Cerebral Aß deposition in an Aß-precursor protein-transgenic rhesus monkey.

With the ultimate goal of developing a more representative animal model of Alzheimer's disease (AD), two female amyloid-ß-(Aß) precursor protein-transgenic (APPtg) rhesus monkeys were generated by lentiviral transduction of the APP gene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The APP-transgene included the AD-associated Swedish K670N/M671L and Indiana V717F mutations (APPSWE/IND) regulated by the human polyubiquitin-C promoter. Overexpression of APP was confirmed in lymphocytes and brain tissue. Upon sacrifice at 10 years of age, one of the monkeys had developed Aß plaques and cerebral Aß-amyloid angiopathy in the occipital, parietal, and caudal temporal neocortices. The induction of Aß deposition more than a decade prior to its usual emergence in the rhesus monkey supports the feasibility of creating a transgenic nonhuman primate model for mechanistic analyses and preclinical testing of treatments for Alzheimer's disease and cerebrovascular amyloidosis.

Evaluation of multi-shell diffusion MRI acquisition strategy on quantitative analysis using multi-compartment models.

BACKGROUND: Multi-compartment diffusion models such as Neurite Orientation Dispersion and Density Imaging (NODDI) have been increasingly used for diffusion MRI (dMRI) data processing in biomedical research. However, those models usually require multiple HARDI shells that may increase scanning duration substantially, and their application can be hindered in uncooperative patients (like infants) accordingly. Also, it is highly expected that the same dataset can be explored with multiple diffusion models for retrieving complementary information. METHODS: Multiple gradient-encoding schemes which consisted of 4-6 shells, moderate b-values (bmax =1,500 or 2,000 s/mm2), and 32-80 gradient directions were explored. The corresponding time of acquisition (TA) for a single scan ranged from 3 to 8 minutes respectively. The dMRI protocols were tested on macaque monkeys using a 3T clinical setting. The data were analysed using both NODDI and diffusion basic spectrum imaging (DBSI) models. RESULTS: The maps of orientation dispersion index (ODI) and CSF were consistent across the 4-6 shell sampling schemes. However, the corresponding intra-cellular volume fraction (ICVF) maps showed reduced pixel counts [1,100±98 (80 directions) vs. 806±70 (32 directions), one slice] in white matter when fewer gradient directions or lower b-value was applied. The hindered diffusion and CSF ratio maps were comparable across these sampling schemes. The maps of restricted diffusion ratio varied across the schemes. However, its mean ratios (0.23±0.02 vs. 0.22±0.01) and pixel counts (1,540±70 vs. 1,510±38, one slice) between the schemes of 80 and 32 directions with b=2,000 s/mm2 were comparable. CONCLUSIONS: The present study reports a fast multi-shell dMRI data acquisition and processing strategy which allows for obtaining complementary information about microstructural alteration and inflammation from a single dMRI data set with both NODDI and DBSI models. The proposed approach may be particularly useful for characterizing the neurodegenerative disorders in uncooperative patients like children or acute stroke patients in which brain injury is associated with inflammation.

Effect of high dose isoflurane on cerebral blood flow in macaque monkeys.

The effect of high dose isoflurane on cerebral blood flow (CBF) was investigated in adult macaque monkeys receiving 1% to 2% isoflurane with the pseudo continuous arterial-spin-labeling (pCASL) MRI technique. High concentration (2%) of isoflurane resulted in significant increase in the mean CBF of the global, cortical, subcortical regions and the regional CBF in all subcortical structures and most cortical structures (such as motor cortex, anterior cingulate cortex, but not media prefrontal cortex). In addition, the changes of regional CBF in the affected regions correlated linearly with increasing isoflurane concentrations. The study demonstrates region-specific CBF abnormal increase in adult macaque monkeys under high dose (2%) isoflurane and suggests that the brain functionality in the corresponding structures may be affected and need to be taken consideration in either human or non-human primate neuroimaging studies.

In vivo evaluation of optic nerve development in non-human primates by using diffusion tensor imaging.

Developmental abnormalities of optic nerve are the leading cause of child blindness. The goal of this study was to use diffusion tensor imaging (DTI) to characterize the optic nerve development of non-human primates during the normal maturation from birth to adulthood. Forty healthy rhesus monkeys aged from 2 weeks to 6 years old were scanned with a clinical 3T scanner. It was demonstrated that the DTI parameters followed an exponential pattern during optic nerve maturation. The time constants of mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (λ∥) and radial diffusivity (λ⊥) were 16, 14, 18 and 15 months in rhesus monkeys, respectively. Significant decrease in RD was observed firstly at 12 months after birth (p<0.05). No significant differences were observed between the left and right optic nerves in any age group. The in vivo imaging results reveal the normal evolution patterns of DTI parameters during optic nerve maturation in primates. The data might be used as a reference in the examination of optic nerve developmental abnormalities or injury in children or preclinical studies.

Dose-dependent effect of isoflurane on regional cerebral blood flow in anesthetized macaque monkeys.

The dose-dependent effect of isoflurane on regional CBF of cortical and subcortical structures in anesthetized macaque monkeys was investigated with the Continuous ASL MRI technique. High concentration of isoflurane resulted in global CBF increase and blood pressure decrease. Evident CBF change was observed in the subcortical structures. Specifically, CBF in thalamus and cerebellum was increased about 39% and 55% when isoflurane concentration was changed from 0.75% to 1.5%, respectively. Also, those regional CBF changes correlated linearly with isoflurane inspiratory concentrations, indicating impaired CBF autoregulation in these structures. In contrast, no obvious CBF changes were observed in anterior cingulated cortex, motor cortex, medial prefrontal cortex, and caudate. The results demonstrate that, under the 0.75-1.5% isoflurane maintenance doses, the CBF auto-regulation is well preserved in the cerebral cortical regions and caudate, but impaired in thalamus and cerebellum, indicating disturbed CBF-metabolism coupling and functional response in specific subcortical regions of anesthetized macaque monkeys.