Monkey Spinal Cord Research Articles

Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys

Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aβ oligomers, constitute the major pathological hallmarks of Alzheimer’s disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aβ accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aβ oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aβ oligomers in the monkey spinal cord. These Aβ oligomers were recognized by several antibodies to Aβ1–42 and contributed to neurodegeneration. However, the generation of Aβ oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aβ oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aβ pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.

Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury

Spinal cord injury (SCI) leads to severe sensory and motor dysfunction below the lesion. However, the cellular dynamic responses and heterogeneity across different regions below the lesion remain to be elusive. Here, we used single-cell transcriptomics to investigate the region-related cellular responses in female rhesus monkeys with complete thoracic SCI from acute to chronic phases. We found that distal lumbar tissue cells were severely impacted, leading to degenerative microenvironments characterized by disease-associated microglia and oligodendrocytes activation alongside increased inhibitory interneurons proportion following SCI. By implanting scaffold into the injury sites, we could improve the injury microenvironment through glial cells and fibroblast regulation while remodeling spared lumbar tissues via reduced inhibitory neurons proportion and improved phagocytosis and myelination. Our findings offer crucial pathological insights into the spared distal tissues and proximal tissues after SCI, emphasizing the importance of scaffold-based treatment approaches targeting heterogeneous microenvironments.

C9orf72 poly(PR) aggregation in nucleus induces ALS/FTD-related neurodegeneration in cynomolgus monkeys

Poly(PR) is a dipeptide repeat protein comprising proline and arginine residues. It is one of the translational product of expanded G4C2 repeats in the C9orf72 gene, and its accumulation is contributing to the neuropathogenesis of C9orf72-associated amyotrophic lateral sclerosis and/or frontotemporal dementia (C9-ALS/FTD). In this study, we demonstrate that poly(PR) protein alone is sufficient to induce neurodegeneration related to ALS/FTD in cynomolgus monkeys. By delivering poly(PR) via AAV, we observed that the PR proteins were located within the nucleus of infected cells. The expression of (PR)50 protein, consisting of 50 PR repeats, led to increased loss of cortical neurons, cytoplasmic lipofuscin, and gliosis in the brain, as well as demyelination and loss of ChAT positive neurons in the spinal cord of monkeys. While, these pathologies were not observed in monkeys expressing (PR)5, a protein comprising only 5 PR repeats. Furthermore, the (PR)50-expressing monkeys exhibited progressive motor deficits, cognitive impairment, muscle atrophy, and abnormal electromyography (EMG) potentials, which closely resemble clinical symptoms seen in C9-ALS/FTD patients. By longitudinally tracking these monkeys, we found that changes in cystatin C and chitinase-1 (CHIT1) levels in the cerebrospinal fluid (CSF) corresponded to the phenotypic progression of (PR)50-induced disease. Proteomic analysis revealed that the major clusters of dysregulated proteins were nuclear-localized, and downregulation of the MECP2 protein was implicated in the toxic process of poly(PR). This research indicates that poly(PR) expression alone induces neurodegeneration and core phenotypes associated with C9-ALS/FTD in monkeys, which may provide insights into the mechanisms of disease pathogenesis.

Human spinal GABA neurons survive and mature in the injured nonhuman primate spinal cord.

Spinal cord injury (SCI) leads to permanent neural dysfunction without effective therapies. We previously showed that human pluripotent stem cell (hPSC)-derived spinal GABA neurons can alleviate spasticity and promote locomotion in rats after SCI, but whether this strategy can be translated into the clinic remains elusive. Here, a nonhuman primate (NHP) model of SCI was established in rhesus macaques (Macaca mulatta) in which the T10 spinal cord was hemisected, resulting in neural conduction failure and neural dysfunction, including locomotion deficits, pain, and spasms. Grafted human spinal GABA neurons survived for up to 7.5months in the injured monkey spinal cord and retained their intrinsic properties, becoming mature and growing axons and forming synapses. Importantly, they are functionally alive, as evidenced by designer receptors exclusively activated by designer drug (DREADD) activation. These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys

PurposeThe sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at −1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T1, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions. MethodsMRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTRmfit). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREXmfit) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites. ResultsThe parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREXmfit of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, −1.6 and −3.5 ppm RF offsets. ConclusionThese results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREXmfit correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

Optimization of a transmit/receive surface coil for squirrel monkey spinal cord imaging

MR Imaging the spinal cord of non-human primates (NHP), such as squirrel monkey, is important since the injuries in NHP resemble those that afflict human spinal cords. Our previous studies have reported a multi-parametric MRI protocol, including functional MRI, diffusion tensor imaging, quantitative magnetization transfer and chemical exchange saturation transfer, which allows non-invasive detection and monitoring of injury-associated structural, functional and molecular changes over time. High signal-to-noise ratio (SNR) is critical for obtaining high-resolution images and robust estimates of MRI parameters. In this work, we describe our construction and use of a single channel coil designed to maximize the SNR for imaging the squirrel monkey cervical spinal cord in a 21 cm bore magnet at 9.4 T. We first numerically optimized the coil dimension of a single loop coil and then evaluated the benefits of a quadrature design. We then built an optimized coil based on the simulation results and compared its SNR performance with a non-optimized single coil in both phantoms and in vivo.

Stimulus outputs induced by subdural electrodes on the cervical spinal cord in monkeys

Objective. Spinal stimulation is a promising method for restoring the function of paralyzed limbs following neurological damage to descending pathways. The present study examined the forelimb movements and muscle responses evoked by subdural spinal stimulation of the cervical cord in sedated monkeys or during an arm-reaching task. Approach. We chronically implanted a platinum subdural electrode array with eight channels over the dorsal-lateral aspect of the cervical enlargement. The electrodes had a diameter of 1 mm and an inter-electrode center-to-center distance of 3 mm. Subdural spinal micro-stimulation was delivered at sites while the monkeys were sedated or performed arm-reaching movements. Main results. The evoked movements clearly showed the somatotopic map of the output sites; the electrodes located on the rostral cervical cord tended to induce movements of the proximal arm, whereas the caudal electrodes tended to induce movements of the distal joints, such as the wrist and digits. To document the muscle responses evoked by subdural spinal stimulation, stimulus-triggered averages of rectified electromyograms were compiled when the monkeys performed an arm-reaching task or were sedated. Under sedation, evoked facilitative muscle responses were observed in vicinity muscles. In contrast, during the task, stimulation evoked facilitative or suppressive responses in multiple muscles, including those located on proximal and distal joints, while somatotopy became blurred under sedation. Furthermore, stimulation during tasks activated synergistic muscle groups. For example, stimuli strongly facilitated finger extensor muscles, but suppressed the antagonist muscles. Significance. These dynamic changes in muscle representation by subdural cervical spinal stimulation between sedated and awake states help our understanding of the nature of spinal circuits and will facilitate the development of neuroprosthetic technology to regain motor function after neural damage to the descending pathways.

Functional organization of motor networks in the lumbosacral spinal cord of non-human primates

Implantable spinal-cord-neuroprostheses aiming to restore standing and walking after paralysis have been extensively studied in animal models (mainly cats) and have shown promising outcomes. This study aimed to take a critical step along the clinical translation path of these neuroprostheses, and investigated the organization of the neural networks targeted by these implants in a non-human primate. This was accomplished by advancing a microelectrode into various locations of the lumbar enlargement of the spinal cord, targeting the ventral horn of the gray matter. Microstimulation in these locations produced a variety of functional movements in the hindlimb. The resulting functional map of the spinal cord in monkeys was found to have a similar overall organization along the length of the spinal cord to that in cats. This suggests that the human spinal cord may also be organized similarly. The obtained spinal cord maps in monkeys provide important knowledge that will guide the very first testing of these implants in humans.

Breaking down the human motor cortex: the layer-specific measurement of corticospinal neuronal activity.

Breaking down the human motor cortex: the layer-specific measurement of corticospinal neuronal activity.

Intrinsic functional architecture of the non-human primate spinal cord derived from fMRI and electrophysiology

Resting-state functional MRI (rsfMRI) has recently revealed correlated signals in the spinal cord horns of monkeys and humans. However, the interpretation of these rsfMRI correlations as indicators of functional connectivity in the spinal cord remains unclear. Here, we recorded stimulus-evoked and spontaneous spiking activity and local field potentials (LFPs) from monkey spinal cord in order to validate fMRI measures. We found that both BOLD and electrophysiological signals elicited by tactile stimulation co-localized to the ipsilateral dorsal horn. Temporal profiles of stimulus-evoked BOLD signals covaried with LFP and multiunit spiking in a similar way to those observed in the brain. Functional connectivity of dorsal horns exhibited a U-shaped profile along the dorsal-intermediate-ventral axis. Overall, these results suggest that there is an intrinsic functional architecture within the gray matter of a single spinal segment, and that rsfMRI signals at high field directly reflect this underlying spontaneous neuronal activity.

Localization of zinc transporters in the spinal cord of cynomolgus monkey

Zinc is abundant in the spinal cord, where it participates in several physiological and pathophysiological processes, including neurotransmission, spinal cord injury, and amyotrophic lateral sclerosis. However, the mechanisms underlying zinc homeostasis in the spinal cord are largely unknown. Zinc transporters (ZnTs) are responsible for transporting zinc from the cytoplasm to the extracellular space or to intracellular compartments. In the present study, we examined the distribution of ZnT1-10 proteins in the spinal cord of cynomolgus monkey. Immunohistochemical studies demonstrate that all detected ZnT family members are expressed in the gray matter. ZnT1-10 immunoreactivity can be seen in both motor and sensory neurons in the dorsal and ventral horn from the cervical to sacral segments. No obvious immunostaining was found in the glia cells. The present study demonstrates that ZnT proteins are functionally important for regulating zinc metabolism in both motor and sensory functions in monkey spinal cord.

Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury

Tissue loss significantly reduces the potential for functional recovery after spinal cord injury. We previously showed that implantation of porous scaffolds composed of a biodegradable and biocompatible block copolymer of Poly-lactic-co-glycolic acid and Poly-l-lysine improves functional recovery and reduces spinal cord tissue injury after spinal cord hemisection injury in rats. Here, we evaluated the safety and efficacy of porous scaffolds in non-human Old-World primates (Chlorocebus sabaeus) after a partial and complete lateral hemisection of the thoracic spinal cord. Detailed analyses of kinematics and muscle activity revealed that by twelve weeks after injury fully hemisected monkeys implanted with scaffolds exhibited significantly improved recovery of locomotion compared to non-implanted control animals. Twelve weeks after injury, histological analysis demonstrated that the spinal cords of monkeys with a hemisection injury implanted with scaffolds underwent appositional healing characterized by a significant increase in remodeled tissue in the region of the hemisection compared to non-implanted controls. The number of glial fibrillary acidic protein immunopositive astrocytes was diminished within the inner regions of the remodeled tissue layer in treated animals. Activated macrophage and microglia were present diffusely throughout the remodeled tissue and concentrated at the interface between the preserved spinal cord tissue and the remodeled tissue layer. Numerous unphosphorylated neurofilament H and neuronal growth associated protein positive fibers and myelin basic protein positive cells may indicate neural sprouting inside the remodeled tissue layer of treated monkeys. These results support the safety and efficacy of polymer scaffolds in a primate model of acute spinal cord injury. A device substantially similar to the device described here is the subject of an ongoing human clinical trial.

Upregulation of Chemokine Ligands and Receptors in the Spinal Cord of Type 2 Diabetic Monkeys

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration and neuron‐glia interactions. Rodent studies have demonstrated that, like other cytokines, chemokine ligands and their cognate receptors in the spinal dorsal horn (SDH) can regulate both acute and chronic/neuropathic pain. Given the high prevalence of pain in patients with type 2 diabetes, it is pivotal to know if chemokine ligand‐receptor systems are upregulated in diabetic primates. Therefore, the aim of this study was to determine and compare the mRNA expression levels of chemokines in the spinal cord of monkeys that had 3–6 years of spontaneously occurring type 2 diabetes (n=7) and age‐matched nondiabetic monkeys (n=6). Chemokine mRNA expressions were analyzed by real‐time RT‐PCR in the SDH of these cynomolgus monkeys. CC‐chemokine ligands, CCL2 (MCP‐1) and CCL3 (MIP‐1alpha), mRNA expression levels were upregulated in the SDH of diabetic monkeys. In addition, their cognate receptors, CC‐chemokine receptors CCR1, CCR2, and CCR5, mRNA levels were upregulated in the SDH. Expression levels of these ligands and receptors mRNA were also higher in the spinal ventral horn of diabetic monkeys. Among numerous chemokines examined, CX3CL1 (Fractalkine) and CX3CR1 are the most highly expressed genes in the spinal cord. However, their expression levels did not differ between diabetic and nondiabetic monkeys. These results indicate that at least two chemokine ligand‐receptor systems (i.e., CCL2‐CCR2 and CCL3‐CCR1/CCR5) were upregulated in the spinal cord of type 2 diabetic monkeys, which is widely regarded as a clinically relevant model. This first‐in‐primate study opens a new avenue to study the functional roles of chemokines and their cognate receptor antagonists for modulating pain in diabetic primates.Support or Funding InformationSupported by US‐PHS grants AR‐059193 and DA‐032568

Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys.

To monitor the spontaneous recovery of cervical spinal cord injury (SCI) using longitudinal multiparametric MRI methods. Quantitative MRI imaging including diffusion tensor imaging, magnetization transfer (MT), and chemical exchange saturation transfer (CEST) were conducted in anesthetized squirrel monkeys at 9.4T. The structural, cellular, and molecular features of the spinal cord were examined before and at different time points after a dorsal column lesion in each monkey. Images with MT contrast enhanced visualization of the gray and white matter boundaries and the lesion and permitted differentiation of core and rim compartments within an abnormal volume (AV). In the early weeks after SCI, both core and rim exhibited low cellular density and low protein content, with high levels of exchanging hydroxyl, amine, and amide protons, as evidenced by increased apparent diffusion coefficient, decreased fractional anisotropy, decreased MT ratio, decreased nuclear Overhauser effect, and large CEST effects. Over time, cellular density and fiber density increased, whereas amide, amine, and hydroxyl levels dropped significantly, but at differing rates. Histology confirmed the nature of the AV to be a cyst. Multiparametric MRI offers a novel method to quantify the spontaneous changes in structure and cellular and molecular compositions of SC during spontaneous recovery from injury.

Quantity and Distribution of Proliferating Cells in the Juvenile and Adult Primate Spinal Cord

Iultipotent progenitors exist in the adult mam- malian central nervous system, capable of producing both neurons and glia. Their proliferation in the spi- nal cord is limited. Generation of putative stem/pro- genitor cells has been reported in intact and injured spinal cord of rodents and in a limited number in monkeys with a spinal injury, but not in intact spi- nal cord in vivo. We recently reported de novo gener- ated cells in the intact spinal cord of macaque mon- keys. Here we extend these findings by showing data of intact juvenile and neonatal monkey spinal cord. We used bromodeoxyuridine (BrdU) to label the de novo generated cells in the experimental animals and stud- ied their quantity and distribution at different time- points after the BrdU infusion. As expected, we found a significant elevation of the BrdU-labeled cells at neo- natal stage. However, there was no difference between juvenile and adult stages. These results suggest that the survival of newly born cells in the intact primate spinal cord does not change after juvenile stage and this could be used to further study repair mechanisms in adult primate spinal cord.

100: Delayed and Persistent Response of Human Mitochondria after Single Exposure to 0.5 to 4 Gy of Gamma Radiation

Figure 1: Plot of initial course percentage BED against that of the second course using a model where slope is inversely proportional to the second dose, raised to a power function, linked to time. Data points are murine and rat data treated at intervals up to 1 year following first exposure. The fitted curves are based on Ang et al (2001), for monkey spinal cord experiments for: black hatched curve 1 year, grey hatched curve 2 years and black 3 years of elapsed time between the exposures, although we assume 95% recovery rather than 100%. The grey straight line represents no recovery with time.

Spike-timing-dependent plasticity in primate corticospinal connections induced during free behavior.

Motor learning and functional recovery from brain damage involve changes in the strength of synapticconnections between neurons. Relevant invivo evidence on the underlying cellular mechanisms remains limited and indirect. We found that the strength of neural connections between motor cortex and spinal cord in monkeys can be modified with an autonomous recurrent neural interface that delivers electrical stimuli in the spinal cord triggered by action potentials of corticospinal cells during free behavior. The activity-dependent stimulation modified the strength of the terminal connections of single corticomotoneuronal cells, consistent with a bidirectional spike-timing-dependent plasticity rule previously derived from invitro experiments. For some cells, the changes lasted for days after the end of conditioning, but most effects eventually reverted to preconditioning levels. These results provide direct evidence of corticospinal synaptic plasticity invivo at the level of single neurons induced by normal firing patterns during free behavior.

Impairment and recovery of hand use after unilateral section of the dorsal columns of the spinal cord in squirrel monkeys

Damage to the ascending forelimb afferents in the dorsal columns (DCs) of the cervical spinal cord in monkeys impairs forelimb use, particularly hand dexterity. Although considerable recovery has been reported, interpretation of the results is complicated by the reproducibility of the lesion and behavioral assessment. Here, we examined the effects of a unilateral DC lesion at the C4–C6 spinal cord level in four adult squirrel monkeys. Behavioral performance was assessed on a reach-to-grasp task over 5–13 weeks after lesion. Retrograde tracers were injected into the skin of the fingertips to determine the distribution of axon terminals in the cuneate nucleus and estimate the effectiveness of lesion at the conclusion of each case. The size and level of DC lesion was reflected in the proportion of spared afferents, which ranged from 1 to 25% across monkeys. The experiments produced two major findings. First, the extent of deafferentation in the DC is directly related to the degree of reaching and grasping impairments, and to the reactivation profile and somatotopic reorganization in contralateral primary somatosensory cortex. Second, considerable behavioral recovery and cortical reorganization occurred even in the monkey with only 1% of axons spared in the DC. Our findings suggest that cutaneous inputs from the hand and forelimb are critical to the integrity of functions such as reaching and grasping. In addition, axon branches from peripheral afferents that terminate on neurons in the dorsal horn of the spinal cord are likely central to the functional recovery.

A Novel Population of Cholinergic Neurons in the Macaque Spinal Dorsal Horn of Potential Clinical Relevance for Pain Therapy

Endogenous acetylcholine (ACh) is a well-known modulator of nociceptive transmission in the spinal cord of rodents. It arises mainly from a sparse population of cholinergic interneurons located in the dorsal horn of the spinal cord. This population was thought to be absent from the spinal cord of monkey, what might suggest that spinal ACh would not be a relevant clinical target for pain therapy. In humans, however, pain responses can be modulated by spinal ACh, as evidenced by the increasingly used analgesic procedure (for postoperative and labor patients) consisting of the epidural injection of the acetylcholinesterase inhibitor neostigmine. The source and target of this ACh remain yet to be elucidated. In this study, we used an immunolabeling for choline acetyltransferase to demonstrate, for the first time, the presence of a plexus of cholinergic fibers in laminae II-III of the dorsal horn of the macaque monkey. Moreover, we show the presence of numerous cholinergic cell bodies within the same laminae and compared their density and morphological properties with those previously described in rodents. An electron microscopy analysis demonstrates that cholinergic boutons are presynaptic to dorsal horn neurons as well as to the terminals of sensory primary afferents, suggesting that they are likely to modulate incoming somatosensory information. Our data suggest that this newly identified dorsal horn cholinergic system in monkeys is the source of the ACh involved in the analgesic effects of epidural neostigmine and could be more specifically targeted for novel therapeutic strategies for pain management in humans.

Regional Cytoplasmic TDP-43 Mislocalization Is Recapitulated in Non-Human Primate Mimicking ALS (IN9-1.002)

Objective: To investigate the pathological role of wild-type TDP-43, we develop non-human primate model of sporadic amyotrophic lateral sclerosis patients (ALS). Background ALS is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of TDP-43 from the nucleus to the cytoplasm and the presence of cystatin C–positive Bunina bodies are considered pathological hallmarks of ALS, but their significance has not been fully elucidated. All reported rodent transgenic models of ALS using wild-type TDP-43 failed to recapitulate these features. Design/Methods: To investigate the pathological role of wild-type TDP-43, we over-expressed Flag tagged human wild-type TDP-43 in spinal motoneurons in 10 non-human primate, cynomolgus monkey by directly injecting adeno-associated virus (AAV) 1 vector to the 6th cervical cord. Results: These monkeys developed progressive motor weakness and muscle atrophy with fasciculation first in distal hand muscles. Despite the diffuse expression of exogenous TDP-43 in the spinal cord, TDP-43 mislocalization and neuron loss predominantly occurred in the lateral nuclear group in Rexed lamina IX, in which large neurons are mostly alpha-motoneurons, reminiscent of the spinal cord pathology of ALS. TDP-43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. cystatin Spinal motoneuron sometimes showed C–positive cytoplasmic aggregates. Intersetingly, immnostaining with an anti-Flag antibody identified its nuclear or cytoplasmic immunoreactivity in some Betz cells in precentral gyrus restricted to the forelimb area contralateral to the injection. Conclusions: These findings suggest that cytoplasmic TDP-43 mislocalization leads to alpha-motoneuron degeneration. The tropism of TDP-43 mislocalization in the monkey spinal cord and motor cortex is similar to the ALS pathology. Our monkey model is expected to be a powerful tool for investigating pathogenesis of sporadic ALS and mechanism of its propagation. Disclosure: Dr. Yokota has nothing to disclose. Dr. Sasaguri has nothing to disclose. Dr. Ohkubo has nothing to disclose. Dr. Mizusawa has received personal compensation for activities with Tanabemitsubishi Co and Sanofi-Aventis Co. Dr. Mizusawa has received personal compensation in an editorial capacity for No to Shinkei and Clinical Neuroscience.