Cerebral blood flow	Inflammation, neural activity (PD-related network)
MRI	Resting state fMRI + large-scale functional connectivity	Blood-oxygen dependent (BOLD) signal change	PD-related network abnormality?
	Resting state fMRI + local functional connectivity	Regional homogeneity of BOLD signal	PD-related striatal local network abnormality, glutamatergic overactivity?
	Structural MRI Proton density image T2-weighted image Neuromelanin (T1) 2 inversion recovery sequences for white-matter and gray-matter suppression multispectral weighted mean (T1, T2, proton density, T2-FLAIR)	Volume of SNc	Neurodegeneration of SNc in PD?
	Susceptibility imaging T2*-weighted image	R2* values in substantia nigra	Iron deposition associated with neurodegeneration of SNc in PD?
	Diffusion tensor imaging	FA and mean diffusivity in substantia nigra.	Neuronal fiber degeneration due to neurodegeneration of SNc in PD?
	Structural MRI -High resolution T1-weighted MRI) + voxel-based morphometry	Regional gray matter volume	Hippocampal atrophy, a potential biomarker for dementia in PD

FA: Fractional anisotropy; fMRI: Functional magnetic resonance imaging; MRI: Magnetic resonance imaging; PD: Parkinson's disease; PET: Positron emission tomography; SNc: Substantia nigra pars compacta; TSPO: Translocator protein 18kDa; VMAT2: Vesicular monoamine transporter.

Table 2. Comparison of neuroimaging modalities.

Imaging instrument	Type of imaging	Temporal resolution	Spatial resolution	Sensitivity
MRI	fMRI	1 ∼ 3 s	∼ 3 mm	∼ 10 mM
	Structural MRI	3 – 10 min	∼ 1 mm
	Diffusion MRI	3 – 10 min	∼ 2 mm
PET	^15O-labeled ligands (e.g., ^15O-H2O)	90 s	∼ 4 – 8 mm	∼ 10 pM
	^11C-labeled ligands (e.g., ^11C-raclopride)	60 min	∼ 4 – 8 mm
	^18F-labeled ligands (e.g., ^18F-FDG, ^18F-DOPA)	60 – 120 min	∼ 4 – 8mm

fMRI: Functional magnetic resonance imaging; MRI: Magnetic resonance imaging; PET: Positron emission tomography.

Figure 1. Dopamine neurons induced from autologous bone marrow mesenchymal stem cells (MSCs) in parkinsonian monkeys and post-graft PET imaging. A) Bone marrow MSCs in primate animals. B) Neuron-like cells induced from MSCs. Immunocytochemistry showed that these neuron-like cells were positive for markers of neurons, Tuj-1 (C) and MAP-2 (D), catecholamine neurons, TH (E), dopaminergic neurons, DAT (F). G) After being autologously grafted into the striatum of MPTP-treated hemi-parkinsonian animals, PET imaging showed high binding potential (BP) of the DAT ligand, ¹¹C-CFT in the dorso-lateral part of the putamen (yellow arrow). White arrow shows high BP in the normal side of the putamen. H) Kinetic analysis of BP data obtained repeatedly till 7 months after transplantation. The kinetic analysis indicated that a major part of the grafted cells (∼ 90%) lost the expression of DAT (or degenerated) with a half-life of 10 days, while the rest of the grafted cells retained the DAT expression at the 7-month post-graft.

Figure 2. Potential predictability of the post-graft inflammatory response for delayed graft cell death. A. T2-weighted MRI brain image of a PD model animal, in which human embryonic stem cells were transplanted bilaterally in the striatum 1 month before MRI scan. B. At the same time point, PET ligands for activated glia, ¹¹C-ketoprofen methyl ester (upper) and ¹¹C-PK11195 (lower) were accumulated in the grafted areas of striatum, suggesting that host tissues have significant immune reactions to the grafted cells. C. Follow-up T2-weighted MRI scan in the same animal (3-month post-transplantation), which showed disappearance of grafts at this later stage. These findings suggest potential usefulness of multi-modal neuroimaging in predicting the long-term graft survival from early stage information of graft–host immune interaction. Unpublished data, courtesy of Prof. Jun Takahashi at Kyoto University.

Hayashi T, Wakao S, Kitada M, et al. Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques. J Clin Invest 2013;123:272-84

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