Interactions between Beta-Amyloid and Pericytes in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by aberrant amyloid precursor protein (APP) cleavage, pathological aggregations of beta-amyloid (Aß) that make up Aß plaques and hyperphosphorylation of Tau that makes up neurofibrillary tangles (NFTs). Although progress has been made in research on AD, the fundamental causes of this disease have not been fully elucidated. Recent studies have shown that vascular dysfunction especially the loss of pericytes plays a significant role in the onset of AD. Pericytes play a variety of important roles in the nervous system including the regulation of the cerebral blood flow (CBF), the formation and maintenance of the blood-brain barrier (BBB), angiogenesis, and the clearance of toxic substances from the brain. Pericytes participate in the transport of Aß through various receptors, and Aß acts on pericytes to cause them to constrict, detach, and die. The loss of pericytes elevates the levels of Aß1-40 and Aß1-42 by disrupting the integrity of the BBB and reducing the clearance of soluble Aß from the brain interstitial fluid. The aggravated deposition of Aß further exacerbates pericyte dysfunction, forming a vicious cycle. The combined influence of these factors eventually results in the loss of neurons and cognitive decline. Further exploration of the interactions between pericytes and Aß is beneficial for understanding AD and could lead to the identification of new therapeutic targets for the prevention and treatment of AD. In this review, we explore the characterization of pericytes, interactions between pericytes and other cells in the neurovascular unit (NVU), and the physiological functions of pericytes and dysfunctions in AD. This review discusses the interactions between pericytes and Aß, as well as current and further strategies for preventing or treating AD targeting pericytes.

"Hot Cross Bun" Sign in a Patient with Glutamic Acid Decarboxylase 65-KDa Isoform Associated Cerebellar Ataxia: Case Report and Review of the Literature.

The "hot cross bun" sign (HCBs) is a cruciform hyperintensity on T2-weighted imaging within the pons initially found in patients diagnosed as multiple system atrophy. However, recent findings have broadened the disease spectrum presented with HCBs. Here is a case report at an academic medical center. Cerebral magnetic resonance imaging (MRI), electroneuromyography, serum, and CSF analysis were performed. Literature is comprehensively reviewed. We investigated a woman presented with blurred speech and cerebellar ataxia. Her MRI showed the vertical line of HCBs 2 weeks after disease onset and gradually enhanced, presenting as an intact HCBs in a year. Glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody IgG was detected in serum and CSF. The patient was diagnosed as GAD65 associated cerebellar ataxia and treated with corticosteroid and rituximab. We found 6 previously reported autoimmune cerebellar ataxia patients with HCBs. Anti-KLHL-11, anti-Homer-3, anti-Ri, and anti-Amphiphysin were associated. All patients had cerebellar ataxia with other neurological symptoms. Five patients were diagnosed with tumor. First-line immunotherapy including corticosteroid, intravenous immunoglobulin, and plasma exchange for most patients was unsatisfied. This case highlights the importance of considering GAD65 IgG evaluation in patients with progressive cerebellar syndrome and HCBs. Early diagnosis and therapy are challenging but imperative. Further studies are required in regard to therapeutic management.

Favorable Outcomes in a Case of Non-paraneoplastic DNER Ataxia Treated with Immunotherapy.

Anti-DNER antibody is associated with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). However, recent studies reported cases absence of HD and that non-tumor anti-DNER antibody-associated ataxia was not well characterized. We present a case of acute cerebellar ataxia and nystagmus with detected anti-DNER antibody. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy. High titer of anti-DNER antibody was detected in CSF and serum. Positron emission tomography (PET) scanning was unremarkable at a 10-month follow up. The patient improved significantly after immunosuppressive therapy with intravenous steroids, immunoglobulin followed by rituximab. Our study suggest that the presence of such anti-neuronal antibodies might not come along with malignancy and that early onset non-tumor patients are more likely to have a better outcome after immunotherapy. Early diagnosis and timely immunosuppressive therapy may prove beneficial for these patients.

Characterization of SNCA Multiplication in Parkinson's Disease: 2 New Cases and Evaluation of the Literature.

Background: Alpha-synuclein (SNCA) copy number variations (CNV) have been certified as a causative mutation in patients with familial and sporadic Parkinson's disease (PD). Case: We report three SNCA duplication cases diagnosed as PD. Through whole-exome sequencing, we identified a de novo 4.56 Mb repeated region in one patient and a 2.50 Mb repeated region in familial PD with two patients. Literature review: In review of previous cases, we suggest that aggressive behavior is more remarkable in CNV4 patients. Meanwhile, frequency of cognition decline and dementia were slightly increased in CNV4 patients. We also illustrate a younger onset age in offspring than parent in familial SNCA multiplication PD cases. No difference was observed in disease duration between parent and offspring generation. Conclusions: Our findings demonstrated the clinical and genetic characteristics in PD with SNCA multiplication and provided strong evidence for genetic anticipation. These results may be instructive for future disease diagnosis and genetic counseling.

Methylglyoxal suppresses microglia inflammatory response through NRF2-IκBζ pathway.

Methylglyoxal (MGO) is a highly reactive metabolite generated by glycolysis. Although abnormal accumulation of MGO has been reported in several autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, the role of MGO in autoimmune diseases has not yet been fully investigated. In this study, we found that the intracellular MGO levels increased in activated immune cells, such as microglia and lymphocytes. Treatment with MGO inhibited inflammatory cell accumulation in the spinal cord and ameliorated the clinical symptoms in EAE mice. Further analysis indicated that MGO suppressed M1-polarization of microglia cells and diminished their inflammatory cytokine production. MGO also inhibited the ability of microglial cells to recruit and activate lymphocytes by decreasing chemokine secretion and expression of co-stimulatory molecules. Furthermore, MGO negatively regulated glycolysis by suppressing glucose transporter 1 expression. Mechanically, we found that MGO could activate nuclear factor erythroid 2-related factor 2 (NRF2) pathway and NRF2 could bind to the promoter of IκBζ gene and suppressed its transcription and subsequently pro-inflammatory cytokine production. In conclusion, our results showed that MGO acts as an immunosuppressive metabolite by activating the NRF2-IκBζ.

A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification.

BACKGROUND: Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized with calcium deposition in multiple brain regions. Mutations in PDGFB have been discovered in sporadic and familial PFBC cases. While several known variants displayed loss-of function, no complete deletion of platelet-derived growth factor B (PDGFB) has been reported. METHODS: For the diagnostic purpose, brain computerized tomography or magnetic resonance imaging scanning and whole-genome sequencing were performed on the proband and family members in the pedigree. RESULTS: We identified a heterozygous PDGFB complete deletion in a Chinese pedigree. The proband presented with paroxysmal kinesigenic dyskinesia (PKD), a rare symptom in PFBC. The proband's mother carrying the same mutation was asymptomatic. CONCLUSIONS: For the first time, we reported a PFBC with a heterozygous deletion of PDGFB, and provided evidence of haploinsufficiency in the pathogenesis of PFBC.

Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE. METHODS: C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis. RESULTS: Here, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1ß in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice. CONCLUSIONS: The present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

Cervical Spinal Involvement in a Chinese Pedigree With Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy Caused by a 3' Untranslated Region Mutation of COL4A1 Gene.

Background and Purpose- Pontine autosomal dominant microangiopathy and leukoencephalopathy, a recently defined subtype of cerebral small vessel disease, is associated with mutations in COL4A1 (collagen type IV alpha 1 chain) 3' untranslated region. We here describe a pontine autosomal dominant microangiopathy and leukoencephalopathy pedigree with COL4A1 mutation presenting both pontine and cervical spinal cord involvement. Methods- For the diagnostic purpose, brain and spinal magnetic resonance imaging scanning, skin biopsy, and whole-exome sequencing were performed on the patients in the pedigree. Suspected pathogenic variants were further confirmed by cosegregation analysis using Sanger sequencing in the family members. Results- We identified a mutation located at the binding site of miR-29 (microRNA-29) in 3' untranslated region of COL4A1(c.*32G>A). The pontine autosomal dominant microangiopathy and leukoencephalopathy patients in this pedigree carried this variant, whereas other healthy family members but one did not. Magnetic resonance imaging showed lesions in the pons, white matter, and cervical spinal cord. Skin biopsy revealed thickened basal lamina in vessels. Conclusions- For the first time, we reported cervical spinal involvement in pontine autosomal dominant microangiopathy and leukoencephalopathy and expanded the clinical spectrum of this disease.

[Consumptions of Meat, Dietary Fat, and Fatty-acids and Prevalence of Overweight/Obesity in Children and Adolescents-a Cross-sectional Survey in Chengdu].

OBJECTIVES: To determine the prevalence of overweight and obesity in children and adolescents aged 7-15 years in Longquanyi District of Chengdu and its association with consumptions of meat, dietary fat and fatty-acids. METHODS: A total of 1 811 children and adolescents aged 7-15 years in Longquanyi District were selected using stratified cluster sampling strategy. Their body mass, height and waist circumference were measured. The prevalence of overweight/obesity was estimated based on body mass index (BMI), body mass index standard deviation score (BMI SDS), and waist-to-height ratio (WHtR). Daily consumptions of meat, dietary fat and fatty-acids were calculated using data collected through a food frequency questionnaire and 3-d 24 h dietary recall. The children with overweight/obesity were compared with those with normal body mass in food/nutrient consumptions using Wilcoxon tests. The BMI SDS, WHtR, and prevalence of overweight and obesity were also compared between those having low, moderate and high food/nutrient consumptions using Chi-square tests or Kruskal-Wallis tests. RESULTS: About 10.34% and 6.59% of participants were found to be overweight and obese, respectively. Boys had higher prevalence of overweight (12.05%) and overweight/obesity (18.97%) than girls (8.55%, 14.80%) ( P<0.05). Girls consumed more meat (including red meat and white meat), saturated fatty-acid (SFA) and monounsaturated fatty-acid (MUFA) than boys ( P<0.05). The consumptions of meat (both red meat and white meat), SFA and MUFA increased with age ( P<0.05). Overweight/obese girls consumed more SFA, MUFA and fat (%EN) than those of normal weight. The BMI SDS and WHtR of girls increased with fat (%EN) consumptions ( P<0.05). The BMI SDS of girls also increased with MUFA consumptions ( P<0.05). CONCLUSIONS: Consumptions of red meat, dietary fat, SFA, and MUFA are associated with overweight/obesity of girls aged 7-15 years in Chengdu. Further studies are needed to understand the gender differences.

[Dietary Fiber and Pubertal Development among Children and Adolescents--a Cross-sectional Study in Chengdu, Sichuan].

OBJECTIVE: To determine the association between intake of dietary fiber and pubertal development among children and adolescents in Chengdu. METHODS: A cross-sectional survey was undertaken in 1 340 children and adolescents aged 9-15 years. Data about dietary intake were collected through 24-h dietary self-recall. Pubertal development was measured by trained investigators using Tanner criteria. Consumptions of total fiber and fiber from different sources were compared among the participants with different stages of pubertal development. RESULTS: Data from 1 328 children and adolescents were analyzed. Boys (n = 667) at a later stage of pubertal development consumed less total fiber and fruit fiber than those at an earlier stage (P < 0.05). Similarly, girls (n = 651) at a later stage of pubertal development consumed less fruit fiber than those at an earlier stage (P < 0.05). CONCLUSION: Dietary fiber intake, especially fruit fiber, is lower in children and adolescents with early commencement of puberty development. Further studies are needed to establish the relationship between dietary fiber and pubertal development.

[Consumptions of Meat and Dairy Products, Zinc Intake and Pubertal Development in Adolescents in Chengdu].

OBJECTIVE: To determine the associations between meat, dairy and zinc intake and pubertal development in adolescents in Chengdu. METHODS: A total of 1320 children and adolescents aged 9-15 years in Chengdu were recruited using a stratified cluster sampling strategy. Dietary intake was assessed by the food frequency questionnaire (FFQ) and 3-day 24-hour dietary recall. Pubertal development was evaluated through physical examinations. Consumptions of meat and dairy, and zinc intake were compared between groups with different levels of pubertal development according to the Tanner criteria. RESULTS: The median age of spermarche was 13. 00 years. The boys who had had spermarche consumed more meat (including red meat) and dairy products than those who had not yet (P<0. 05). Daily consumption of total meat was positively correlated with the level of pubertal development (P<0. 05). The median age of menarche was 12. 11 years. The girls who had had menarche consumed more meat and less diiry products than those who had not yet (P<0. 05). Daily consumption of dairy products was negatively associated with breast development and the level of pubertal development (P < 0. 05). CONCLUSION: Consumptions of meat, red meat and dairy products are associated with pubertal development in adolescents in Chengdu. However, the differences between boys and girls warrant further studies.

Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway.

BACKGROUND: IL-1ß has been shown to play a pivotal role in autoimmunity. Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor may be an important drug target for autoimmune diseases. However, the effects of caspase-1 inhibitor on myasthenia gravis (MG) remain undefined. METHODS: To investigate the effects of caspase-1 inhibitor on experimental autoimmune myasthenia gravis (EAMG), an animal model of MG, caspase-1 inhibitor was administered to Lewis rats immunized with region 97-116 of the rat AChR α subunit (R97-116 peptide) in complete Freund's adjuvant. The immunophenotypical characterization by flow cytometry and the levels of autoantibody by ELISA were carried out to evaluate the neuroprotective effect of caspase-1 inhibitor. RESULTS: We found that caspase-1 inhibitor improved EAMG clinical symptom, which was associated with decreased IL-17 production by CD4+ T cells and γδ T cells, lower affinity of anti-R97-116 peptide IgG. Caspase-1 inhibitor decreased expression of CD80, CD86, and MHC class II on DCs, as well as intracellular IL-1ß production from DCs. In addition, caspase-1 inhibitor treatment inhibited R97-116 peptide-specific cell proliferation and decreased follicular helper T cells relating to EAMG development. CONCLUSIONS: Our results suggest that caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate DC IL-1-IL-17 pathway and provides new evidence that caspase-1 is an important drug target in the treatment of MG and other autoimmune diseases.

A robust principal component analysis algorithm for EEG-based vigilance estimation.

Feature dimensionality reduction methods with robustness have a great significance for making better use of EEG data, since EEG features are usually high-dimensional and contain a lot of noise. In this paper, a robust principal component analysis (PCA) algorithm is introduced to reduce the dimension of EEG features for vigilance estimation. The performance is compared with that of standard PCA, L1-norm PCA, sparse PCA, and robust PCA in feature dimension reduction on an EEG data set of twenty-three subjects. To evaluate the performance of these algorithms, smoothed differential entropy features are used as the vigilance related EEG features. Experimental results demonstrate that the robustness and performance of robust PCA are better than other algorithms for both off-line and on-line vigilance estimation. The average RMSE (root mean square errors) of vigilance estimation was 0.158 when robust PCA was applied to reduce the dimensionality of features, while the average RMSE was 0.172 when standard PCA was used in the same task.