Operational Parameters for Sub-Nano Tesla Field Resolution of PHMR Sensors in Harsh Environments.

The resolution of planar-Hall magnetoresistive (PHMR) sensors was investigated in the frequency range from 0.5 Hz to 200 Hz in terms of its sensitivity, average noise level, and detectivity. Analysis of the sensor sensitivity and voltage noise response was performed by varying operational parameters such as sensor geometrical architectures, sensor configurations, sensing currents, and temperature. All the measurements of PHMR sensors were carried out under both constant current (CC) and constant voltage (CV) modes. In the present study, Barkhausen noise was revealed in 1/f noise component and found less significant in the PHMR sensor configuration. Under measured noise spectral density at optimized conditions, the best magnetic field detectivity was achieved better than 550 pT/√Hz at 100 Hz and close to 1.1 nT/√Hz at 10 Hz for a tri-layer multi-ring PHMR sensor in an unshielded environment. Furthermore, the promising feasibility and possible routes for further improvement of the sensor resolution are discussed.

Bridge Resistance Compensation for Noise Reduction in a Self-Balanced PHMR Sensor.

Advanced microelectromechanical system (MEMS) magnetic field sensor applications demand ultra-high detectivity down to the low magnetic fields. To enhance the detection limit of the magnetic sensor, a resistance compensator integrated self-balanced bridge type sensor was devised for low-frequency noise reduction in the frequency range of 0.5 Hz to 200 Hz. The self-balanced bridge sensor was a NiFe (10 nm)/IrMn (10 nm) bilayer structure in the framework of planar Hall magnetoresistance (PHMR) technology. The proposed resistance compensator integrated with a self-bridge sensor architecture presented a compact and cheaper alternative to marketable MEMS MR sensors, adjusting the offset voltage compensation at the wafer level, and led to substantial improvement in the sensor noise level. Moreover, the sensor noise components of electronic and magnetic origin were identified by measuring the sensor noise spectral density as a function of temperature and operating power. The lowest achievable noise in this device architecture was estimated at ~3.34 nV/Hz at 100 Hz.

Performance Validation of a Planar Hall Resistance Biosensor through Beta-Amyloid Biomarker.

Magnetic sensors have great potential for biomedical applications, particularly, detection of magnetically-labeled biomolecules and cells. On the basis of the advantage of the planar Hall effect sensor, which consists of improved thermal stability as compared with other magnetic sensors, we have designed a portable biosensor platform that can detect magnetic labels without applying any external magnetic field. The trilayer sensor, with a composition of Ta (5 nm)/NiFe (10 nm)/Cu (x = 0 nm~1.2 nm)/IrMn (10 nm)/Ta (5 nm), was deposited on a silicon wafer using photolithography and a sputtering system, where the optimized sensor sensitivity was 6 µV/(Oe∙mA). The detection of the magnetic label was done by comparing the signals obtained in first harmonic AC mode (1f mode) using an external magnetic field and in the second harmonic AC mode (2f mode) with a self-field generated by current passing through the sensor. In addition, a technique for the ß-amyloid biomarker-based antibody-antigen sandwich model was demonstrated for the detection of a series of concentrations of magnetic labels using the self-field mode method, where the signal-to-noise ratio (SNR) was high. The generated self-field was enough to detect an immobilized magnetic tag without an additional external magnetic field. Hence, it could be possible to reduce the device size to use the point-of-care testing using a portable circuit system.

Rise of the Visible Monkey: Sectioned Images of Rhesus Monkey.

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.

Fast field echo resembling CT using restricted echo-spacing (FRACTURE) MR sequence can provide craniocervical region images comparable to a CT in dogs.

Magnetic resonance imaging (MRI) is essential for evaluating cerebellar compression in patients with craniocervical junction abnormalities (CJA). However, it is limited in depicting cortical bone because of its short T2 relaxation times, low proton density, and organized structure. Fast field echo resembling a computed tomography (CT) scan using restricted echo-spacing (FRACTURE) MRI, is a new technique that offers CT-like bone contrast without radiation. This study aimed to assess the feasibility of using FRACTURE MRI for craniocervical junction (CCJ) assessment compared with CT and conventional MRI, potentially reducing the need for multiple scans and radiation exposure, and simplifying procedures in veterinary medicine. CT and MRI of the CCJ were obtained from five healthy beagles. MRI was performed using three-dimensional (3D) T1-weighted, T2-weighted, proton density-weighted (PDW), single echo-FRACTURE (sFRACTURE), and multiple echo-FRACTURE (mFRACTURE) sequences. For qualitative assessment, cortical delineation, trabecular bone visibility, joint space visibility, vertebral canal definition, overall quality, and artifacts were evaluated for each sequence. The geometrical accuracy, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were quantified. Both sFRACTURE and CT images provided significantly higher scores for cortical delineation and trabecular bone visibility than conventional MRI. Joint space visibility and vertebral canal definition were similar to those observed on CT images, regardless of the MR sequence. In the quantitative assessment, the distances measured on T2-weighted images differed significantly from those measured on CT. There were no significant differences between the distances taken using T1-weighted, PD-weighted, sFRACTURE, mFRACTURE and those taken using CT. T1-weighted and sFRACTURE had a higher SNR for trabecular bone than CT. The CNR between the cortical bone and muscle was high on CT and FRACTURE images. However, the CNR between the cortical and trabecular bones was low in mFRACTURE. Similar to CT, FRACTURE sequences showed higher cortical delineation and trabecular bone visibility than T2-weighted, T1-weighted, and PDW CCJ sequences. In particular, sFRACTURE provided a high signal-to-noise ratio (SNR) of the trabecular bone and a high CNR between the cortical bone and muscle and between the cortical and trabecular bones. FRACTURE sequences can complement conventional MR sequences for bone assessment of the CCJ in dogs.

Fast field echo resembling a CT using restricted echo-spacing (FRACTURE) sequence for shoulder joint in normal dogs.

Shoulder disease is a common cause of forelimb lameness in dogs. Determining the precise underlying cause of shoulder lameness can be challenging, especially in veterinary practice. Computerized tomography (CT) is often the preferred imaging modality for bone evaluation; however, it uses ionizing radiation and provides limited soft tissue contrast. Conversely, magnetic resonance imaging (MRI) offers excellent soft tissue contrast but has limitations in bone imaging. This study aimed to introduce a new technical innovation that enhances cortical and trabecular bone contrast on MRI, which we refer to as Fast Field Echo Resembling a CT Using Restricted Echo-Spacing (FRACTURE). In this prospective pilot study, we aimed to evaluate the use of FRACTURE, CT, and conventional MRI sequences in assessing the normal canine shoulder using a 3.0 Tesla MRI scanner. Five research beagle dogs were included, and the following pulse sequences were acquired for each dog (1): three-dimensional (3D) FRACTURE, (2) T2-weighted (T2W) images using 3D turbo spin echo (TSE), (3) T1-weighted (T1W) images using 3D TSE, (4) PD-weighted (PDW) images using 3D TSE, and (5) CT. Various parameters, including the delineation of cortical bone (intertubercular groove, greater tubercle, and lesser tubercle), conspicuity of the trabecular bone, shoulder joint visualization, and image quality, were measured for each dog and sequence. In all sequences, the shoulder joint was successfully visualized in all planes with mild motion artifacts. The intertubercular groove was best visualized on CT and FRACTURE. Both the greater and lesser tubercles were easily identified on the CT, FRACTURE, and PDW images. The trabecular pattern scored significantly higher in the CT and FRACTURE images compared to the T1W, T2W, and PDW images. Overall, the visualization of the shoulder joint was excellent in all sequences except for T1W. The use of FRACTURE in combination with conventional MRI sequences holds promise for facilitating not only soft tissue evaluation but also cortical and trabecular bone assessment. The findings from this study in normal dogs can serve as a foundation for further FRACTURE studies in dogs with shoulder diseases.

Comparative Anatomy of the Dentate Mossy Cells in Nonhuman Primates: Their Spatial Distributions and Axonal Projections Compared With Mouse Mossy Cells.

Glutamatergic mossy cells (MCs) mediate associational and commissural connectivity, exhibiting significant heterogeneity along the septotemporal axis of the mouse dentate gyrus (DG). However, it remains unclear whether the neuronal features of MCs are conserved across mammals. This study compares the neuroanatomy of MCs in the DG of mice and monkeys. The MC marker, calretinin, distinguishes two subpopulations: septal and temporal. Dual-colored fluorescence labeling is utilized to compare the axonal projection patterns of these subpopulations. In both mice and monkeys, septal and temporal MCs project axons across the longitudinal axis of the ipsilateral DG, indicating conserved associational projections. However, unlike in mice, no MC subpopulations in monkeys make commissural projections to the contralateral DG. In monkeys, temporal MCs send associational fibers exclusively to the inner molecular layer, while septal MCs give rise to wide axonal projections spanning multiple molecular layers, akin to equivalent MC subpopulations in mice. Despite conserved septotemporal heterogeneity, interspecies differences are observed in the topological organization of septal MCs, particularly in the relative axonal density in each molecular layer along the septotemporal axis of the DG. In summary, this comparative analysis sheds light on both conserved and divergent features of MCs in the DG of mice and monkeys. These findings have implications for understanding functional differentiation along the septotemporal axis of the DG and contribute to our knowledge of the anatomical evolution of the DG circuit in mammals.

Hypothalamic neuronal activation in non-human primates drives naturalistic goal-directed eating behavior.

Maladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.

Effects of Sodium Nitroprusside Administered Via a Subdural Intracranial Catheter on the Microcirculation, Oxygenation, and Electrocortical Activity of the Cerebral Cortex in a Pig Cardiac Arrest Model.

Background Postischemic cerebral hypoperfusion has been indicated as an important contributing factor to secondary cerebral injury after cardiac arrest. We evaluated the effects of sodium nitroprusside administered via a subdural intracranial catheter on the microcirculation, oxygenation, and electrocortical activity of the cerebral cortex in the early postresuscitation period using a pig model of cardiac arrest. Methods and Results Twenty-nine pigs were resuscitated with closed cardiopulmonary resuscitation after 14 minutes of untreated ventricular fibrillation. Thirty minutes after restoration of spontaneous circulation, 24 pigs randomly received either 4 mg of sodium nitroprusside (IT-SNP group) or saline placebo (IT-saline group) via subdural intracranial catheters and were observed for 5 hours. The same dose of sodium nitroprusside was administered intravenously in another 5 pigs. Compared with the IT-saline group, the IT-SNP group had larger areas under the curve for tissue oxygen tension and percent changes of arteriole diameter and number of perfused microvessels from baseline (all P<0.05) monitored on the cerebral cortex during the 5-hour period, without severe hemodynamic instability. This group also showed faster recovery of electrocortical activity measured using amplitude-integrated electroencephalography. Repeated-measures analysis of variance revealed significant group-time interactions for these parameters. Intravenously administered sodium nitroprusside caused profound hypotension but did not appear to increase the cerebral parameters. Conclusions Sodium nitroprusside administered via a subdural intracranial catheter increased post-restoration of spontaneous circulation cerebral cortical microcirculation and oxygenation and hastened electrocortical activity recovery in a pig model of cardiac arrest. Further studies are required to determine its impact on the long-term neurologic outcomes.

XperCT-guided Intra-cisterna Magna Injection of Streptozotocin for Establishing an Alzheimer's Disease Model Using the Cynomolgus Monkey (Macaca fascicularis).

Till date, researchers have been developing animal models of Alzheimer's disease (AD) in various species to understand the pathological characterization and molecular mechanistic pathways associated with this condition in humans to identify potential therapeutic treatments. A widely recognized AD model that mimics the pathology of human AD involves the intracerebroventricular (ICV) injection with streptozotocin (STZ). However, ICV injection as an invasive approach has several limitations related to complicated surgical procedures. Therefore, in the present study, we created a customized stereotaxic frame using the XperCT-guided system for injecting STZ in cynomolgus monkeys, aiming to establish an AD model. The anatomical structures surrounding the cisterna magna (CM) were confirmed using CT/MRI fusion images of monkey brain with XperCT, the c-arm cone beam computed tomography. XperCT was used to determine the appropriate direction in which the needle tip should be inserted within the CM region. Cerebrospinal fluid (CSF) was collected to confirm the accurate target site when STZ was injected into the CM. Cynomolgus monkeys were administered STZ dissolved in artificial CSF once every week for 4 weeks via intracisterna magna (ICM) injection using XperCT-guided stereotactic system. The molecular mechanisms underlying the progression of STZ-induced AD pathology were analyzed two weeks after the final injection. The monkeys subjected to XperCT-based STZ injection via the ICM route showed features of AD pathology, including markedly enhanced neuronal loss, synaptic impairment, and tau phosphorylation in the hippocampus. These findings suggest a new approach for the construction of neurodegenerative disease models and development of therapeutic strategies.

Determination of the Unilaterally Damaged Region May Depend on the Asymmetry of Carotid Blood Flow Velocity in Hemiparkinsonian Monkey: A Pilot Study.

The hemiparkinsonian nonhuman primate model induced by unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the carotid artery is used to study Parkinson's disease. However, there have been no studies that the contralateral distribution of MPTP via the cerebral collateral circulation is provided by both the circle of Willis (CoW) and connections of the carotid artery. To investigate whether MPTP-induced unilaterally damaged regions were determined by asymmetrical cerebral blood flow, the differential asymmetric damage of striatal subregions, and examined structural asymmetries in a circle of Willis, and blood flow velocity of the common carotid artery were observed in three monkeys that were infused with MPTP through the left internal carotid artery. Lower flow velocity in the ipsilateral common carotid artery and a higher ratio of ipsilateral middle cerebral artery diameter to anterior cerebral artery diameter resulted in unilateral damage. Additionally, the unilateral damaged monkey observed the apomorphine-induced contralateral rotation behavior and the temporary increase of plasma RANTES. Contrastively, higher flow velocity in the ipsilateral common carotid artery was observed in the bilateral damaged monkey. It is suggested that asymmetry of blood flow velocity and structural asymmetry of the circle of Willis should be taken into consideration when establishing more efficient hemiparkinsonian nonhuman primate models.

Quantification of renal T2 relaxation rate by use of blood oxygen level-dependent magnetic resonance imaging before and after furosemide administration in healthy Beagles.

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* (ΔR2*) 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 ΔR2* 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 ΔR2* values had good or excellent reliability and repeatability, except the cortical ΔR2*, 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.

Renal Diffusion-Weighted Imaging in Healthy Dogs: Reproducibility, Test-Retest Repeatability, and Selection of the Optimal b-value Combination.

Diffusion-weighted imaging (DWI) magnetic resonance imaging can evaluate alterations in the microstructure of the kidney. The purpose of this study was to assess the apparent diffusion coefficient (ADC) and the intravoxel incoherent motion model (IVIM) parameters of a normal kidney in healthy dogs, to evaluate the effect of b-value combinations on the ADC value, and the reproducibility and test-retest repeatability in monoexponential and IVIM analysis. In this experimental study, the ADC, pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f p) were measured from both kidneys in nine healthy beagles using nine b-values (b = 0, 50, 70, 100, 150, 200, 500, 800, and 1,000 s/mm2) twice with a 1-week interval between measurements. Interobserver and intraobserver reproducibility, and test-retest repeatability of the measurements were calculated. ADC values were measured using 10 different b-value combinations consisting of three b-values each, and were compared to the ADC obtained from nine b-values. All the ADC, D, D*, and f p values measured from the renal cortex, medulla, and the entire kidney had excellent interobserver and intraobserver reproducibility, and test-retest repeatability. The ADC obtained from a b-value combination of 0, 100, and 800 s/mm2 had the highest intraclass correlation coefficient with the ADC from nine b-values. The results of this study indicated that DWI MRI using multiple b-values is feasible for the measurement of ADC and IVIM parameters with high reproducibility and repeatability in the kidneys of healthy dogs. A combination of b = 0, 100, and 800 s/mm2 can be used for ADC measurements when multiple b-values are not available in dogs.

Comparison of static-fluid or excretory magnetic resonance urography with computed tomography urography for visualization of nondilated renal pelvises and ureters in healthy Beagles.

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.

Coronary Circulatory Indexes Before and After Percutaneous Coronary Intervention in a Porcine Tandem Stenoses Model.

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 <0.01). After initial acute changes, hyperemic averaged peak velocity and microvascular resistance did not show significant difference from the baseline 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<0.001) and resting microvascular resistance decreased (6.0±0.1 to 2.2±0.7; P<0.001). Transstenotic pressure gradient across distal stenosis was significantly increased in both resting (13.1±7.6 to 25.3±4.2; P=0.040) and hyperemic conditions (11.0±3.0 to 27.4±3.3 mm Hg; P<0.001). Actual post-percutaneous coronary intervention Pd/aortic pressure and FFR were significantly lower than predicted values (Pd/aortic pressure, 0.68±0.22 versus 0.85±0.14; P<0.001; FFR, 0.63±0.08 versus 0.81±0.08; P<0.001). 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.

Quantitative magnetic susceptibility assessed by 7T magnetic resonance imaging in Alzheimer's disease caused by streptozotocin administration.

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.

Synaptic loss and amyloid beta alterations in the rodent hippocampus induced by streptozotocin injection into the cisterna magna.

To date, researchers have developed various animal models of Alzheimer's disease (AD) to investigate its mechanisms and to identify potential therapeutic treatments. A widely recognized model that mimics the pathology of human sporadic AD involves intracerebroventricular (ICV) injection with streptozotocin (STZ). However, ICV injections are an invasive approach, which creates limitations in generalizing the results. In this study, we produced a rodent model of AD using STZ (3 mg/kg) injection via the cisterna magna (CM) once every week for 4 weeks, and analyzed at 4 weeks and 16 weeks after final injection. In the CM-STZ rodent model of AD, we observed increase in extracellular amyloid-beta (Aß) deposition and decrease and abnormal morphology of post-synaptic protein, PSD95 in 16 weeks STZ-injected group. The model developed using our less-invasive method induced features of AD-like pathology, including significantly increased extracellular amyloid-beta deposition, and decreased synaptic protein in the hippocampus. These findings supporting the success of this alternative approach, and thus, we suggest this is a promising, less invasive model for use in future AD research.

Streptozotocin Induces Alzheimer's Disease-Like Pathology in Hippocampal Neuronal Cells via CDK5/Drp1-Mediated Mitochondrial Fragmentation.

Aberrant brain insulin signaling plays a critical role in the pathology of Alzheimer's disease (AD). Mitochondrial dysfunction plays a role in the progression of AD, with excessive mitochondrial fission in the hippocampus being one of the pathological mechanisms of AD. However, the molecular mechanisms underlying the progression of AD and mitochondrial fragmentation induced by aberrant brain insulin signaling in the hippocampal neurons are poorly understood. Therefore, we investigated the molecular mechanistic signaling associated with mitochondrial dynamics using streptozotocin (STZ), a diabetogenic compound, in the hippocampus cell line, HT-22 cells. In this metabolic dysfunctional cellular model, hallmarks of AD such as neuronal apoptosis, synaptic loss, and tau hyper-phosphorylation are induced by STZ. We found that in the mitochondrial fission protein Drp1, phosphorylation is increased in STZ-treated HT-22 cells. We also determined that inhibition of mitochondrial fragmentation suppresses STZ-induced AD-like pathology. Furthermore, we found that phosphorylation of Drp1 was induced by CDK5, and inhibition of CDK5 suppresses STZ-induced mitochondrial fragmentation and AD-like pathology. Therefore, these findings indicate that mitochondrial morphology and functional regulation may be a strategy of potential therapeutic for treating abnormal metabolic functions associated with the pathogenesis of AD.

Which pathologic staining method can visualize the hyperacute infarction lesion identified by diffusion MRI?: A comparative experimental study.

BACKGROUND: 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. NEW METHOD: Thirteen rats with 1 -h middle cerebral artery (MCA) infarction were included. Five different staining methods (Hematoxylin and eosin (H&E), 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 (ROIA), abnormal in two stains (ROIB), and abnormal in only one (ROIC). Microscopic cellular changes were evaluated and graded according to each region. RESULTS: Mean Dice indices of the H&E stain were significantly higher than those of the Nissl- and MAP2-stained specimens (0.83 ±â€¯0.052, 0.58 ±â€¯0.107, and 0.56 ±â€¯0.059, respectively; p = 0.000). Grading scores for ROIs in the DWI abnormal lesions varied by region: ROIA exhibited the most severe damage [median (IQR), 3 (1)], followed respectively by ROIB [median (IQR), 2 (0)] and ROIC [median (IQR), 1 (0)] COMPARISON WITH EXISTING METHODS: H&E stain best reflects 1 h hyperacute DWI abnormal lesions. CONCLUSIONS: H&E stain allowed for the macroscopic delineation of the 1 h DWI-abnormal lesions, while MAP2 and Nissl stains could only partially depict lesions.

Assessment of Hand Motor Function in a Non-human Primate Model of Ischemic Stroke.

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.