Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer's disease.

The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with Alzheimer's disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aß1-42, Aß1-40, Aß1-42/Aß1-40, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (r = 0.181, p < 0.001; r = 0.411, p < 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (p < 0.001, p < 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (r = 0.137, p < 0.05; r = 0.106, p < 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (p < 0.001, p < 0.001, p < 0.001, p < 0.05, respectively). Moreover, after adjusting for age, gender, and APOE alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (p < 0.05). The model combining visual rating scales, age, gender, and APOE alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aß1-42 (p < 0.031, p < 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and APOE alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice.

The Protective Effects of Osteocyte-Derived Extracellular Vesicles Against Alzheimer's Disease Diminished with Aging.

Both Alzheimer's disease (AD) and osteoporosis (OP) are common age-associated degenerative diseases and are strongly correlated with clinical epidemiology. However, there is a lack of clear pathological relationship between the brain and bone in the current understanding. Here, it is found that young osteocyte, the most abundant cells in bone, secretes extracellular vesicles (OCYYoung -EVs) to ameliorate cognitive impairment and the pathogenesis of AD in APP/PS1 mice and model cells. These benefits of OCYYoung -EVs are diminished in aged osteocyte-derived EVs (OCYAged -EVs). Based on the self-constructed OCY-EVs tracer transgenic mouse models and the in vivo fluorescent imaging system, OCY-EVs have been observed to be transported to the brain under physiological and pathological conditions. In the hippocampal administration of Aß40 induced young AD model mice, the intramedullary injection of Rab27a-shRNA adenovirus inhibits OCYYoung -EVs secretion from bone and aggravates cognitive impairment. Proteomic quantitative analysis reveals that OCYYoung -EVs, compared to OCYAged -EVs, enrich multiple protective factors of AD pathway. The study uncovers the role of OCY-EV as a regulator of brain health, suggesting a novel mechanism in bone-brain communication.

Mutations in GBA, SNCA, and VPS35 are not associated with Alzheimer's disease in a Chinese population: a case-control study.

SNCA, GBA, and VPS35 are three common genes associated with Parkinson's disease. Previous studies have shown that these three genes may be associated with Alzheimer's disease (AD). However, it is unclear whether these genes increase the risk of AD in Chinese populations. In this study, we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA, SNCA, and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China. The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population. These findings suggest that the mutations in GBA, SNCA, and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations. The study was approved by the Ethics Committee of Xiangya Hospital, Central South University, China on March 9, 2016 (approval No. 201603198).

Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population.

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

Analysis of Salivary Microbiome in Patients with Alzheimer's Disease.

Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer's disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOEɛ4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different in those patients who were APOEɛ4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella, Leptotrichia, and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOEɛ4 (-) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOEɛ4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development.

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature.

BACKGROUND: Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY: A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION: We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

Design of an adaptive stator for bundled piezo-walk motors.

Bundled piezoelectric motors combine several actuators to achieve high output power. However, mutual interference between the actuators leads to reduction in working efficiency. This work presents an adaptive stator that can reduce the mutual interference in bundled piezowalk motors. The stator consists of leaf springs for improving motor contact condition and proof masses that serve as an inertial body for maintaining high output force. Parameters of the proof masses and leaf springs are analyzed, and the working zone of the stator is discussed. A prototype of a linear motor with the designed adaptive stator is fabricated and tested. The maximum speed of a six-leg motor is 103 mm/s, and the stall force is approximately 1.2 N, driven with sinusoidal waveforms of 25Vpp at 30 kHz. Mutual interference between actuators is reduced remarkably with the adaptive stator. A comparison of six- and four-leg motors proves that motor performance has a linear relationship with the number of actuators, thereby indicating the potential of increasing output capability with additional actuators.

Spin labeling artery method perfusion MRI study of SPG4 and SCA3/MJD.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) and Machado-Joseph disease (MJD) are similar diseases that are often referred to jointly as SCA3/MJD. As the most common autosomal-dominantly inherited subtype of hereditary spastic paraplegia (HSP), HSP4 (or SPG4) has overlapping symptoms with SCA3/MJD, which hinders their diagnoses. Arterial spin labeling (ASL) is a noninvasive, contrast-agent free, magnetic resonance perfusion imaging method used to obtain maps of the cerebral blood flow (CBF). Here, we investigated the diagnostic value of ASL in SCA3/MJD and SPG4 patients. METHODS: A total of 13 SPG4 cases, 38 SCA3/MJD cases (22 onset patients and 16 genetic abnormality-only patients), and 27 healthy volunteers were examined by ASL. Data were processed to obtain the regional CBF (rCBF) and comparatively studied. RESULTS: In the pons, cerebellar dentate nucleus, and cerebellar cortex, rCBF of the onset SCA3/MJD group was significantly lower than that of the normal control group. In the cerebellar dentate nucleus and cerebellar cortex, the rCBF of the non-onset SCA3/MJD group was significantly lower than that of the control group. In the pons and cerebellar cortex, the rCBF of the onset SCA3/MJD group was significantly lower than that of the SPG4 group. CONCLUSIONS: SCA3/MJD lesions are mainly located in the cerebellum and brainstem. Gray matter and white matter were both involved, although the deep cerebellar nuclei may be the earliest involved region. Cerebellar and brainstem lesions of SCA3/MJD were more severe than those of SPG4. ASL can aid the diagnosis of SCA3/MJD and SPG4.

Association study between SNP rs150689919 in the DNA demethylation gene, TET1, and Parkinson's disease in Chinese Han population.

BACKGROUND: Recent studies suggest that epigenetic factors may play an important role in the pathogenesis of Parkinson's disease (PD). In our previous work, we sequenced the exomes of sixteen patients from eight Chinese PD families using whole exome sequencing technology, consequently three patients from different pedigrees were found sharing the variant c.1460C > T (rs150689919) in the coding region of the Tet methyl cytosine dioxygenase 1 (TET1) gene. METHODS: In order to evaluate the possible association between sporadic PD and the single nucleotide polymorphism (SNP) rs150689919 in TET1, a case-control cohort study was conducted in 514 sporadic PD patients and 529 normal controls. Genotyping was determined by PCR and direct sequencing. Statistical significance was analyzed by the Chi-squared test. RESULTS: There was no statistical significance in TET1 rs150689919 genotype or allele frequencies between the PD cases and healthy controls, even after being stratified by gender and age at onset. CONCLUSIONS: Our findings suggest that rs150689919 in TET1 may not be associated with PD in Chinese population. However, due to the limited data in this study, replication studies in larger sample and other populations are required.

Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia.

Genetic heterogeneity is common in many Mendelian disorders such as hereditary spastic paraplegia (HSP), which makes the genetic diagnosis more complicated. The goal of this study was to investigate a Chinese family with recessive hereditary spastic paraplegia, of which causative mutations could not be identified using the conventional PCR-based direct sequencing. Next-generation sequencing of all the transcripts of whole genome exome, after on-array hybrid capture, was performed on two affected male subjects (the proband and his brother). A missense mutation (c.1661G>A, p.R554H) was identified in ABCD1. Subsequently, PCR-based direct sequencing of other family members revealed that the mutation was co-segregating with the disease, indicating that ABCD1 mutation was the pathogenic event for this family. Very long-chain fatty acids (VLCFA) assay in the two affected cases confirmed X-ALD. Our study suggests exome sequencing can be used not only to find a novel causative gene, but also to quickly identify mutations of known genes when the clinical elements are etiologically misleading.

[Variations of the amount of sialic acids on hepatocellular carcinoma cell membrane].

OBJECTIVE: To observe the change in the amount of sialic acids on hepatocellular carcinoma (HCC) cell membrane. METHODS: Surgical specimens of HCC and liver cirrhosis tissues were obtained from 28 patients to prepare carcinoma cell and hepatocyte suspensions by collagenase digestion. For assay of α2, 3 and α2, 6-sialic acids, the cells were suspended in the staining buffer containing either fluorescein isothiocyanate-Maackia amurensis lectin (FITC-MAL) or fluorescein isothiocyanate-Sambucus nigra bark lectin (FITC-SNA) and incubated for 1 h, respectively. Flow cytometric analysis was carried out to measure the mean fluorescence intensity (MFI) on the cell surface. RESULTS: In both FITC-MAL- and FITC-SNA-incubated HCC cells, the MFI on the cell surface was greater than that of the hepatocytes. CONCLUSION: Both of α2, 3 and α2, 6- sialic acids increases significantly on the hepatocyte membrane after the carcinomatous change.

[Protocols for cloning human bone marrow-derived hepatic stem cells in vitro].

OBJECTIVE: To explore practical protocols for cloning bone marrow-derived hepatic stem cells in vitro. METHODS: The cell fraction rich in CD117(+) cells and CD184(+) cells was separated from fresh bone marrow by density gradient centrifugation and cultured for 0, 7 and 14 days in high-glucose DMEM supplemented with or without 10% autologous serum or in serum-free high-glucose DMEM. All the media were supplemented with different concentrations of hepatocyte growth promoting factors (HGPF), thrombopoietin (TPO) and interleukin-3 (IL-3). The quantitative changes of CD117(+) cells and CD184(+) cells were measured by flow cytometry. RESULTS: The optimal effect for cell cloning was achieved with high-glucose DMEM with 10% autologous serum group supplemented with 40 microg/ml HGPF, 50 ng/ml TPO, and 10 ng/ml IL-3. At day 7 of cell culture in this media, the quantity of CD117(+) cells and CD184(+) cells increased by 6.55 and 6.20 folds, and by 11.62 and 20.57 folds at day 14, respectively. CONCLUSION: It is practical for cloning bone marrow-derived hepatic stem cells in high-glucose DMEM with 10% autologous serum supplemented with 40 microg/ml HGPF, 50 ng/ml TPO, and 10 ng/ml IL-3.