On-scene time delays for epileptic seizures in developed community-based integrated care system regions.

BACKGROUND: Delayed on-scene time by emergency medical services (EMS) can have detrimental effects on critical cases for people with epilepsy (PWE). In preparation for a super-aged society, a Community-based Integrated Care System is crucial to manage healthcare costs. However, sufficient coordination irrespective of sociomedical changes among medical providers is challenging. AIM: This study aimed to evaluate on-scene time delays in the treatment of PWE, identify factors associated with such delays, and clarify regional differences. The focus was on the volume of acute care beds in regions with a developed Community-based Integrated Care System. METHODS: This population-based observational study evaluated on-scene time delays in the treatment of PWE across six major cities in western Japan between 2017 and 2021. In addition, we also evaluated the association between regional differences focusing on volume of acute care beds ("Reduced region" and "Preserved region", as cities with numbers of acute care beds per 1,000 people below and above the national average, respectively) along with sociomedical factors associated with on-scene time delays. RESULTS: This study included 8,737 PWE transported by EMS, with a mean on-scene time for EMS ranging from 12.9 ± 6.8 min to 21.7 ± 10.6 min. On-scene time delays were evident in Reduced regions, with an increase of 1.45 min (95 % confidence interval 0.86-2.03 min, p < 0.001). A high total EMS call volume independently influenced on-scene time delays during the middle period of the pandemic in Reduced regions. CONCLUSION: Optimal coordination must be facilitated to ensure the effective functioning of the Community-based Integrated Care System, particularly during unusual circumstances.

A case of bronchopulmonary sequestration combined with congenital pulmonary airway malformation prenatally diagnosed as having two aberrant arteries originating from the celiac artery.

We report a case of BPS combined with CPAM prenatally diagnosed as having two aberrant arteries from the celiac artery by fetal 3D-US. Although the pattern of arterial feeding vessels was extremely rare in our case, the vasculature images obtained using fetal 3D-US were comparable to those obtained using postnatal CT angiography.

Emergency medical service response for cases of stroke-suspected seizure: A population-based study.

OBJECTIVES: We evaluated the on-scene time of emergency medical services (EMS) for cases where discrimination between acute stroke and epileptic seizures at the initial examination was difficult and identified factors linked to delays in such scenarios. MATERIALS AND METHODS: A retrospective review of cases with suspected seizure using the EMS database of fire departments across six Japanese cities between 2016 and 2021 was conducted. Patient classification was based on transport codes. We defined cases with stroke-suspected seizure as those in whom epileptic seizure was difficult to differentiate from stroke and evaluated their EMS on-scene time compared to those with epileptic seizures. RESULTS: Among 30,439 cases with any seizures, 292 cases of stroke-suspected seizure and 8,737 cases of epileptic seizure were included. EMS on-scene time in cases of stroke-suspected seizure was shorter than in those with epileptic seizure after propensity score matching (15.1±7.2 min vs. 17.0±9.0 min; p = 0.007). Factors associated with delays included transport during nighttime (odds ratio [OR], 1.73, 95 % confidence interval [CI] 1.02-2.93, p = 0.041) and transport during the 2020-2021 pandemic (OR, 1.77, 95 % CI 1.08-2.90, p = 0.022). CONCLUSION: This study highlighted the difference between the characteristics in EMS for stroke and epileptic seizure by evaluating the response to cases with stroke-suspected seizure. Facilitating prompt and smooth transfers of such cases to an appropriate medical facility after admission could optimize the operation of specialized medical resources.

Enhanced reactivity of Li+@C60 toward thermal [2 + 2] cycloaddition by encapsulated Li+ Lewis acid.

Lithium ion-endohedral fullerene (Li+@C60), a member of the burgeoning family of ion-endohedral fullerenes, holds substantial promise for diverse applications owing to its distinctive ionic properties. Despite the high demand for precise property tuning through chemical modification, there have been only a few reports detailing synthetic protocols for the derivatization of this novel material. In this study, we report the synthesis of Li+@C60 derivatives via the thermal [2 + 2] cycloaddition reaction of styrene derivatives, achieving significantly higher yields of monofunctionalized Li+@C60 compared to previously reported reactions. Furthermore, by combining experimental and theoretical approaches, we clarified the range of applicable substrates for the thermal [2 + 2] cycloaddition of Li+@C60, highlighting the expanded scope of this straightforward and selective functionalization method.

Apolipoprotein E genotype-dependent accumulation of amyloid ß in APP-knock-in mouse model of Alzheimer's disease.

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid ß (Aß) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aß without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aß pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aß in vivo, which may not be addressed appropriately by using other transgenic mouse models.

On-scene time delays for epileptic seizures in emergencies during a social pandemic: A population-based study.

OBJECTIVES: The on-scene time of Emergency Medical Services (EMS), including time for hospital selection, is critical for people in an emergency. However, the outbreak of the novel coronavirus disease 2019 (COVID-19) led to longer delays in providing immediate care for individuals with non-COVID-19-related emergencies, such as epileptic seizures. This study aimed to examine factors associated with on-scene time delays for people with epilepsy (PWE) with seizures needing immediate amelioration. MATERIALS & METHODS: We conducted a population-based retrospective cohort study for PWE transported by EMS between 2016 and 2021. We used data from the Hiroshima City Fire Service Bureau database, divided into three study periods: "Pre period", the period before the COVID pandemic (2016-2019); "Early period", the early period of the COVID pandemic (2020); and "Middle period", the middle period of the COVID pandemic (2021). We performed linear regression modeling to identify factors associated with changes in EMS on-scene time for PWE during each period. In addition, we estimated the rate of total EMS call volume required to maintain the same on-scene time for PWE transported by EMS during the pandemic expansion. RESULTS: Among 2,205 PWE transported by EMS, significant differences in mean age and prevalence of impaired consciousness were found between pandemic periods. Total EMS call volume per month for all causes during the same month <5,000 (-0.55 min, 95% confidence interval [CI] -1.02 - -0.08, p = 0.022) and transport during the Early period (-1.88 min, 95%CI -2.75 - -1.00, p < 0.001) decreased on-scene time, whereas transport during the Middle period (1.58 min, 95%CI 0.70 - 2.46, p < 0.001) increased on-scene time for PWE transported by EMS. The rate of total EMS call volume was estimated as 0.81 (95%CI -0.04 - 1.07) during the expansion phase of the pandemic to maintain the same degree of on-scene time for PWE transported by EMS before the pandemic. CONCLUSIONS: On-scene time delays on PWE in critical care settings were observed during the Middle period. When the pandemic expanded, the EMS system required resource allocation to maintain EMS for time-sensitive illnesses such as epileptic seizures. Timely system changes are critical to meet dramatic social changes.

Paradoxical effects of levetiracetam in people with epilepsy with rhythmic epileptiform discharges.

OBJECTIVE: To elucidate the incidence and risk factors for paradoxical effects (i.e., increased seizure frequency, increased seizure severity, or onset of new seizure types) of levetiracetam (LEV) in people with epilepsy (PWE) and identify the usefulness of electroencephalography (EEG) in predicting these effects. METHODS: We examined data for consecutive PWE treated with LEV. All PWE underwent EEG and magnetic resonance imaging (MRI) before LEV administration. We also evaluated the incidence of paradoxical LEV effects and conducted multivariate logistic regression analyses to identify the associated factors. RESULTS: In total, 210 (66.2%) of 317 PWEs treated in our department had a history of LEV use. The incidence of paradoxical LEV effects was 5.2% (n = 11) and was significantly associated with a high LEV dose (p = 0.029), high seizure frequency (p = 0.005), temporal lobe epilepsy (p = 0.004), focal awareness seizure (p = 0.004), focal impaired awareness seizure (p = 0.007), spike (p = 0.015), rhythmic epileptiform discharges (REDs; p = 0.003), and MRI-identified focal cortical dysplasia (FCD; p < 0.0001). Multivariate analyses revealed that REDs (odds ratio [OR] = 5.35, p = 0.048, 95% confidence interval [CI]: 1.01-28.21) were independently associated with paradoxical LEV effects. CONCLUSIONS: Paradoxical LEV effects occurred in PWE, particularly in those with drug-resistant focal epilepsy. Furthermore, the occurrence of REDs in EEG was an independent factor associated with the paradoxical effects of LEV in PWE.

Immediate and 6-month seizure outcomes following first and second SARS-CoV2 mRNA vaccinations: A multicenter study with a nationwide survey.

OBJECTIVE: This study aimed to identify seizure outcomes in people with epilepsy (PWE) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) messenger RNA vaccination. METHODS: We examined PWE (n = 332, age ≥ 14 years) treated in four tertiary hospitals between 2021 and 2022 to assess the incidence of seizure worsening following vaccination using closed questions. We identified the clinical factors associated with worsening and 6-month vaccination outcomes. We also conducted a nationwide survey on self-reported seizure worsening using open questions, to which 261 general practitioners from 99 institutes contributed. RESULTS: Of the 282 PWE vaccinated in the four hospitals, 16 (5.7%) exhibited seizure worsening; most of them emerged within 48 h of vaccination and were not sustained. Thus, all PWE were at baseline condition 6 months after their vaccination. PWE with seizure worsening were more significantly associated with focal impaired awareness seizures (p < 0.001), high seizure frequency (p = 0.025), and drug-resistant epilepsy (p = 0.007) at baseline compared to PWE without worsening. Multivariate logistic regression analysis revealed that focal impaired awareness seizures were independently associated with worsening (odds ratio, 7.0; 95% confidence interval, 1.50-32.77). A nationwide survey of 5156 PWE data (real-world data) confirmed an extremely low incidence rate of self-reported seizure worsening (0.43%). SIGNIFICANCE: Some PWE, particularly refractory focal epilepsy, exhibit seizure worsening. However, the worsening events were infrequent, non-sustainable, and probably under-reported by PWE, suggesting that there is little evidence that worsening seizures discourage current and future vaccinations.

Three-Dimensional Analysis of Human Laryngeal and Tracheobronchial Cartilages during the Late Embryonic and Early Fetal Period.

Laryngeal and tracheobronchial cartilages are present as unique U-shaped forms around the respiratory tract and contribute to the formation of rigid structures required for the airway. Certain discrepancies still exist concerning cartilage formation in humans. To visualize the accurate timeline of cartilage formation, tracheobronchial and laryngeal cartilages were 3D reconstructed based on serial tissue sections during the embryonic period (Carnegie stage [CS] 18-23) and early fetal period (crown rump length [CRL] = 35-45 mm). The developmental phases of the cartilage were estimated by histological studies, which were performed on the reconstructed tissue sections. The hyoid greater horns were recognizable at CS18 (phase 2). Fusion of 2 chondrification centers in the mid-sagittal region was observed at CS19 in the hyoid bone, at CS20 in the cricoid cartilage, and in the specimen with CRL 39 mm in the thyroid cartilage. Phase 3 differentiation was observed at the median part of the hyoid body at CS19, which was the earliest among all other laryngeal and tracheobronchial cartilages. Most of the laryngeal cartilages were in phase 3 differentiation at CS22 and in phase 4 differentiation at CS23. The U-shaped tracheobronchial cartilages with phase 2 differentiation covered the entire extrapulmonary region at CS20. Phase 3 differentiation started on the median section and propagates laterally at CS21. The tracheobronchial cartilages may form simultaneously during the embryonic period at CS22-23 and early fetal periods, similar to adults in number and distribution. The spatial propagation of the tracheal cartilage differentiation provided in the present study indicates that cartilage differentiation may have propagated differently on phase 2 and phase 3. This study demonstrates a comprehensible timeline of cartilage formation. Such detailed information of the timeline of cartilage formation would be useful to improve our understanding of the development and pathophysiology of congenital airway anomalies.

ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain.

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer's disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-ß (Aß) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components.

OBJECTIVE: The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. CONCLUSIONS: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.

Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression.

While the accumulation and aggregation of amyloid-ß and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-ß40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-ß40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-ß40, amyloid-ß42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-ß and tau pathologies.

Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease.

INTRODUCTION: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases. METHODS: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aß40], Aß42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA. RESULTS: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aß40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels. DISCUSSION: Refining the molecular mechanisms connecting tau, Aß, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

ABCA7 Deficiency Accelerates Amyloid-ß Generation and Alzheimer's Neuronal Pathology.

In Alzheimer's disease (AD), the accumulation and deposition of amyloid-ß (Aß) peptides in the brain is a central event. Aß is cleaved from amyloid precursor protein (APP) by ß-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aß was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aß by increasing the levels of ß-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. SIGNIFICANCE STATEMENT: Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-ß (Aß) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aß deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aß production by increasing the levels of ß-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aß clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer's Disease.

Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). While amyloid-ß (Aß) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist. Although further clinical studies should clarify whether BBB disruption is a specific feature of AD pathogenesis, increasing evidence indicates that each component of the neurovascular unit is significantly affected in the presence of AD-related pathologies in animal models and human patients. Conversely, since some portions of Aß are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in exacerbated Aß accumulation in the brain. Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Aß accumulation and neurovascular unit impairments during disease progression.

Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway.

Pericytes play a critical role in the cerebrovasculature within the CNS. These small contractile cells produce large quantities of apolipoprotein E (apoE) whose isoforms influence cerebrovascular functions and determine the genetic risk for Alzheimer disease. Despite extensive studies on astrocyte-secreted apoE, which supports synapses by transporting cholesterol to neurons, the biochemical properties and function of apoE secreted by pericytes are not clear. Because pericytes mediate important functions in the CNS, including the initiation of glial scar formation, angiogenesis, and maintenance of the blood-brain barrier, we investigated the potential role of apoE in pericyte mobility. We found that knockdown of apoE expression significantly accelerates pericyte migration, an effect that can be rescued by exogenous apoE3, but not apoE4, a risk factor for Alzheimer disease. ApoE-regulated migration of pericytes also requires the function of the low-density lipoprotein receptor-related protein 1 (LRP1), a major apoE receptor in the brain that is abundantly expressed in pericytes. Because apoE-knockdown also leads to enhanced cell adhesion, we investigated the role of apoE in the regulation of the actin cytoskeleton. Interestingly, we found that the levels of active RhoA are increased significantly in apoE knockdown pericytes and that RhoA inhibitors blocked pericyte migration. Taken together, our results suggest that apoE has an intrinsic role in pericyte mobility, which is vital in maintaining cerebrovascular function. These findings provide novel insights into the role of apoE in the cerebrovascular system.

Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown.

BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity. METHODS: Effects of vascular cell senescence on tight junction and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells, pericytes, and astrocytes. In addition, tight junction coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1(H/H)) mice, which display senescence cell-dependent phenotypes, were examined. RESULTS: When an in vitro BBB model was constructed with senescent endothelial cells and pericytes, tight junction structure and barrier integrity (evaluated by transendothelial electric resistance and tracer efflux assay using sodium fluorescein and Evans blue-albumin were significantly impaired. Endothelial cells and pericytes from BubR1(H/H) mice had increased senescent-associated ß-galactosidase activity and p16(INK4a) expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1(H/H) mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4-immunoreactive astrocytes was not altered in the cortex of the BubR1(H/H) mice. CONCLUSIONS: Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-ß (Aß) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aß40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aß40/Aß42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aß40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aß42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aß40 and apoE.

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles.

AIMS: Among the pathological findings in Alzheimer's disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin-1, a marker of lipid rafts, accumulates in lysosomes of tangle-bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders. METHODS: We compared PtdIns(4,5)P2 immunoreactivity in the hippocampus, entorhinal cortex and neocortex of five AD cases, 17 cases of other neurodegenerative disorders and four controls. In addition, we performed double staining using markers of GVD, NFTs and lipid rafts for further characterization. RESULTS: Immunohistochemical analysis revealed that PtdIns(4,5)P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for PtdIns(4,5)P2 was also evident in NFTs composed of hyperphosphorylated tau, PtdIns(4,5)P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, PtdIns(4,5)P2 colocalized with the lipid raft markers flotillin-1 and annexin 2, within GVD bodies and NFTs. CONCLUSIONS: These results suggest that lipid raft components including PtdIns(4,5)P2 play a role in the formation of both GVD bodies and NFTs.

Diagnostic value of lower extremity ultrasonographic nerve enlargement for differentiating demyelinating Charcot-Marie-Tooth disease from chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: We previously reported that nerve enlargement assessment by nerve ultrasonography of the intermediate upper limb is applicable for distinguishing demyelinating Charcot-Marie-Tooth disease (CMT) from chronic inflammatory demyelinating polyneuropathy (CIDP). However, differences in the severity and distribution patterns of lower extremity nerve enlargement have not been established for either disease. Therefore, we examined the utility of lower extremity nerve ultrasonography for differentiating between CMT and CIDP. METHODS: Twelve patients with demyelinating CMT and 17 patients with CIDP were evaluated. The median, ulnar, tibial, and fibular nerves were evaluated in three regions: the distal upper extremity, intermediate upper extremity, and lower extremity. Of the 14 selected screening sites, the number of sites that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined. RESULTS: The screening ESNs in the intermediate region and lower extremities were greater in patients with demyelinating CMT than in patients with CIDP and greater than the ESN in the distal region (p = 0.010, p = 0.001, and p = 0.101, respectively). The ESNs in the intermediate region and lower extremities significantly differed among patients with typical CIDP, CIDP variants, and demyelinating CMT (p = 0.084 and p < 0.001). Among the 14 selected screening sites, the combined upper and lower extremity ESNs exhibited the highest AUC (0.92; p < 0.001). CONCLUSIONS: Combining the upper and lower extremities for ultrasonographic nerve measurement more accurately distinguishes CIDP from demyelinating CMT.