Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.

Although both choroidal and retinal blood flow and vision were altered after prolonged diabetes in the Ins2(Akita) mouse, choroidal blood flow was reduced even in young diabetic animals, suggesting ocular blood flow deficit could be an early pathological change in diabetic retinopathy.

This paper reviews recent developments in high-resolution magnetic resonance imaging (MRI) and its application to image anatomy, physiology, and function in the retina of animals. It describes technical issues and solutions in performing retinal MRI, anatomical MRI, blood oxygenation level-dependent functional MRI (fMRI), and blood-flow MRI both of normal retinas and of retinal degeneration. MRI offers unique advantages over existing retinal imaging techniques, including the ability to image multiple layers without depth limitation and to provide multiple clinically relevant data in a single setting. Retinal MRI has the potential to complement existing retinal imaging techniques.

Continuous arterial spin labeling MRI with a separate neck labeling coil provides a highly sensitive method to image cerebral blood flow (CBF). In mice, however, this has not been possible because the proximity of the neck coil to the brain uses the neck coil to significantly saturate the brain signal. To overcome this limitation the cardiac spin labeling (CSL) technique is introduced in which the labeling coil is placed at the heart position. Cerebral blood flow (CBF) is tightly regulated and intricately coupled to basal metabolic function under normal physiologic conditions. Perturbations of basal CBF and stimulus-evoked CBF responses have been implicated in many neurological diseases such as stroke, brain tumor, and neurodegeneration. CBF MRI is becoming increasingly popular because it is noninvasive and has high spatial resolution. CBF MRI commonly employs: 1) the dynamic susceptibility contrast (DSC) technique by administering a bolus of an exogenous intravascular contrast agent, or 2) the arterial spin labeling (ASL) technique by magnetically labeling the endogenous water in the in-flowing blood (see review, Ref. 1). The DSC technique is efficient but has relatively low spatial resolution and is incompatible with real-time CBF functional MRI (fMRI) measurements because the long half-life of the exogenous contrast agent allows only one measurement per bolus injection. ASL, on the other hand, allows multiple repeated CBF measurements because the magnetically labeled water has a favorable short half-life (blood T 1 of Ϸ2.0 sec), which can be used for dynamic fMRI measurements, augmentation of spatial resolution, and/or signal-to-noise ratio (SNR).ASL can be performed using the same coil or separate coils for labeling and imaging. The latter approach yields improved CBF SNR because magnetization-transfer effect is avoided. While continuous ASL using a separate neck labeling coil is commonly employed in rats (2), humans (3), and monkeys (4), its extension to mice has not been possible because the proximity of the neck coil and the brain coil (Ϸ1 cm from center to center) results in significant saturation of the brain signal by the neck coil, causing significant CBF measurement errors. This occurs even when the coils are actively decoupled, coil sizes are minimized, and the intercoil distance is maximized. CBF using other MRI techniques in mice is sparse; only a few CBF studies using the single-coil ASL method (5,6) and the DSC method (7) have been reported. This study introduces a practical means to overcome the above limitations. This approach is referred to as the cardiac spin labeling (CSL) technique in which continuous spin labeling is performed with a separate labeling coil placed at the heart position to avoid saturation of the brain signal. To demonstrate its utility, multislice echo-planarimaging was employed to image quantitative basal CBF and CBF fMRI associated with hypercapnic challenge. MATERIALS AND METHODS Animal PreparationsMice (C57BL6, 21-28 g, 6 -10 weeks, n ϭ 9) were imaged under Ϸ1.2% isofl...

The retina is nourished by two distinct circulations: the retinal vessels within the inner retina and the choroidal vessels behind the neural retina. The outer nuclear layer and the inner and outer segments of the photoreceptors in between are avascular. The aim of this study was to determine whether arterial spin labeling MRI could provide sufficient resolution to differentiate between quantitative retinal blood flow (rBF) and choroidal blood flow (chBF), and whether this technique is sufficiently sensitive to detect vascular-specific blood flow (BF) changes modulated by anesthetics. Arterial spin labeling MRI was performed at 42 × 42 × 400 µm 3 in the mouse retina at 7 T, and was used to investigate the effects of isoflurane and ketamine/xylazine anesthesia on rBF and chBF. MRI yielded unambiguous differentiation of rBF, chBF and the avascular layer in between. Under isoflurane, chBF was 7.7 ± 2.1 mL/g/min and rBF was 1.3 ± 0.44 mL/g/min (mean ± SD, n = 7, p < 0.01). Under ketamine/xylazine anesthesia in the same animals, chBF was 4.3 ± 1.9 mL/g/min and rBF was 0.88 ± 0.22 mL/g/min (p < 0.01). Under ketamine/xylazine anesthesia, rBF was lower by 29% (P < 0.01) and chBF by 42% (P < 0.01) relative to isoflurane. This study demonstrates, for the first time, the quantitative imaging of rBF and chBF in vivo, providing a new method to study basal values and alterations of rBF and chBF.

Purpose To apply resting-state functional magnetic resonance (MR) imaging to map functional connectivity of the human spinal cord. Materials and Methods Studies were performed in nine self-declared healthy volunteers with informed consent and institutional review board approval. Resting-state functional MR imaging was performed to map functional connectivity of the human cervical spinal cord from C1 to C4 at 1 × 1 × 3-mm resolution with a 3.0-T clinical MR imaging unit. Independent component analysis (ICA) was performed to derive resting-state functional MR imaging z-score maps rendered on two-dimensional and three-dimensional images. Seed-based analysis was performed for cross validation with ICA networks by using Pearson correlation. Results Reproducibility analysis of resting-state functional MR imaging maps from four repeated trials in a single participant yielded a mean z score of 6 ± 1 (P < .0001). The centroid coordinates across the four trials deviated by 2 in-plane voxels ± 2 mm (standard deviation) and up to one adjacent image section ± 3 mm. ICA of group resting-state functional MR imaging data revealed prominent functional connectivity patterns within the spinal cord gray matter. There were statistically significant (z score > 3, P < .001) bilateral, unilateral, and intersegmental correlations in the ventral horns, dorsal horns, and central spinal cord gray matter. Three-dimensional surface rendering provided visualization of these components along the length of the spinal cord. Seed-based analysis showed that many ICA components exhibited strong and significant (P < .05) correlations, corroborating the ICA results. Resting-state functional MR imaging connectivity networks are qualitatively consistent with known neuroanatomic and functional structures in the spinal cord. Conclusion Resting-state functional MR imaging of the human cervical spinal cord with a 3.0-T clinical MR imaging unit and standard MR imaging protocols and hardware reveals prominent functional connectivity patterns within the spinal cord gray matter, consistent with known functional and anatomic layouts of the spinal cord.

The retina consists of multiple cellular and synaptic layers and is nourished by two distinct (retinal and choroidal) circulations bounding the retina, separated by an avascular layer. High spatiotemporal resolution, layer-specific MRI of the retina remains challenging due to magnetic inhomogeneity-induced artifacts. This study reports passband balanced steady-state free-precession (bSSFP) MRI at 453453500 mm and 1.6 s temporal resolution to image the mouse retina, overcoming geometric distortion and signal dropout while maintaining rapid acquisition and high signal-to-noise ratio. bSSFP images revealed multiple alternating dark-bright-dark-bright retinal layers. Hypoxic (10% O 2 ) inhalation decreased bSSFP signals in the two layers bounding the retina, corresponding to the retinal and choroidal vasculatures. The layer in between showed no substantial response and was assigned the avascular photoreceptor layers. Choroidal responses (225.966.4%, mean6SD, n56) were significantly (P<0.05) larger than retinal vascular responses (211.662.4%). bSSFP offers very high spatiotemporal resolution and could have important applications in imaging layer-specific changes in retinal diseases.

This is the first report of simultaneous resolution of layer-specific functional responses of the retinal and choroid vascular layers to visual stimulation in the retina. This imaging approach could have applications in early detection and longitudinal monitoring of retinal diseases where retinal and choroidal hemodynamics may be differentially perturbed at various stages of the diseases.