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OBJECTIVE To assess the feasibility of blood oxygen level–dependent (BOLD) MRI for measurement of the renal T2* relaxation rate (R2*; proxy for renal oxygenation) before and after furosemide administration and to evaluate the reliability and repeatability of those measurements in healthy dogs. ANIMALS 8 healthy adult Beagles (4 males and 4 females). PROCEDURES Each dog was anesthetized and underwent BOLD MRI before (baseline) and 3 minutes after administration of furosemide (1 mg/kg, IV) twice, with a 1-week interval between scanning sessions. Mapping software was used to process MRI images and measure R2* and the difference in R2* (∆R2*) before and after furosemide administration. The intraclass correlation coefficient was calculated to assess measurement reliability, and the coefficient of variation and Bland-Altman method were used to assess measurement repeatability. RESULTS Mean ± SD baseline R2* in the renal medulla (24.5 ± 3.8 seconds−1) was significantly greater than that in the renal cortex (20.6 ± 2.7 seconds−1). Mean R2* in the renal cortex (18.6 ± 2.6 seconds−1) and medulla (17.8 ± 1.5 seconds−1) decreased significantly after furosemide administration. Mean ∆R2* in the medulla (6.7 ± 2.4 seconds−1) was significantly greater than that in the renal cortex (2.1 ± 0.7 seconds−1). All R2* and ∆R2* values had good or excellent reliability and repeatability, except the cortical ∆R2*, which had poor repeatability. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that BOLD MRI, when performed before and after furosemide administration, was noninvasive and highly reliable and repeatable for dynamic evaluation of renal oxygenation in healthy dogs. more...

Implantable sensors can be used to monitor biomechanical strain continuously. However, three key challenges need to be addressed before they can be of use in clinical practice: the structural mismatch between the sensors and tissue or organs should be eliminated; a practical suturing attachment process should be developed; and the sensors should be equipped with wireless readout. Here, we report a wireless and suturable fibre strain-sensing system created by combining a capacitive fibre strain sensor with an inductive coil for wireless readout. The sensor is composed of two stretchable conductive fibres organized in a double helical structure with an empty core, and has a sensitivity of around 12. Mathematical analysis and simulation of the sensor can effectively predict its capacitive response and can be used to modulate performance according to the intended application. To illustrate the capabilities of the system, we use it to perform strain measurements on the Achilles tendon and knee ligament in an ex vivo and in vivo porcine leg. A capacitive, fibre-like stretchable strain sensor, formed of two conductors in a double helical structure, can be combined with an inductive coil to create a wireless strain-sensing system for biomedical applications. more...

Ischemic stroke results from arterial occlusion and can cause irreversible brain injury. A non-human primate (NHP) model of ischemic stroke was previously developed to investigate its pathophysiology and for efficacy testing of therapeutic candidates; however, fine motor impairment remains to be well-characterized. We evaluated hand motor function in a cynomolgus monkey model of ischemic stroke. Endovascular transient middle cerebral artery occlusion (MCAO) with an angiographic microcatheter induced cerebral infarction. In vivo magnetic resonance imaging mapped and measured the ischemia-induced infarct lesion. In vivo diffusion tensor imaging (DTI) of the stroke lesion to assess the neuroplastic changes and fiber tractography demonstrated three-dimensional patterns in the corticospinal tract 12 weeks after MCAO. The hand dexterity task (HDT) was used to evaluate fine motor movement of upper extremity digits. The HDT was modified for a home cage-based training system, instead of conventional chair restraint training. The lesion was localized in the middle cerebral artery territory, including the sensorimotor cortex. Maximum infarct volume was exhibited over the first week after MCAO, which progressively inhibited ischemic core expansion, manifested by enhanced functional recovery of the affected hand over 12 weeks after MCAO. The total performance time decreased with increasing success rate for both hands on the HDT. Compensatory strategies and retrieval failure improved in the chronic phase after stroke. Our findings demonstrate the recovery of fine motor skill after stroke, and outline the behavioral characteristics and features of functional disorder of NHP stroke model, providing a basis for assessing hand motor function after stroke. more...

Study of interactions between the nervous system and immunity offers insights into the pathogenesis of Parkinson’s disease (PD) and potential therapeutic strategies for neurodegenerative diseases. Studies on rodents have revealed regulatory mechanisms of microglial activation and T lymphocyte recruitment in PD. However, the mechanisms underlying chronic T lymphocyte infiltration into the brain after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection into a non-human primate (NHP) model of PD remain unknown. This study aimed to investigate changes in serum RANTES (regulated on activation, normal T cell expression and secretion) and analyze the chronic infiltration of T lymphocytes into the brain and microglia activation in NHPs at 48 weeks post-MPTP administration. We found selective and local chronic infiltration of CD4+ and CD8+ T lymphocytes, loss of dopaminergic neurons, dopamine transporter expression, chronic normalization of RANTES in the peripheral blood, and altered microglial morphology at 48 weeks after MPTP injection. This study confirms the involvement of CD4+ and CD8+ T lymphocyte infiltration in MPTP-induced NHP models of PD. Additionally, we corroborated previous findings regarding the mechanisms of T lymphocyte-induced neurodegeneration. The findings of chronic infiltration of T lymphocytes in our NHP model of PD provide novel insights into PD pathogenesis and the development of preventive and therapeutic agents. more...

OBJECTIVE To assess the usefulness of magnetic resonance urography (MRU) for the visualization of nondilated renal pelvises and ureters in dogs and to compare our findings for MRU versus CT urography (CTU). ANIMALS 9 healthy Beagles. PROCEDURES Dogs underwent CTU, static-fluid MRU, and excretory MRU, with ≥ 7 days between procedures. Contrast medium was administered IV during CTU and excretory MRU, whereas urine in the urinary tract was an intrinsic contrast medium for static-fluid MRU. For each procedure, furosemide (1 mg/kg, IV) was administered, and reconstructed dorsal plane images were acquired 3 minutes (n = 2) and 7 minutes (2) later. Images were scored for visualization of those structures and for image quality, diameters of renal pelvises and ureters were measured, and results were compared across imaging techniques. RESULTS Excretory MRU and CTU allowed good visualization of the renal pelvises and ureters, whereas static-fluid MRU provided lower visualization of the ureters. Distention of the renal pelvises and ureters was good in excretory MRU and CTU. Distention of the ureters in static-fluid MRU was insufficient compared with that in CTU and excretory MRU. Distinct artifacts were not observed in CTU and excretory MRU images. Static-fluid MRU images had several mild motion artifacts. CLINICAL RELEVANCE Our findings indicated that excretory MRU with furosemide administration was useful for visualizing nondilated renal pelvises and ureters of dogs in the present study. When performing MRU for the evaluation of dogs without urinary tract dilation, excretory MRU may be more suitable than static-fluid MRU. more...

Streptozotocin treatment has emerged as an alternative model of sporadic Alzheimer’s disease (SAD). Streptozotocin-induced alterations in iron and calcium levels reflect magnetic susceptibility changes, while susceptibility distribution in the cerebral regions has not been reported yet. This study aimed to investigate susceptibility distribution in the limbic system after streptozotocin administration to cynomolgus monkeys for exploring informative SAD biomarkers. Quantitative susceptibility mapping (QSM) using 7T magnetic resonance imaging (MRI) was utilized to quantitatively compare the susceptibility distributions in monkeys with sporadic Alzheimer disease and age-matched healthy controls. Compared to healthy controls, overall susceptibility values differed in the SAD models. Notable substantial susceptibility changes were observed in the hypothalamus with a 4.38-time decrease (AD: −47.45±12.19 ppb, healthy controls: 14.02±9.51 ppb) and in the posterior parts of the corpus callosum with a 2.83-times increase (AD: 31.49±15.90 ppb; healthy controls: 11.13±4.02 ppb). These susceptibility alterations may reflect neuronal death, and could serve as key biomarkers in the SAD. These results may be useful for specifying AD pathologies such as cognitive and non-cognitive symptoms. more...

Pigs are often selected for large animal models including for neuroscience and behavioral research, because their anatomy and biochemistry are similar to those of humans. However, behavioral assessments, in combination with objective long-term monitoring, is difficult. In this study, we introduced an automated video tracking system which was previously used in rodent studies, for use with pig models. Locomotor behaviors (total distance, number of zone transitions, and velocity) were evaluated and their changes were validated by different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration methods and dosing regimens. Three minipigs (23-29 kg) received subcutaneous or intravenous MPTP, either 1 or 3 times per week. Immediately after MPTP injection, the minipigs remained in a corner and exhibited reduced trajectory. In addition, the total distance travelled, number of zone transitions, and velocity were greatly reduced at every MPTP administration in all the minipigs, accompanying to increased resting time. However, the MPTP-induced symptoms were reversed when MPTP administration was terminated. In conclusion, this automated video-tracking system was able to monitor long-term locomotor activity and differentiate detailed alterations in large animals. It has the advantages of being easy to use, higher resolution, less effort, and more delicate tracking. Additionally, as our method can be applied to the animals' home pen, no habituation is needed. more...

Background Although the thalamus is known to modulate basal ganglia function related to motor control activity, the abnormal changes within the thalamus during distinct medical complications have been scarcely investigated. In order to explore the feasibility of assessing iron accumulation in the thalamus as an informative biomarker for Parkinson’s disease (PD), this study was designed to employ quantitative susceptibility mapping using a 7 T magnetic resonance imaging system in cynomolgus monkeys. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-injected cynomolgus monkey and a healthy control (HC) were examined by 7 T magnetic resonance imaging. Positron emission tomography with 18F-N-(3-fluoro propyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane was also employed to identify the relationship between iron deposits and dopamine depletion. All acquired values were averaged within the volume of interest of the nigrostriatal pathway. Findings Compared with the HC, the overall elevation of iron deposition within the thalamus in the Parkinson’s disease model (about 53.81% increase) was similar to that in the substantia nigra (54.81%) region. Substantial susceptibility changes were observed in the intralaminar part of the thalamus (about 70.78% increase). Additionally, we observed that in the Parkinson’s disease model, binding potential values obtained from positron emission tomography were considerably decreased in the thalamus (97.51%) and substantia nigra (92.48%). Conclusions The increased iron deposition in the thalamus showed negative correlation with dopaminergic activity in PD, supporting the idea that iron accumulation affects glutaminergic inputs and dopaminergic neurons. This investigation indicates that the remarkable susceptibility changes in the thalamus could be an initial major diagnostic biomarker for Parkinson’s disease-related motor symptoms. more...

The function of microglia/macrophages after ischemic stroke is poorly understood. This study examines the role of microglia/macrophages in the focal infarct area after transient middle cerebral artery occlusion (MCAO) in rhesus monkeys. We measured infarct volume and neurological function by magnetic resonance imaging (MRI) and non-human primate stroke scale (NHPSS), respectively, to assess temporal changes following MCAO. Activated phagocytic microglia/macrophages were examined by immunohistochemistry in post-mortem brains (n=6 MCAO, n=2 controls) at 3 and 24 hours (acute stage), 2 and 4 weeks (subacute stage), and 4, and 20 months (chronic stage) following MCAO. We found that the infarct volume progressively decreased between 1 and 4 weeks following MCAO, in parallel with the neurological recovery. Greater presence of cluster of differentiation 68 (CD68)-expressing microglia/macrophages was detected in the infarct lesion in the subacute and chronic stage, compared to the acute stage. Surprisingly, 98~99% of transforming growth factor beta (TGFβ) was found co-localized with CD68-expressing cells. CD68-expressing microglia/macrophages, rather than CD206+ cells, may exert anti-inflammatory effects by secreting TGFβ after the subacute stage of ischemic stroke. CD68+ microglia/macrophages can therefore be used as a potential therapeutic target. more...

Background In tandem stenoses, nonhyperemic pressure ratio pullback is the preferred method to fractional flow reserve (FFR), based on the assumption of stable resting coronary flow. This study aimed to evaluate temporal changes of coronary circulatory indexes in tandem stenoses before and after angioplasty for proximal stenosis. Methods and Results Coronary tandem stenoses were created by porcine restenosis model with 2 bare metal stents in the left anterior descending artery. Four weeks later, changes in distal coronary pressure (Pd), averaged peak velocity, microvascular resistance, transstenotic pressure gradient across distal stenosis, resting Pd/aortic pressure, and FFR were measured before and 1, 5, 10, 15, and 20 minutes after balloon angioplasty for proximal stenosis. After angioplasty, there were significant changes in both resting and hyperemic Pd, averaged peak velocity, microvascular resistance, and transstenotic pressure gradient across distal stenosis (all P values P =0.712 and 0.972, respectively). Conversely, resting averaged peak velocity remained increased (10.1±0.7 to 17.8±0.7; P P P =0.040) and hyperemic conditions (11.0±3.0 to 27.4±3.3 mm Hg; P P P Conclusions After angioplasty for proximal stenosis, transstenotic pressure gradient across distal stenosis showed similar changes between resting and hyperemic conditions. Both actual post–percutaneous coronary intervention resting Pd/aortic pressure and FFR were significantly lower than predicted values. more...

Symptoms of Parkinson's disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed the alteration in Parkinsonian tremor signs and the functionality of presynaptic dopaminergic neuron using positron emission tomography imaging of dopamine transporters in these models. In addition, a significant inverse correlation between HDT and DAT level was identified, but no local bias was found. The correlation with intention tremor signs was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors. more...

Background: Gait analysis in non-human primate models has been performed to elucidate the neural systems involved in controlling quadrupedal locomotor behavior. This study aimed to use a pressure-sensing walkway to identify characteristics of species-specific quadrupedal locomotion in rhesus monkeys. A total of nine healthy adult female rhesus monkeys (Macaca mulatta) were used for gait analysis. We measured the temporo-spatial and kinetic parameters of quadrupedal gait using a custom-built pressure-sensing walkway and compared the left- and right-side parameters to assess the symmetry of the gait pattern. Results: All temporo-spatial and kinetic parameter values showed no significant differences among the nine rhesus monkeys for both the forelimbs and hindlimbs. However, significant differences were observed between forelimb and hindlimb kinetic parameters such as peak vertical force, vertical impulse, and the percentage of body weight distribution. All kinetic parameter values were higher for the forelimbs than for the hindlimbs. These data indicated that the center of gravity in healthy rhesus monkeys is located at the forelimbs rather than at the hindlimbs while walking. Furthermore, the symmetry indices considered for symmetric gait pattern showed a low variability. Most median symmetry index values were nearly zero, indicating no difference between the right and left sides. Conclusions: This study described valid methods for assessing gait parameters and demonstrated rhesus-specific characteristics of quadrupedal locomotion, providing a basis for the assessment of gait normality in rhesus monkeys. more...

Symptoms of Parkinson’s disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed an alteration in Parkinsonian tremor symptoms, loss of dopaminergic neuron, and positron emission tomography (PET) imaging of dopamine transporters (DAT) in these models. HDT latency significantly increased in NHP-PD models. In addition, a significant inverse correlation between HDT and DAT was identified, but no local bias was found. The correlation with intention tremor symptoms was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors. more...

To assess hyperacute focal cerebral ischemia in rats on 3.0-Tesla diffusion-weighted imaging (DWI), we developed a novel voxel-wise lesion segmentation technique that overcomes intra- and inter-subject variation in apparent diffusion coefficient (ADC) distribution. Our novel technique involves the following: (1) intensity normalization including determination of the optimal type of region of interest (ROI) and its intra- and inter-subject validation, (2) verification of focal cerebral ischemic lesions at 1 h with gross and high-magnification light microscopy of hematoxylin-eosin (H&E) pathology, (3) voxel-wise segmentation on ADC with various thresholds, and (4) calculation of dice indices (DIs) to compare focal cerebral ischemic lesions at 1 h defined by ADC and matching H&E pathology. The best coefficient of variation was the mode of the left hemisphere after normalization using whole left hemispheric ROI, which showed lower intra- (2.54 ± 0.72%) and inter-subject (2.67 ± 0.70%) values than the original. Focal ischemic lesion at 1 h after middle cerebral artery occlusion (MCAO) was confirmed on both gross and microscopic H&E pathology. The 83 relative threshold of normalized ADC showed the highest mean DI (DI = 0.820 ± 0.075). We could evaluate hyperacute ischemic lesions at 1 h more reliably on 3-Tesla DWI in rat brains. more...

In research on cognitive function, the use of experimental animals is essential for the study of human cognitive processes and mechanisms. Furthermore, non-human primates are necessary for understanding higher cognitive functions in humans. However, there are few cognitive function tests available for non-human primates, Thus, we modified a finger maze test for application to non-human primates. In this study, we assessed learning and memory in 12 adult rhesus monkeys using a finger maze test that was developed to assess cognitive functions in captive non-human primates. The monkeys were trained with moving rewards indicating the correct direction, which allowed the monkeys to obtain the reward. Following training, subjects completed a learning trial and a memory trial two months later. Although the time required for training varied among the monkeys, 11 out of 12 monkeys completed the training and achieved a high success rate in the learning trial as well as in the memory trial conducted 2 months later. This is the first study to apply the finger maze test to adult rhesus monkeys. The finger maze test enabled us to assess learning and memory in several adult rhesus monkeys simultaneously. more...

The study aimed to establish a staining method that could delineate the macroscopic lesion boundary of a hyperacute infarction depicted by diffusion-weighted MRI (DWI) and to validate the infarction boundary by comparing different staining methods.Thirteen rats with 1 -h middle cerebral artery (MCA) infarction were included. Five different staining methods (Hematoxylin and eosin (HE), Nissl, 2,3,5-triphenyltetrazolium hydrochloride (TTC), microtubule associated protein 2 (MAP2), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stains) were used to identify whether the hyperacute infarction could be histopathologically identified. Dice indices were compared to evaluate similarities in the lesion area ascertained by DWI and the staining methods. Through macroscopic lesion delineation, each region was subdivided into abnormal regions in all three stains (ROIMean Dice indices of the HE stain were significantly higher than those of the Nissl- and MAP2-stained specimens (0.83 ± 0.052, 0.58 ± 0.107, and 0.56 ± 0.059, respectively; p = 0.000). Grading scores for ROIs in the DWI abnormal lesions varied by region: ROIHE stain allowed for the macroscopic delineation of the 1 h DWI-abnormal lesions, while MAP2 and Nissl stains could only partially depict lesions. more...

Mitochondria continuously fuse and divide to maintain homeostasis. An impairment in the balance between the fusion and fission processes can trigger mitochondrial dysfunction. Accumulating evidence suggests that mitochondrial dysfunction is related to neurodegenerative diseases such as Parkinson's disease (PD), with excessive mitochondrial fission in dopaminergic neurons being one of the pathological mechanisms of PD. Here, we investigated the balance between mitochondrial fusion and fission in the substantia nigra of a non-human primate model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. We found that MPTP induced shorter and abnormally distributed mitochondria. This phenomenon was accompanied by the activation of dynamin-related protein 1 (Drp1), a mitochondrial fission protein, through increased phosphorylation at S616. Thereafter, we assessed for activation of the components of the cyclin-dependent kinase 5 (CDK5) and extracellular signal-regulated kinase (ERK) signaling cascades, which are known regulators of Drp1(S616) phosphorylation. MPTP induced an increase in p25 and p35, which are required for CDK5 activation. Together, these findings suggest that the phosphorylation of Drp1(S616) by CDK5 is involved in mitochondrial fission in the substantia nigra of a non-human primate model of MPTP-induced PD., Graphical Abstract more...

Background Gross anatomy and sectional anatomy of a monkey should be known by students and researchers of veterinary medicine and medical research. However, materials to learn the anatomy of a monkey are scarce. Thus, the objective of this study was to produce a Visible Monkey data set containing cross sectional images, computed tomographs (CTs), and magnetic resonance images (MRIs) of a monkey whole body. Methods Before and after sacrifice, a female rhesus monkey was used for 3 Tesla MRI and CT scanning. The monkey was frozen and sectioned at 0.05 mm intervals for the head region and at 0.5 mm intervals for the rest of the body using a cryomacrotome. Each sectioned surface was photographed using a digital camera to obtain horizontal sectioned images. Segmentation of sectioned images was performed to elaborate three-dimensional (3D) models of the skin and brain. Results A total of 1,612 horizontal sectioned images of the head and 1,355 images of the remaining region were obtained. The small pixel size (0.024 mm × 0.024 mm) and real color (48 bits color) of these images enabled observations of minute structures. Conclusion Due to small intervals of these images, continuous structures could be traced completely. Moreover, 3D models of the skin and brain could be used for virtual dissections. Sectioned images of this study will enhance the understanding of monkey anatomy and foster further studies. These images will be provided to any requesting researcher free of charge., Graphical Abstract more...

Background The guidelines for applying individual adjustments to macaques according to the severity of behavioral symptoms during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment were provided to reproduce stable chronic Parkinsonism in a recent study (Potts et al., 2014). But, since there are insufficient guidelines regarding objective severity criteria of individual symptoms for adjustments of MPTP treatment, it is difficult to develop MPTP-induced chronic non-human primate (NHP) models with stable symptoms. New method The individual adjustments of MPTP administration based on results of automatic quantification of global activity (GA) using a video-based tracking system were applied to develop MPTP-PD model. Low-dose (0.2 mg/kg) intramuscular injection was repeated continuously until GA was lower than 8% of baseline Parkinsonian behavior scores. The positron emission tomography imaging were used to follow the longitudinal course of Parkinson’s disease (PD). Results Significant reductions in GA and dopamine transporter activity, along with significant increases in Parkinsonian behavior scores were found from 4 to 48 weeks following the first administration. GA was correlated with the Parkinsonian behavior score. The dopamine transporter activity was correlated with GA and the Parkinsonian behavior score. However, it was not correlated with the total dose of MPTP. Damage of dopaminergic neuronal systems in the basal ganglia was confirmed by immunohistochemistry and Western blot. Comparison with existing method This study reinforces previous guidelines regarding production of NHP models with stable Parkinsonian symptoms. Conclusions This novel strategy of MPTP administration based on global activity evaluations provides an important conceptual advance for the development of chronic NHP Parkinsonian models. more...

Background It has been generally speculated that paraspinal muscle weakness is related to the spinal degeneration including intervertebral disc failure. The purpose of this study was to investigate the effects of paraspinal muscle weakness induced by the botulinum toxin type-A on the lumbar spine and behavior pattern in an in-vivo primate model which has an upright locomotion similar to that of humans. Methods Botox injections into paraspinal muscle of one cynomolgus monkey were conducted biweekly up to 19 weeks at L2–L3, L3–L4 and L4–L5. MRIs were performed for measurement of muscle cross-sectional areas and behavioral data were collected using a high-resolution portable digital video camera. Findings The cross-sectional areas of the paraspinal muscles at L2–L3, L3–L4 and L4–L5 decreased by 8%, 12% and 8% at 21 weeks after the Botox injection, respectively. Intervertebral disc thickness at L2–L3, L3–L4 and L4–L5 decreased by 6%, 8% and 5% at 21 weeks after initial Botox injection, respectively. After the Botox injections, locomotion and movement activity of the monkey was decreased. The duration of sitting increased from 21% to a maximum of 97% at 9 weeks after the Botox injection, while stance time decreased from 9% to a minimum of 1% at 11 weeks post Botox injection. Interpretation The findings of this study revealed that paraspinal muscle atrophy affects intervertebral disc morphology and locomotion activity of a primate and may lead to an onset of intervertebral disc degeneration. more...

In line with recent findings showing Alzheimer's disease (AD) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-STZ) administration has been proposed as a representative experimental model of AD. Although icv-STZ rodent models of AD have been increasingly researched, studies in non-human primate models are very limited. In this study, we aimed to characterize the cerebral damage caused by icv-STZ in non-human primates; to achieve this, three cynomolgus monkeys (Macaca fascicularis) were administered four dosages of STZ (2 mg/kg) dissolved in artificial cerebrospinal fluid and another three controls were injected with only artificial cerebrospinal fluid at the cerebellomedullary cistern. In vivo neuroimaging was performed with clinical 3.0 T MRI, followed by quantitative analysis with FSL for evaluation of structural changes of the brain. Immunohistochemistry was performed to evaluate cerebral histopathology. We showed that icv-STZ caused severe ventricular enlargement and parenchymal atrophy, accompanying amyloid-β deposition, hippocampal cell loss, tauopathy, ependymal cell loss, astrogliosis, and microglial activation, which are observed in human aged or AD brain. The findings suggest that the icv-STZ monkey model would be a valuable resource to study the mechanisms and consequences of a variety of cerebral pathologies including major pathological hallmarks of AD. Furthermore, the study of icv-STZ monkeys could contribute to the development of treatments for age- or AD-associated cerebral changes. more...