Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

Age-Dependent Changes in Regulation of Water Inflow Into the Vitreous Body.

Purpose: Water inflow into the vitreous body regulated by retinal aquaporin-4 distributed within Müller cells has been observed in mice; however, the changes in this phenomenon with age remain unknown. This study aimed to evaluate whether intravenously injected H2O also flows into the vitreous body of human subjects and to investigate whether water dynamics in the human posterior eye change with age using [15O]H2O positron emission tomography (PET). Methods: Forty-six normal adult volunteers underwent [15O]H2O PET, and the standard uptake value (SUV) in the center of the vitreous body after 1000-MBq [15O]H2O administration was assessed. The SUV was fitted to an exponential curve, and y0, the steady state of the SUV, and b, the speed of increase in the SUV, were calculated. The results for patients ranging from in age from 20 to 39, 40 to 59, and 60 to 79 years were compared using analyses of variance followed by Games to Howell tests. Results: For the parameter y0, statistical analysis revealed no statistically significant differences among the three groups. For parameter b, statistical analysis revealed statistically significant differences between the 20 to 39 and 60 to 79 age groups (P = 0.000), the 40 to 59 and 60 to 79 age groups (P = 0.025), and the 20 to 39 and 40 to 59 age groups (P = 0.037). Conclusions: The present study revealed that H2O injected into the vein flows into the human vitreous body and that the speed of increase in water flow into the vitreous body decreases with aging. This study suggests that water dynamics in the posterior eye, or the retinal glymphatic pathway, change significantly with aging.

Changes in functional connectivity among vestibulo-visuo-somatosensory and spatial cognitive cortical areas in persistent postural-perceptual dizziness: resting-state fMRI studies before and after visual stimulation.

Introduction: Persistent postural-perceptual dizziness (PPPD) is a functional chronic vestibular syndrome with symptom exacerbation by upright posture, motion, and complex visual stimuli. Among these exacerbating factors, visual exacerbation is the most specific characteristic of PPPD requiring further investigation. We hypothesized that stimulus-induced changes occur in the functional connectivity (FC) rather than simple neural activation that is involved in visual stimulation. The present study aimed to identify the neural basis of PPPD by investigating FC before and after visual stimulation. Methods: Eleven patients with PPPD and 11 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI (rs-fMRI) before and after task-based fMRI with visual stimuli. Results: At pre-stimulus, FC between the vestibular cortex and visual areas was low, while that between the somatosensory and visual areas was high in PPPD compared with that in HCs. FC between the visuospatial (parahippocampal gyrus) and spatial cognitive areas (inferior parietal lobule) was elevated in PPPD even in the pre-stimulus condition, which no longer increased at post-stimulus as observed in HCs. In the post-stimulus condition, FC between the visual and spatial cognitive areas and that between the visual and prefrontal areas increased compared with that in the pre-stimulus condition in PPPD. Task-based fMRI demonstrated that no brain regions showed different activities between the HC and PPPD groups during visual stimulation. Discussion: In PPPD, vestibular inputs may not be fully utilized in the vestibulo-visuo-somatosensory network. Given that the FC between visuospatial and spatial cognitive areas increased even in HCs after visual stimuli, elevated status of this FC in combination with the high FC between the somatosensory and visual areas would be involved in the visual exacerbation in PPPD. An increase in FC from the visual areas to spatial cognitive and prefrontal areas after visual stimuli may account for the prolonged symptoms after visual exacerbation and anxious status in PPPD.

Gaze instability after exposure to moving visual stimuli in patients with persistent postural-perceptual dizziness.

Introduction: Persistent postural-perceptual dizziness (PPPD) is a chronic vestibular syndrome lasting more than 3 months. The core vestibular symptoms are dizziness, unsteadiness, and non-spinning vertigo, which are exacerbated by upright posture or walking, active or passive motion, and exposure to moving or complex visual stimuli. Among these, visual exacerbation is a key feature of PPPD for which the neural mechanisms are unknown. We hypothesized that vestibular symptoms may be exacerbated by visual stimuli through gaze behavioral change after exposure to moving or complex visual stimuli. The study aimed to examine gaze stability after exposure to moving visual stimuli in patients with PPPD. Methods: Fourteen healthy controls (HCs), 27 patients with PPPD, and 12 patients with unilateral vestibular hypofunction (UVH), showing chronic vestibular symptoms for >3 months, were enrolled in the study. The participants were instructed to fixate on the gazing point at the center of a screen for 30 s before and after 90 s of exposure to moving visual stimuli. Gaze stability, best represented by the bivariate contour ellipse area (BCEA), was compared among three groups, both before and after exposure to the moving visual stimuli. Comparisons between pre- and post-moving visual stimuli in BCEA were also conducted. Correlation between the post/pre ratio of BCEA and vestibular tests, several clinical symptom scales including the Dizziness Handicap Inventory, Niigata PPPD Questionnaire, and Hospital Anxiety and Depression Scale, and the exacerbation of dizziness by exposure to moving visual stimuli was examined in the PPPD group. Results: BCEA, both before and after exposure to moving visual stimuli in the PPPD group, was not different from that in HC and UVH groups. In the PPPD group, BCEA increased significantly after exposure to moving visual stimuli. The post/pre ratio of BCEA correlated with the occurrence of exacerbation of the dizziness sensation by exposure to moving visual stimuli; however, it did not correlate with vestibular tests or clinical symptom scales. Conclusion: Patients with PPPD were more likely to exhibit gaze instability after exposure to moving visual stimuli, which potentially exacerbated vestibular symptoms. This phenomenon may help elucidate the neural mechanisms of visual exacerbation in patients with PPPD.

Blood Cerebrospinal Fluid Barrier Function Disturbance Can Be Followed by Amyloid-ß Accumulation.

BACKGROUND: Elucidation of the mechanism of amyloid-ß accumulation plays an important role in therapeutic strategies for Alzheimer's disease (AD). The aim of this study is to elucidate the relationship between the function of the blood-cerebrospinal fluid barrier (BCSFB) and the clearance of amyloid-ß (Aß). METHODS: Twenty-five normal older adult volunteers (60-81 years old) participated in this PET study for clarifying the relationship between interstitial water flow and Aß accumulation. Water dynamics were analyzed using two indices in [15O]H2O PET, the influx ratio (IR) and drain rate (DR), and Aß accumulation was assessed qualitatively by [18F]flutemetamol PET. RESULTS: [15O]H2O PET examinations conducted initially and after 2 years showed no significant changes in both indices over the 2-year period (IR: 1.03 ± 0.21 and 1.02 ± 0.20, DR: 1.74 ± 0.43 and 1.67 ± 0.47, respectively). In [18F]flutemetamol PET, on the other hand, one of the 25 participants showed positive results and two showed positive changes after 2 years. In these three participants, the two indices of water dynamics showed low values at both periods (IR: 0.60 ± 0.15 and 0.60 ± 0.13, DR: 1.24 ± 0.12 and 1.11 ± 0.10). CONCLUSIONS: Our results indicated that BCSFB function disturbances could be followed by Aß accumulation, because the reduced interstitial flow preceded amyloid accumulation in the positive-change subjects, and amyloid accumulation was not observed in the older adults with sufficiently high values for the two indices. We believe that further elucidation of interstitial water flow will be the key to developing therapeutic strategies for AD, especially with regard to prevention.

Cerebral cortical processing time is elongated in human brain evolution.

An increase in number of neurons is presumed to underlie the enhancement of cognitive abilities in brain evolution. The evolution of human cognition is then expected to have accompanied a prolongation of net neural-processing time due to the accumulation of processing time of individual neurons over an expanded number of neurons. Here, we confirmed this prediction and quantified the amount of prolongation in vivo, using noninvasive measurements of brain responses to sounds in unanesthetized human and nonhuman primates. Latencies of the N1 component of auditory-evoked potentials recorded from the scalp were approximately 40, 50, 60, and 100 ms for the common marmoset, rhesus monkey, chimpanzee, and human, respectively. Importantly, the prominent increase in human N1 latency could not be explained by the physical lengthening of the auditory pathway, and therefore reflected an extended dwell time for auditory cortical processing. A longer time window for auditory cortical processing is advantageous for analyzing time-varying acoustic stimuli, such as those important for speech perception. A novel hypothesis concerning human brain evolution then emerges: the increase in cortical neuronal number widened the timescale of sensory cortical processing, the benefits of which outweighed the disadvantage of slow cognition and reaction.

Detection of 2-Hydroxyglutarate by 3.0-Tesla Magnetic Resonance Spectroscopy in Gliomas with Rare IDH Mutations: Making Sense of "False-Positive" Cases.

We have previously published a study on the reliable detection of 2-hydroxyglutarate (2HG) in lower-grade gliomas by magnetic resonance spectroscopy (MRS). In this short article, we re-evaluated five glioma cases originally assessed as isocitrate dehydrogenase (IDH) wildtype, which showed a high accumulation of 2HG, and were thought to be false-positives. A new primer was used for the detection of IDH2 mutation by Sanger sequencing. Adequate tissue for DNA analysis was available in 4 out of 5 cases. We found rare IDH2 mutations in two cases, with IDH2 R172W mutation in one case and IDH2 R172K mutation in another case. Both cases had very small mutant peaks, suggesting that the tumor volume was low in the tumor samples. Thus, the specificity of MRS for detecting IDH1/2 mutations was higher (81.3%) than that originally reported (72.2%). The detection of 2HG by MRS can aid in the diagnosis of rare, non-IDH1-R132H IDH1 and IDH2 mutations in gliomas.

Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor ß (TGF-ß) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-ß binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Visual outcome of aquaporin-4 antibody-positive optic neuritis with maintenance therapy.

PURPOSE: To assess the effect of maintenance therapy on visual outcomes in preventing recurrences one year after first onset in patients with aquaporin-4 antibody (AQP4Ab)-positive optic neuritis. STUDY DESIGN: Retrospective study. METHODS: The medical charts of 56 patients with optic neuritis (22 with AQP4Ab-positive and 34 with AQP4Ab-negative) at Niigata University Medical and Dental Hospital were retrospectively analyzed. Clinical characteristics, including visual acuity and number of recurrences one year after first onset, were compared among patients who were AQP4Ab-positivie with and those without maintenance therapy such as oral prednisolone and azathioprine, as well as those who were AQP4Ab-negative. RESULTS: The mean ages were 49.3 and 45.2 years in the AQP4Ab-positive and the AQP4Ab-negative groups. The female to male ratio was 21:1 and 18:16 in the two groups, respectively. Multiple between-group comparison showed a statistically significant difference in visual acuity one year after first onset between the AQP4Ab-positive without maintenance therapy group and the AQP4Ab-negative group (0.05 (median, same applies below) vs. 1.0, p < 0.01). There was also a statistically significant difference in the number of recurrences in the year after first onset between the AQP4Ab-positive with and without maintenance therapy groups (1 vs. 0, p < 0.01). CONCLUSION: This study demonstrates that patients with AQP4Ab-positive optic neuritis without maintenance therapy had the poorest visual acuity and the most recurrences one year after first onset. These results indicate that reducing the number of recurrences with maintenance therapy could improve the visual outcomes in patients with AQP4Ab-positive optic neuritis.

Noninvasive scalp recording of the middle latency responses and cortical auditory evoked potentials in the alert common marmoset.

The common marmoset (Callithrix jacchus), a New World monkey, serves as a useful animal model in clinical and basic neuroscience. The present study recorded scalp auditory evoked potentials (AEP) in non-sedated common marmoset monkeys (n = 4) using a noninvasive method similar to that used in humans, and aimed to identify nonhuman primate correlates of the human AEP components. A pure tone stimulus was presented while electroencephalograms were recorded using up to 16 disk electrodes placed on the scalp and earlobes. Candidate homologues of two categories of the human AEP, namely, the middle latency responses (MLR; Na, Pa, Nb, and Pb) and the cortical auditory evoked potentials (CAEP; P1, N1, P2, N2, and the sustained potential, SP) were identified in the marmoset. These waves were labeled as CjNa, CjPa, CjNb, CjPb, CjP1, CjN1, CjP2, CjN2, and CjSP, where Cj stands for Callithrix jacchus. The last MLR component, CjPb, was identical to the first CAEP component, CjP1, similar to the relationship between Pb and P1 in humans. The peak latencies of the marmoset MLR and CAEP were generally shorter than in humans, which suggests a shorter integration time in neural processing. To our knowledge, the present study represents the first scalp recorded MLR and CAEP in the alert common marmoset. Further use of these recording methods would enable valid species comparisons of homologous brain indices between humans and animals.

[Proton magnetic resonance spectroscopy (1H-MRS)].

Proton magnetic resonance spectroscopy(1H-MRS)is a non-invasive method for evaluating brain function and metabolism. 1H-MRS can quantify low-molecular-weight metabolites in a living brain; it shows their spectra without tracer administration. In this paper, we introduce 1H-MRS and MRS for imaging the distribution of metabolites. The applications of 1H-MRS imaging for several neurological disorders will be outlined.

Retinal Aquaporin-4 and Regulation of Water Inflow Into the Vitreous Body.

Purpose: Details of the posterior eye water dynamics are unclear. Aquaporin-4 (AQP4), a water channel, plays an important role in water dynamics in the central nervous system and is also present in the ocular tissue. The purpose of this study was to reveal the role of AQP4 in the water dynamics of the posterior eye using in vivo JJ vicinal coupling proton exchange (JJVCPE) magnetic resonance imaging (MRI) of AQP4 knockout (KO) mice and their wild-type littermates (controls). Methods: JJVCPE MRI of the eye was performed on five AQP4 KO mice and seven control mice. We assessed the normalized signal intensities of a region of interest (ROI) set in the vitreous body after H217O administration. The results of the two groups were compared using a two-tailed Mann-Whitney U test. Results: A statistical analysis revealed that the normalized ROI signal intensities at the steady state were significantly lower (P = 0.010, <0.05) in the AQP4 KO mice (mean ± SD, 84.5% ± 2.7%) than the controls (mean ± SD, 88.8% ± 1.9%). Conclusions: The present study using JJVCPE MRI of the eye demonstrated that retinal AQP4 has a potential role in the regulation of water inflow into the vitreous body. Absence of AQP4 in the KO mice probably induces lower water outflow from the vitreous body. Our results could help clarify the pathogenesis of various ocular diseases.

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.

Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model.

Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.

Vascular Hyperintensity on Fluid-Attenuated Inversion Recovery Indicates the Severity of Hypoperfusion in Acute Stroke.

BACKGROUND AND AIM: Although fluid-attenuated inversion recovery vascular hyperintensities may be frequently seen in acute large-artery ischemic stroke, reports on their prognostic utility had been conflicting due to lack of quantitative evaluation of the perfusion status based on the signal intensity. We hypothesized that greater hyperintensity represents more severe hypoperfusion. METHODS: Overall, 27 patients with acute occlusion of the proximal middle cerebral artery were divided into 2 groups, based on their signal intensity in the insular segment of middle cerebral artery on the affected side, relative to that of the insular cortex: the low signal intensity group (hypo- or isointense signals, n = 12) and the high signal intensity group (hyperintense signals, n = 15). Using dynamic susceptibility contrast magnetic resonance imaging, we assessed the time of the maximum value of the residue function and mean transit time, in the entire middle cerebral artery cortical area and diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score regions, including the corona radiata. RESULTS: The high signal intensity group had significantly longer time of the maximum value of the residue function in all the diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score regions, except the M3 and M6 regions, and significantly longer mean transit time in the M1 and M4 regions. CONCLUSIONS: Quantitative analysis of the perfusion parameters revealed more severely compromised and widely disturbed perfusion status in the high signal intensity group than in the low signal intensity group.

Auditory T-Complex Reveals Reduced Neural Activities in the Right Auditory Cortex in Musicians With Absolute Pitch.

Absolute pitch (AP) is the ability to identify the pitch names of arbitrary musical tones without being given a reference pitch. The acquisition of AP typically requires early musical training, the critical time window for which is similar to that for the acquisition of a first language. This study investigated the left-right asymmetry of the auditory cortical functions responsible for AP by focusing on the T-complex of auditory evoked potentials (AEPs), which shows morphological changes during the critical period for language acquisition. AEPs evoked by a pure-tone stimulus were recorded in high-AP musicians, low-AP musicians, and non-musicians (n = 19 each). A balanced non-cephalic electrode (BNE) reference was used to examine the left-right asymmetry of the N1a and N1c components of the T-complex. As a result, a left-dominant N1c was observed only in the high-AP musician group, indicating "AP negativity," which has previously been described as an electrophysiological marker of AP. Notably, this hemispheric asymmetry was due to a diminution of the right N1c rather than enhancement of the left N1c. A left-dominant N1a was found in both musician groups, irrespective of AP. N1c and N1a exhibited no left-right asymmetry in non-musicians. Hence, music training and the acquisition of AP are both accompanied by a left-dominant hemispheric specialization of auditory cortical functions, as indexed by N1a and N1c, respectively, but the N1c asymmetry in AP possessors was due to reduced neural activities in the right hemisphere. The use of a BNE is recommended for evaluating these radially oriented components of the T-complex.

Automaticity of pitch class-color synesthesia as revealed by a Stroop-like effect.

Pitch classes (e.g., do, re, and mi) in music evoke color sensations in pitch class-color synesthesia, which is a recently described form of synesthesia in musicians. The synesthetic color sensations were confirmed to be consistent over an extended time interval, fulfilling a widely-accepted criterion for the authenticity of synesthesia. However, it remains unclear whether the color sensations occurred automatically (i.e., without voluntary effort), which is another defining property of synesthesia. We utilized the Stroop paradigm to investigate this issue in 10 pitch class-color synesthetes. Participants were visually presented with pitch class names in font colors that were either congruent or incongruent with the participants' own color sensations. The speed for reporting the font color was slower when it was incongruent with the synesthetic sensation than when it was congruent. The finding verifies the authenticity of pitch class-color synesthesia by demonstrating that the color sensations occur automatically, even when unnecessary.

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.