GlyCEST: Magnetic Resonance Imaging of Glycine-Distribution in the Normal Murine Brain and Alterations in 5xFAD Mice.

The glycine level in the brain is known to be altered in neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease (AD). Several studies have reported the in vivo measurement of glycine concentrations in the brain using proton magnetic resonance spectroscopy (1H-MRS), but 1H-MRS is not capable of imaging the distribution of glycine concentration with high spatial resolution. Chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) is a new technology that can detect specific molecules, including amino acids, in tissues. To validate the measurements of glycine concentrations in living tissues using CEST from glycine to water (GlyCEST), we extracted the brain tissues from mice and performed biochemical tests. In wild-type C57BL/6 mice, GlyCEST effects were found to be higher in the thalamus than in the cerebral cortex (P < 0.0001, paired t-test), and this result was in good agreement with the biochemical results. In 5xFAD mice, an animal model of AD, GlyCEST measurements demonstrated that glycine concentrations in the cerebral cortex (P < 0.05, unpaired t-test) and thalamus (P < 0.0001, unpaired t-test), but not in the hippocampus, were decreased compared to those in wild-type mice. These findings suggest that we have successfully applied the CEST-MRI technique to map the distribution of glycine concentrations in the murine brain. The present method also captured the changes in cerebral glycine concentrations in mice with AD. Imaging the distribution of glycine concentrations in the brain can be useful in investigating and elucidating the pathological mechanisms of neuropsychiatric disorders.

Longitudinal GluCEST MRI Changes and Cerebral Blood Flow in 5xFAD Mice.

Many of the focal neurological symptoms associated with Alzheimer's disease (AD) are due to synaptic loss. Glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) is a candidate method to assess synaptic dysfunction. We assessed chronological changes in GluCEST in a 5xFAD mouse model of AD, comparing Glucest effects and regional cerebral blood flow (CBF). GluCEST effects and CBF in 5xFAD mice aged 1-15 months and their littermates (WT) were measured. Neurite orientation dispersion and density imaging (NODDI) MRI reflecting dendritic/axonal density was also measured and compared with GluCEST in 7-month-old mice. While regional CBF's decrease began at 7 months, GluCEST-reduction effects preceded hypoperfusion of the temporal cortex and hippocampus. While longitudinal 5xFAD mouse measurements revealed a correlation between the regional GluCEST effects and CBF, a generalized linear mixed model revealed statistically different correlations in cortical and basal brain regions. Further, NODDI-derived neurite density correlated with GluCEST effects in the parietal cortex, but not in the hippocampus, thereby revealing regional differences in pathophysiological mechanisms. Finally, GluCEST's effects correlated with regional synaptophysin. These results demonstrate that GluCEST can reflect subtle synaptic changes and may be a potential imaging method for AD diagnosis as well as serve as a biomarker of AD progression.

Skull diploë is rich in aquaporin-4.

Aquaporin-4 (AQP4) is a water conducting membrane integral protein channel which is widely expressed in the astrocyte system of the brain. During the development of the AQP4 positron emission tomography (PET) imaging agent [11C]TGN-020 (N-(1,3,4-thiadiazol-2-yl)pyridine-3-[11C]-carboxamide), significant radioligand uptake was observed in the skull, where there was no known distribution of any aquaporin family proteins. Herein we confirmed via a newly developed method for bone-tissue immunohistology, a hitherto unrecognized distribution of AQP4, and not AQP1, in the skull. Other bony structures, by contrast, showed virtually no uptake of [11C]TGN-020, and likewise, do not express either AQP4 or AQP1. Immunohistological analysis demonstrated that the AQP4 expression in the skull is restricted to the diploë. Consequently, we suspect AQP4 plays a pivotal role in the formation and maintenance of yellow marrow and the diploë. However, elucidating the exact nature of that role will require further studies.

Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging.

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and Cerebrospinal Fluid Circulation in the Brain.

The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of brain fluid dynamics. The brain is protected by barriers preventing free access of systemic fluid. The same barrier system, however, also isolates brain interstitial fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic interstitial fluid circulation, cannot be propagated to the interstitial fluid compartment of the brain. Without a proper alternative mechanism, brain interstitial fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate interstitial fluid motion. Interstitial flow in peri-arterial VRS constitutes an essential part of the clearance system for ß-amyloid, whereas interstitial flow in peri-venous VRS creates bulk interstitial fluid flow, which, together with the choroid plexus, creates the necessary ventricular cerebrospinal fluid (CSF) volume for proper CSF circulation.

Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier: [17O]H2O JJVCPE MRI study.

The blood-brain barrier (BBB), which imposes significant water permeability restriction, effectively isolates the brain from the systemic circulation. Seemingly paradoxical, the abundance of aquaporin-4 (AQP-4) on the inside of the BBB strongly indicates the presence of unique water dynamics essential for brain function. On the basis of the highly specific localization of AQP-4, namely, astrocyte end feet at the glia limitans externa and pericapillary Virchow-Robin space, we hypothesized that the AQP-4 system serves as an interstitial fluid circulator, moving interstitial fluid from the glia limitans externa to pericapillary Virchow-Robin space to ensure proper glymphatic flow draining into the cerebrospinal fluid. The hypothesis was tested directly using the AQP-4 facilitator TGN-073 developed in our laboratory, and [O]H2O JJ vicinal coupling proton exchange MRI, a method capable of tracing water molecules delivered into the blood circulation. The results unambiguously showed that facilitation of AQP-4 by TGN-073 increased turnover of interstitial fluid through the system, resulting in a significant reduction in [O]H2O contents of cortex with normal flux into the cerebrospinal fluid. The study further suggested that in addition to providing the necessary water for proper glymphatic flow, the AQP-4 system produces a water gradient within the interstitial space promoting circulation of interstitial fluid within the BBB.

Aquaporin Positron Emission Tomography Differentiates Between Grade III and IV Human Astrocytoma.

BACKGROUND: Aquaporin (AQP) water channels play a significant role in mesenchymal microvascular proliferation and infiltrative growth. AQPs are highly expressed in malignant astrocytomas, and a positive correlation is observed between their expression levels and histological tumor grade. OBJECTIVE: To examine the utility of aquaporin positron emission tomography (PET) for differentiating between astrocytoma grade III and grade IV using the AQP radioligand [11C]TGN-020. METHODS: Fifteen astrocytoma patients, grade III (n = 7) and grade IV (n = 8), and 10 healthy volunteers underwent [11C]TGN-020 aquaporin PET imaging. Surgical tissues of astrocytoma patients were examined for histopathological grading using the WHO classification standard and expression of AQP1 and AQP4 immunohistochemically. RESULTS: Mean standardized uptake values of astrocytoma grade III and IV (0.51 ± 0.11 vs 1.50 ± 0.44, respectively) were higher than normal white matter (0.17 ± 0.02, P < .001) for both tumor grades. Importantly, mean standardized uptake values of astrocytoma grade IV were significantly higher than grade III (P < .01). CONCLUSION: Our study demonstrated that [11C]TGN-020 aquaporin PET imaging differentiated between astrocytoma grades III and IV. We suggest its clinical application as a noninvasive diagnostic tool would lead to advancements in the management of these malignant brain tumors.

Musical pitch classes have rainbow hues in pitch class-color synesthesia.

Synesthesia, an anomalous blending of senses in which stimulation of one sensory modality produces sensation in a different modality, provides a unique opportunity to study how multimodal information is represented in the human brain. We investigated how pitch classes (do, re, mi, etc.) are associated with the three dimensions of color (hue, saturation, and value/brightness) in 15 subjects who possessed "pitch class-color synesthesia". Across-subject averaging of reported colors revealed that pitch classes have rainbow hues, beginning with do-red, re-yellow, and so forth, ending with si-violet, accompanied by a decrease in saturation. Enharmonic pitch classes that referred to the same pitch class with a different name produced color sensations according to the name of the base pitch class, e.g., a reddish color for do-sharp and a yellowish color for re-flat. Thus the main factor producing color sensations was the name, not the sound, of the note; behavioral experiments corroborated this interpretation. Pitch class-color synesthesia represents a newly described type of synesthesia that is distinct from the well-known crossmodal association between pitch height and value/brightness. Findings suggest that the two dimensions of musical pitch, pitch class and pitch height, are mapped to the hue-saturation plane and the value/brightness dimension of color, respectively.

Inferior colliculus syndrome: Clinical magnetic resonance microscopy anatomic analysis on a 7 T system.

We performed detailed structural analysis of a case of a unilateral lesion of the inferior colliculus using magnetic resonance microscopy on a 7 T system. A 36-year-old right-handed man had an intracerebral hemorrhage circumscribed to the right inferior colliculus. Following recovery from the acute phase, he had only residual left ear tinnitus and left trochlear palsy and no hearing loss. Microscopic imaging analysis on a 7 T magnetic resonance imaging system demonstrated a chronic lesion confined primarily to the right central nucleus of the inferior colliculus. Sound localization was significantly impaired in the contralateral hemispace. The case confirms prior clinical reports of unilateral inferior colliculus dysfunction, the specific anatomic characterization of which was demonstrated in this case by magnetic resonance microscopy. It furthermore supports the notion that central nucleus of the inferior colliculus dysfunction can produce tinnitus and sound localization deficits, without hearing loss.

MRI characteristics of the glia limitans externa: A 7T study.

PURPOSE: To perform a systematic analysis of the intrinsic contrast parameters of the FLAIR hyperintense rim (FHR), a thin layer of high intensity covering the entire surface of the cerebral cortex detected on fluid-attenuated inversion recovery (FLAIR) sequence T2 weighted imaging performed on a 7T system, in an attempt to identify its anatomical correlate. METHODS: Fast spin echo inversion recovery (FSE-IR) and cardiac-gated fast spin echo (FSE) images were obtained with defined parameters in eight normal volunteers on a 7 T MRI system to determine T2 and proton density, T1 characteristics. K-means clustering analysis of parameter sets was performed using MATLAB version R2015b for the purpose of identifying the cluster reflecting FHR. The results were subsequently confirmed by independent component analysis (ICA) based on T1 behavior on FSE-IR using a MATLAB script of FastICA algorithm. RESULTS: The structure giving rise to FHR was found to have a unique combination of intrinsic contrast parameters of low proton density, long T2, and disproportionally short T1. The findings are in strong agreement with the functional and structural specifics of the glia limitans externa (GLE), a structure composed of snuggled endfeet of astrocytes containing abundant aquaporin-4 (AQP-4), the main water channel of the brain. CONCLUSION: Intrinsic contrast parameters of FHR reflect structural and functional specifics of the GLE, and their values are highly dependent on the physiologic functionality of AQP-4. Microscopic imaging on a 7T system and analysis of GLE contrast parameters can be developed into a method for evaluating AQP-4 functionality.

Aquaporin-4 Functionality and Virchow-Robin Space Water Dynamics: Physiological Model for Neurovascular Coupling and Glymphatic Flow.

The unique properties of brain capillary endothelium, critical in maintaining the blood-brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the interstitial fluid inside the BBB by the tightly sealed endothelium of brain capillaries. Instead, fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (interstitial) fluid. Brain interstitial fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the brain equivalent of systemic lymphatics.

Reduced CSF Water Influx in Alzheimer's Disease Supporting the ß-Amyloid Clearance Hypothesis.

OBJECTIVE: To investigate whether water influx into cerebrospinal fluid (CSF) space is reduced in Alzheimer's patients as previously shown in the transgenic mouse model for Alzheimer's disease. METHODS: Ten normal young volunteers (young control, 21-30 years old), ten normal senior volunteers (senior control, 60-78 years old, MMSE ≥ 29), and ten Alzheimer's disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) participated in this study. All AD patients were diagnosed by neurologists specializing in dementia based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq [15O]H2O synthesized on-line. RESULTS: Water influx into CSF space in AD patients, expressed as influx ratio, (0.755 ± 0.089) was significantly reduced compared to young controls (1.357 ± 0.185; p < 0.001) and also compared to normal senior controls (0.981 ± 0.253, p < 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p < 0.01). CONCLUSION: Water influx into the CSF is significantly reduced in AD patients. ß-amyloid clearance has been shown to be dependent on interstitial flow and CSF production. The current study indicates that reduction in water influx into the CSF may disturb the clearance rate of ß-amyloid, and therefore be linked to the pathogenesis of AD. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000011939.

Covert effects of "one drink" of alcohol on brain processes related to car driving: an event-related potential study.

The effects of a low dose of alcohol on car driving remain controversial. To address this issue, event-related potentials were recorded while subjects performed a simple car-following task in a driving simulator before and after consuming either "one drink" of beer (representing one standard alcoholic beverage containing 14 g of alcohol) or mineral water (control condition). Subjects who had consumed the determined amount of alcohol demonstrated no detectable outward behavioral signs of intoxication while performing the driving task, an observation in agreement with previous findings. However, the parietal P3 elicited by the brake lights of the preceding car was significantly reduced in amplitude, approximately 50% that observed under the control condition, likely indicating alteration of the neural processing of visual information critical for safe driving. The finding suggests that alcohol begins to affect neural processes for driving even at quantities too low to modify behavior.

Ligand-based molecular MRI: O-17 JJVCPE amyloid imaging in transgenic mice.

BACKGROUND: Development of molecular MR imaging (MRI) similar to PET imaging using contrast agents such as gadolinium as probe have been inherently hampered by incompatibility between potential probe (charged molecules) and membrane permeability. Nevertheless, considering the inherent spatial resolution limit for PET of 700µ, the superior microscopic resolution of MRI of 4 µ presents a strong incentive for research into ligand-based molecular MRI. METHODS: (17) O exhibits JJ vicinal coupling with a covalently bound proton in a hydroxyl group. This (17) O coupled proton can be ionized in water solution and interexchange with other water protons. This property can be utilized as "probe" in T2-weighted imaging and developed into ligand-based molecular MRI. We examined ß-amyloid distribution in human APP overexpressed transgenic mice in vivo following injection of (17) O labeled Pittsburg compound B ((17) O-PiB). RESULTS: JJVCPE imaging successfully imaged (17) O-PiB, unequivocally establishing that (17) O JJVCPE imaging can be developed into PET-like molecular MRI in clinical medicine. CONCLUSIONS: The study represents the first successful ligand-based molecular MRI in vivo. This is also the first in vivo amyloid imaging using MRI. High-resolution molecular MRI with high specificity under clinical settings, such as in vivo microscopic imaging of senile plaque, is a foreseeable aim.

Water influx into cerebrospinal fluid is significantly reduced in senile plaque bearing transgenic mice, supporting beta-amyloid clearance hypothesis of Alzheimer's disease.

Recent studies on cerebrospinal fluid (CSF) homeostasis emphasize the importance of water influx into the peri-capillary (Virchow-Robin) space through aquaporin 4 (AQP-4). This water flow is believed to have the functionality equivalent to the systemic lymphatic system and plays a critical role in beta-amyloid clearance. Using a newly developed molecular imaging technique capable of tracing water molecules, in vivo, water influx into the CSF was quantitatively analyzed in senile plaque (SP) bearing transgenic Alzheimer's disease (AD) model mice. The results unequivocally demonstrated that water influx into CSF is significantly impaired in SP-bearing transgenic mice, the degree of which being virtually identical to that previously observed in AQP-4 knockout mice. The study strongly indicates that disturbance in AQP-4-based water flow and, hence, impairment in beta-amyloid clearance play a significant role in SP formation.

Water influx into cerebrospinal fluid is primarily controlled by aquaporin-4, not by aquaporin-1: 17O JJVCPE MRI study in knockout mice.

Recent studies on cerebrospinal fluid (CSF) homeostasis emphasize the importance of water flux through the pericapillary (Virchow-Robin) space for both CSF production and reabsorption (Oreskovic and Klarica hypothesis), and challenge the classic CSF circulation theory, which proposes that CSF is primarily produced by the choroid plexus and reabsorbed by the arachnoid villi. Active suppression of aquaporin-1 (AQP-1) expression within brain capillaries and preservation of AQP-1 within the choroid plexus together with pericapillary water regulation by AQP-4 provide a unique opportunity for testing this recent hypothesis. We investigated water flux into three representative regions of the brain, namely, the cortex, basal ganglia, and third ventricle using a newly developed water molecular MRI technique based on JJ vicinal coupling between O and adjacent protons and water molecule proton exchanges (JJVCPE imaging) in AQP-1 and AQP-4 knockout mice in vivo. The results clearly indicate that water influx into the CSF is regulated by AQP-4, and not by AQP-1, strongly supporting the Oreskovic and Klarica hypothesis.

Inhibition of aquaporin-4 significantly increases regional cerebral blood flow.

The effects of the aquaporin-4 (AQP-4) inhibitor TGN-020 on regional cerebral blood flow (rCBF) was examined in wild-type (WT) and AQP-4 knockout (KO) mice in vivo. Although baseline absolute rCBF of WT and KO mice were equivalent (158.9 ± 17.7 and 155.5 ± 10.4 ml/100 g/min, respectively), TGN-020 produced a significant increase in rCBF compared with saline-treated WT mice (control), reaching a plateau 20 min after administration (118.45 ± 8.13%, P<0.01). TGN-020 showed no effect on KO mice, supporting the concept that the observed increase in rCBF in WT mice was AQP-4 dependent. Administration of acetazolamide (positive control) produced an even greater increase in rCBF in WT compared with TGN-020 and a similar response in KO mice as well, reaching a sustained plateau 5 min after administration (138.50 ± 9.75 and 138.52 ± 9.76%, respectively, P<0.01 compared with baseline or saline-treated control mice). The study demonstrated that AQP-4 plays a role in regulation of rCBF.

Effects of musical training on the early auditory cortical representation of pitch transitions as indexed by change-N1.

The effects of musical training on the early auditory cortical response to pitch transitions in music were investigated by use of the change-N1 component of auditory event-related potentials. Musicians and non-musicians were presented with music stimuli comprising a melody and a harmony under various listening conditions. First, when the subjects played a video game and were instructed to ignore the auditory stimuli, the onset of stimuli elicited a typical, fronto-central onset-N1, whereas melodic and harmonic pitch transitions within the stimuli elicited so-called change-N1s that were more posterior in scalp distribution. The pitch transition change-N1s, but not onset-N1, were enhanced in musicians. Second, when the listeners attended to the same stimuli as above to detect infrequently occurring target stimuli, the change-N1 elicited by pitch changes (in non-target stimuli) was augmented, in non-musicians only when the target was easily detectable, and in both musicians and non-musicians when it was difficult to detect. Thus, the early, obligatory cortical response to pitch transitions during passive listening was chronically enhanced by training in musicians, and, reflecting this training-induced enhancement, the task-related modulation of this response was also different between musicians and non-musicians. These results are the first to demonstrate the long-term effects of training, short-term effects of task and the effects of their interaction on the early (~100-ms) cortical processing of pitch transitions in music. The scalp distributions of these enhancement effects were generally right dominant at temporal electrode sites, suggesting contributions from the radially oriented subcomponent of change-N1, namely, the Tb (N1c) wave of the T-complex.

Neural strategies for reading Japanese and Chinese sentences: a cross-linguistic fMRI study of character-decoding and morphosyntax.

Japanese and Chinese share virtually identical morphographic characters invented in ancient China. Whereas modern Chinese retained the original morphographic functionality of these characters (hanzi), modern Japanese utilizes these characters (kanji) as complex syllabograms. This divergence provides a unique opportunity to systematically investigate brain strategies for sentence reading in Japanese-Chinese bi-literates. Accordingly, we investigated brain activation associated with Japanese and Chinese reading in 14 native Japanese speakers literate in Mandarin and 14 native Mandarin speakers literate in Japanese using functional magnetic resonance imaging performed on a 3T system. The activation pattern exhibited clearly distinct features specific for each language. Regardless of the subject's native language literacy, Chinese reading activated an area significantly larger than Japanese reading, suggesting that brain processes involved in Chinese reading were much more complex than Japanese reading. Significant recruitment of corresponding cortical areas in the right hemisphere with Chinese reading was also apparent. The activation patterns associated with Japanese reading by native Japanese literates was highly consistent with previous reports, and included the left inferior frontal gyrus (IFG), left posterior temporal lobe (PTL), and left ventral premotor cortex (PMv). The activation pattern associated with Chinese reading by native Chinese literates was also highly consistent with previous reports, namely the left IFG, left PTL, left PMv, left anterior temporal lobe (ATL), and bilateral parieto occipital lobes (LPOL). The activation pattern associated with Chinese reading by native Japanese literates was virtually identical to that by native Chinese literates, whereas the activation pattern associated with Japanese reading by native Chinese literates was signified by additional activation of LPOL compared to that by native Japanese literate. The study indicated that IFG and PTL are universal language areas, while PMv is the area for decoding complex syllabograms. LPOL is the "Chinese language area," while ATL is essential for languages with analytic morphosyntax.

Expansion of corticomedullary junction high-susceptibility region (CMJ-HSR) with aging: a clue in the pathogenesis of Alzheimer's disease?

BACKGROUND: Susceptibility-weighted imaging (SWI) microscopy on a 7.0T system demonstrated the corticomedullary junction (CMJ) to be a high-susceptibility region (HSR) in young normal subjects, suggesting that functional alteration of cortical microcirculation could be assessed with this imaging method. METHODS: Focused microscopic studies were performed on the parietal association cortex in 74 normal volunteers (ages 20-79 years; 35 female, 39 male) using a SWI algorithm on a system constructed based on General Electric Signa LX (Waukesha, WI, USA), equipped with a 900-mm clear bore superconducting magnet operating at 7.0T. RESULTS: There was a clear-cut reduction in the thickness of the normal-appearing cortex (cortex, R2 = .5290, P < .001) and expansion of CMJ-HSR (R(2) = .6919, P < .001). The sum of cortex thickness and CMJ-HSR thickness was essentially constant, suggesting that the observed expansion of CMR-HSR with aging likely occurred within the cortical mantle. CONCLUSION: CMJ-HSR expands significantly as a function of aging. Since CMJ-HSR represents a functionally distinct area with relatively slow venous flow, the observed expansion is believed to reflect alteration in cerebral microcirculation with increased age, providing another clue for pathogenesis of Alzheimer's disease.