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The blood–brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as β-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer’s disease. Measurements of BBB function are essential toward a better understanding of Alzheimer’s pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer’s disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer’s disease and related dementias. First, we give an overview of the relationship between Alzheimer’s pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer’s disease continuum. Fourth, we introduce a wide range of Alzheimer’s pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer’s disease and related dementias.

•Susceptibility source separation with adaptive relaxometric constant estimation.•QSM-ARCS provided the better susceptibility source separation result.•Opposing susceptibility sources were correlated with FA in the white matter.•Only the diamagnetic sources represented the susceptibility anisotropic property. To separate the contributions of paramagnetic and diamagnetic sources within a voxel, a magnetic susceptibility source separation method based solely on gradient-echo data has been developed. To measure the opposing susceptibility sources more accurately, we propose a novel single-orientation quantitative susceptibility mapping method with adaptive relaxometric constant estimation (QSM-ARCS) for susceptibility source separation. Moreover, opposing susceptibilities and their anisotropic effects were determined in healthy volunteers in the white matter. Multiple spoiled gradient echo and diffusion tensor imaging of ten healthy volunteers was obtained using a 3 T magnetic resonance scanner. After the opposing susceptibility and fractional anisotropy (FA) maps had been reconstructed, the parametric maps were spatially normalized. To evaluate the agreements of QSM-ARCS against the susceptibility source separation method using R2 and R2* maps (χ-separation) by Bland–Altman plots, the opposing susceptibility values were measured using white and deep gray matter atlases. We then evaluated the relationships between the opposing susceptibilities and FAs in the white matter and used a field-to-fiber angle to assess the fiber orientation dependencies of the opposing susceptibilities. The susceptibility maps in QSM-ARCS were successfully reconstructed without large artifacts. In the Bland–Altman analyses, the opposing QSM-ARCS susceptibility values excellently agreed with the χ-separation maps. Significant inverse and proportional correlations were observed between FA and the negative and positive susceptibilities estimated by QSM-ARCS. The fiber orientation dependencies of the negative susceptibility represented a nonmonotonic feature. Conversely, the positive susceptibility increased linearly with the fiber angle with respect to the B0 field. The QSM-ARCS could accurately estimate the opposing susceptibilities, which were identical values of χ-separation, even using gradient echo alone. The opposing susceptibilities might offer direct biomarkers for assessment of the myelin and iron content in glial cells and, through the underlying magnetic sources, provide biologic insights toward clinical transition.

Background Mounting evidence suggests that the blood-brain barrier (BBB) plays an important role in the regulation of brain iron homeostasis in normal brain development, but these imaging profiles remain to be elucidated. We aimed to establish a relationship between brain iron dynamics and BBB function during childhood using a combined quantitative magnetic resonance imaging (MRI) to depict both physiological systems along developmental trajectories. Methods In this single-center prospective study, consecutive outpatients, 2–180 months of age, who underwent brain MRI (3.0-T scanner; Ingenia; Philips) between January 2020 and January 2021, were included. Children with histories of preterm birth or birth defects, abnormalities on MRI, and diagnoses that included neurological diseases during follow-up examinations through December 2022 were excluded. In addition to clinical MRI, quantitative susceptibility mapping (QSM; iron deposition measure) and diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL; BBB function measure) were acquired. Atlas-based analyses for QSM and DP-pCASL were performed to investigate developmental trajectories of regional brain iron deposition and BBB function and their relationships. Results A total of 78 children (mean age, 73.8 months ± 61.5 [SD]; 43 boys) were evaluated. Rapid magnetic susceptibility progression in the brain (Δsusceptibility value) was observed during the first two years (globus pallidus, 1.26 ± 0.18 [× 10 − 3 ppm/month]; substantia nigra, 0.68 ± 0.16; thalamus, 0.15 ± 0.04). The scattergram between the Δsusceptibility value and the water exchange rate across the BBB ( k w ) divided by the cerebral blood flow was well fitted to the sigmoidal curve model, whose inflection point differed among each deep gray-matter nucleus (globus pallidus, 2.96–3.03 [mL/100 g] −1 ; substantia nigra, 3.12–3.15; thalamus, 3.64–3.67) in accordance with the regional heterogeneity of brain iron accumulation. Conclusions The combined quantitative MRI study of QSM and DP-pCASL for pediatric brains demonstrated the relationship between brain iron dynamics and BBB function during childhood. Trial registration UMIN Clinical Trials Registry identifier: UMIN000039047, registered January 6, 2020.

 Background/Objectives: This study aimed to elucidate the effect of rhythm jump training on the rhythm and motor abilities of elementary school students to provide insights into its potential benefits for their physical performance and coordination. Methods: A non-randomized controlled trial was conducted involving 101 elementary school students (grades 1–6) attending a soccer school. Participants were divided into a rhythm jump group (n = 51, age: 7.5 years, height: 126.0 cm, weight: 25.7 kg) and a control group (n = 39, age: 8.0 years, height: 128.8 cm, weight: 26.5 kg) based on their practice venue. The rhythm jump group engaged in 10 min of rhythm jump at the beginning of soccer practice once a week over 8 weeks (intervention period), while the control group continued regular soccer training. Measurements included rhythmic reproduction ability during jumps, Pro Agility Test (PAT) values, and Reactive Strength Index (RSI) scores, assessed before and after the intervention period. Rhythmic reproduction ability was measured by comparing the data of the timing of jumps to 4- and 8-beat audio tracks. These were analyzed using repeated-measures analysis of variance, with significance set at p < 0.05. Results: Significant interactions were observed between 8-beat rhythmic reproduction ability and PAT values. In 8-beat rhythm deviation, a significant decrease was observed in the rhythm jump group (0.048 s) compared to that in the control group (0.013 s) (p < 0.01). PAT time significantly decreased in the rhythm jump group (0.18 s) compared to the control group (−0.25 s) (p < 0.01). There was no observed interaction between 4-beat rhythmic reproduction ability and RSI. Conclusions: This study revealed that rhythm jump training can be effective even with short sessions and infrequent practice, emphasizing its efficiency. The short-term rhythm jump intervention improved the 8-beat rhythmic reproduction ability and agility of elementary school students.

PurposeTo explore the CT findings and pneumonnia progression pattern of the Alpha and Delta variants of SARS-CoV-2 by comparing them with the pre-existing wild type.MethodIn this retrospective comparative study, a total of 392 patients with COVID-19 were included: 118 patients with wild type (70 men, 56.8 ± 20.7 years), 137 with Alpha variant (93 men, 49.4 ± 17.0 years), and 137 with Delta variant (94 men, 45.4 ± 12.4). Chest CT evaluation included opacities and repairing changes as well as lesion distribution and laterality. Chest CT severity score was also calculated. These parameters were statistically compared across the variants.ResultsGround glass opacity (GGO) with consolidation and repairing changes were more frequent in the order of Delta variant, Alpha variant, and wild type throughout the disease course. Delta variant showed GGO with consolidation more conspicuously than did the other two on days 1–4 (vs. wild type, Bonferroni corrected p = 0.01; vs. Alpha variant, Bonferroni corrected p = 0.003) and days 5–8 (vs. wild type, Bonferroni corrected p < 0.001; vs. Alpha variant, Bonferroni corrected-p = 0.003). Total lung CT severity scores of Delta variant were higher than those of wild type on days 1–4 and 5–8 (Bonferroni corrected p = 0.01 and Bonferroni corrected p = 0.005, respectively) and that of Alpha variant on days 1–4 (Bonferroni corrected p = 0.002). There was no difference in the CT findings between wild type and Alpha variant.ConclusionsPneumonia progression of Delta variant may be more rapid and severe in the early stage than in the other two.

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer’s disease and Lewy body dementia.

Background/Objectives: Successful discourse relies not only on linguistic but also on prosodic information. Difficulty recognizing emotion conveyed through prosody (receptive affective aprosodia) following right hemisphere stroke (RHS) significantly disrupts communication participation and personal relationships. Growing evidence suggests that damage to white matter in addition to gray matter structures impairs affective prosody recognition. The current study investigates lesion–symptom associations in receptive affective aprosodia during RHS recovery by assessing whether disruptions in distinct white matter structures impact different underlying affective prosody recognition skills. Methods: Twenty-eight adults with RHS underwent neuroimaging and behavioral testing at acute, subacute, and chronic timepoints. Fifty-seven healthy matched controls completed the same behavioral testing, which comprised tasks targeting affective prosody recognition and underlying perceptual, cognitive, and linguistic skills. Linear mixed-effects models and multivariable linear regression were used to assess behavioral performance recovery and lesion–symptom associations. Results: Controls outperformed RHS participants on behavioral tasks earlier in recovery, and RHS participants’ affective prosody recognition significantly improved from acute to chronic testing. Affective prosody and emotional facial expression recognition were affected by external capsule and inferior fronto-occipital fasciculus lesions while sagittal stratum lesions impacted prosodic feature recognition. Accessing semantic representations of emotions implicated the superior longitudinal fasciculus. Conclusions: These findings replicate previously observed associations between right white matter tracts and affective prosody recognition and further identify lesion–symptom associations of underlying prosodic recognition skills throughout recovery. Investigation into prosody’s behavioral components and how they are affected by injury can help further intervention development and planning.

Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer’s disease. The aim of the present study was to elucidate the relationship between glutamatergic neural functional decline and cholinergic neural dysfunction in the hippocampus. We report the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the medial septal nucleus. Here, we demonstrate that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic function via a decrease in vesicular acetylcholine transporter in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. The results, in combination with our previous reports that show the reduction of hippocampal theta power through a decrease of a region-specific choline acetyltransferase in the stratum oriens of CA1 and the decrease of acetylcholine concentration in the hippocampus, may indicate the defined cholinergic dysfunction in HCNP-pp KO mice. This may also support that HCNP-pp KO mice are appropriate genetic models for cholinergic functional impairment in septo-hippocampal interactions. Therefore, according to the cholinergic hypothesis, the model mice might are potential partial pathological animal models for Alzheimer’s disease.