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Several anti‑Aβ monoclonal antibody drugs have been approved for clinical use at home and abroad recently. In order to facilitate its safe and effective treatment of anti‑Aβ monoclonal antibody drugs for Alzheimer's disease (AD) in China, we present recommendations for the clinical use of anti‑Aβ monoclonal antibody drugs based on existing clinical trials and the clinical practice of AD treatment with Aducanumab at Ruijin Hospital Hainan Branch, Shanghai Jiaotong University School of Medicine. The recommendations include clinical indications, pre ‑ medication assessment and preparation, medication instructions and precautions, as well as post ‑ medication clinical monitoring, which is aimed to furnish clinicians with comprehensive medication guidance.

Alzheimer's disease (AD) is a chronic progressive degenerative disease with gradually decreasing cognition. Because of the high prevalence, heavy social burden and wide interaction with others, the ethical issues are increasingly prominent. This article focuses on the details, such as disclosing diagnosis, breaking bad news, advance directives, hospice care and palliative care, and driving. From these issues, as a medical staff, we should know and respect our patients and their families sufficiently. We should make a reasonable treatment with patients and their families for a better outcome. At the same time, more propaganda about advance directives and hospice care should be taken for a healthier perception. doi:10.3969/j.issn.1672⁃6731.2021.04.005

Background: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. Objective: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. Methods: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. Results: Gene sequencing of SIGMAR1 revealed a rare 3′UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. Conclusion: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype. [ABSTRACT FROM AUTHOR]

Introduction: The increasing prevalence of Alzheimer's disease and related dementias (ADRD) presents both a burden and an opportunity for intervention. This study aims to estimate the impacts of health insurance and resources on the burden attributed to ADRD. Method: Data were mainly collected from global databases for ADRD. Analysis of variance, Pearson correlation, random‐effects, and fixed‐effects model analyses were used in this study. Results: Although the current medical expenditures were increasing and out of pocket (OOP) expenditures were declining generally in various countries, the collected global data showed an increased burden of ADRD on patients both physically and economically. Furthermore, health resources were negatively associated with disability‐adjusted life years (DALY), death, and years of life lost (YLL), but were otherwise positively associated with years of life lived with disability (YLD). Discussion: Effective measures should be considered to cope with the rising burden. Meanwhile, there is an urgent call for constructive and sustainable rational plans and global collaboration. Highlights: We explored how health insurance and resources affect Alzheimer's disease and related dementias (ADRD)‐related burden.Health insurance and resources were imbalanced among four income level groups.Health insurance and resources may decrease the total ADRD burden primarily from a reduction in death‐related burden.Health insurance and resources may increase disability‐related burden. [ABSTRACT FROM AUTHOR]

Introduction: We investigated the association between Alzheimer's disease (AD) and the risk of cancer in the Chinese population. Methods: In this retrospective cohort study, multivariate Cox proportional hazard regression analysis was used to determine the correlation between AD and the risk of various cancers, as shown by hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Of 8097 AD patients, the HR for all subsequent cancers was 0.822 (95% CI, 0.728‐0.928; P =.002). Among them, three specific cancers were associated with AD: lung cancer (HR, 0.656; 95% CI, 0.494‐ 0.871; P =.004), prostate and testicular cancer (HR, 0.414; 95% CI, 0.202‐0.847; P =.016), and lymphoma (HR, 2.202; 95% CI, 1.005‐4.826; P =.049). Conclusion: Patients with AD might have a lower chance of developing several cancers, including lung cancer and prostate and testicular cancer. Meanwhile, a positive association between AD and a higher incident rate of lymphoma was observed. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits. [ABSTRACT FROM AUTHOR]

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron‐specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD‐associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA‐425 (miR‐425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque‐associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR‐425, a neuronal‐specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR‐425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR‐425‐deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR‐425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal‐specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s). [ABSTRACT FROM AUTHOR]

Background: Language dysfunction is a frequently reported symptom in Alzheimer's disease (AD). However, computer-assisted analysis of spontaneous speech in AD and mild cognitive impairment (MCI) is rarely used to date.Objective: To characterize the language impairment in AD and amnestic MCI (aMCI) with computer-based automatic analysis via the "Automatic Speech Recognition (ASR) software for cognitive impairment V1.3".Methods: A total of 64 subjects, including 20 AD patients, 20 aMCI patients, and 24 healthy controls were recruited. All subjects underwent neuropsychological tests, and spontaneous speech samples were recorded through the description of the "Cookie-Theft Picture" and then analyzed by the computerized software. Subsequently, we compared the speech parameters between the subjects and the controls.Results: We identified seven spontaneous speech parameters (percentage of silence duration, average duration of phrasal segments, average duration of silence segments, number of speech segments, number of long pauses, ratio of hesitation/speech counts and ratio of short pause/speech counts) demonstrating significant differences between the three groups (p < 0.05). All seven speech parameters significantly correlated with cognitive performance, with average duration of silence segments demonstrating the best correlation to cognitive performance on stepwise multiple linear regression analysis.Conclusion: Computer-assisted automated analysis of speech/silence segments demonstrated the potential to reflect the intrinsic linguistic impairment associated with MCI and AD. It has a promising prospect in the early detection of AD and assessment of disease severity. [ABSTRACT FROM AUTHOR]

Background : Urine samples, which capture an individual's metabolic profile, are ideal for the exploration of non-invasive biomarkers to confirm the amnestic mild cognitive impairment (aMCI) status of patients vs. unimpaired ones. Objective: We aimed to detect differentially metabolized amino acids, which are important objectives in metabolomics, garnering particular attention in biomedical pathogenesis from the urine of aMCI patients, which may give clinicians the possibility to intervene with early treatments that curb Alzheimer's disease (AD). Methods : The study included 208 subjects, 98 of whom were aMCI patients, and 110 who were control subjects without dementia. Urine samples were taken from each participant and supernatant was obtained for analysis. The concentrations of amino acids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results : Urinary arginine levels in aMCI patients are obviously lower than in normal controls (q < 0.2 and p < 0.05). Meanwhile, aMCI patients had significant reduced urinary global arginine bioavailability ratio (GABR), and GABR in urine displayed a positive correlation with the score of CMMSE. Conclusion : Urinary dysregulated arginine metabolism that may serve as a helpful clinical diagnostic biomarker for aMCI in older adults. [ABSTRACT FROM AUTHOR]

As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China. [ABSTRACT FROM AUTHOR]

Background: Disclosing the diagnosis of Alzheimer's disease (AD) to a patient is controversial. There is significant stigma associated with a diagnosis of AD or dementia in China, but the attitude of the society toward disclosure of such a diagnosis had not been formally evaluated prior to our study. Therefore, we aimed to evaluate the attitude toward disclosing an AD diagnosis to patients in China with cognitive impairment from their caregivers, and the factors that may affect their attitude.Methods: We designed a 17-item questionnaire and administered this questionnaire to caregivers, who accompanied patients with cognitive impairment or dementia in three major hospitals in Shanghai, China. The caregiver's attitude toward disclosing the diagnosis of AD as evaluated by the questionnaire was compared to that of disclosing the diagnosis of terminal cancer.Results: A majority (95.7%) of the 175 interviewed participants (mean 14.2 years of education received) wished to know their own diagnosis if they were diagnosed with AD, and 97.6% preferred the doctor to tell their family members if they were diagnosed with AD. If a family member of the participants suffered from AD, 82.9% preferred to have the diagnosis disclosed to the patient. "Cognitive impairment" was the most accepted term by caregivers to disclose AD diagnosis in Chinese.Conclusion: This study suggests most of the well-educated individuals in a Chinese urban area favored disclosing the diagnosis when they or their family members were diagnosed with AD. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical.Case Presentation: A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients.Conclusion: The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS). [ABSTRACT FROM AUTHOR]

Micro RNA regulation of transcript expression has been reported in patients with Alzheimer's disease ( AD). Here, we investigate the role of micro RNA-146a (mi RNA-146a), a brain-enriched mi RNA, which is upregulated in AD patients. Through analysis of predicted targets of mi RNA-146a, low-density lipoprotein receptor-related protein-2 (Lrp2), a member of the LDLR family that is known to play a protective role in AD, was identified. Overexpression of mi RNA-146a in SH- SY5Y cells significantly decreased Lrp2 expression, resulting in a reduction of Akt activation and induction of proapoptotic caspase-3, thereby increasing cell apoptosis. Thus, specific mi RNA-146a regulation may contribute to AD by downregulating the Lrp2/Akt pathway. [ABSTRACT FROM AUTHOR]

Background/Aims: As a suitable test to screen for Alzheimer's disease (AD) or mild cognitive impairment (MCI), studies to validate the Chinese version of Addenbrooke's Cognitive Examination-Revised (ACE-R) are rare. Methods: A total of 151 subjects were recruited and the neuropsychological assessments were employed. One-way analysis of variance and Bonferroni correction were used to compare scores of different psychometric scales. Intraclass correlation coefficient (ICC) and Cronbach's coefficient α were used to evaluate the reliability of psychometric scales. The validity of ACE-R to screen for mild AD and amnestic subtype of MCI (a-MCI) was assessed by receiver operating characteristic (ROC) curves. Results: The Chinese ACE-R had good reliability (inter-rater ICC = 0.994; test-retest ICC = 0.967) as well as reliable internal consistency (Cronbach's coefficient α = 0.859). With its cutoff of 67/68, the sensitivity (0.920) and specificity (0.857) were lower than for the Mini-Mental State Examination (MMSE) cutoff (sensitivity 1.000 and specificity 0.937) to screen for mild AD. However, the sensitivity of ACE-R to screen for a-MCI was superior to the MMSE with a cutoff of 85/86. The specificity of ACE-R was lower than that of the MMSE to screen for a-MCI. The area under the ROC curve of ACE-R was much larger than that of the MMSE (0.836 and 0.751) for detecting a-MCI rather than mild AD. Conclusion: The Chinese ACE-R is a reliable assessment tool for cognitive impairment. It is more sensitive and accurate in screening for a-MCI rather than for AD compared to the MMSE. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) exhibits a protective effect against neural injury in vitro and in vivo. However, it has not been reported whether peripheral intravenous administration of PACAP could confer benefits in animal models of Parkinson’s disease (PD). Furthermore, the underlying molecular mechanisms responsible for these effects are poorly understood. In the present experiments, we determined the effects and mechanism of action of intravenously administered PACAP27 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Our results indicate that intravenous injection of PACAP27 offers neuroprotective effects in the MPTP-induced PD mouse model which may not be directly associated with the expression levels of the monoamine transporters. However, this effect may be correlated with its ability to selectively regulate not only KATP subunits, but D2 receptors in the striatum. Our findings suggest that the benefit of PACAP may accompany with changes not only in dopaminergic neurotransmission, but also in cholinergic neurotransmission that are relatively associated with the KATP subunits and D2 receptors in the striatum. [Copyright &y& Elsevier]

The article presents a study on the GRB2-associated binding protein 2 (GAB2) as a risk factor for the development of Alzheimer's disease (AD) in the Chinese population. A case-control study was used to determine the prevalence of five single nucleotide polymorphisms (SNPs) of GAB2 gene and to investigate the risk factor for AD. The study concludes that the implications of the three SNPs with an association at SNP rs7101429 C allele might increase the risk factor for AD.

Rho‐associated coiled‐coil kinase 1 (ROCK1) is proposed to be implicated in Aβ suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce Aβ was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased β‐secretase cleavage of APP. Furthermore, we firstly confirmed that APP served as a substrate for ROCK1 and its major phosphorylation site was located at Ser655. The increased level of APP Ser655 phosphorylation was observed in the brain of APP/PS1 mice and AD patients compared to controls. Moreover, blockade of APP Ser655 phosphorylation, or inhibition of ROCK1 activity with either shRNA knockdown or Y‐27632, ameliorated amyloid pathology and improved learning and memory in APP/PS1 mice. These findings suggest that activated ROCK1 targets APP Ser655 phosphorylation, which promotes amyloid processing and pathology. Inhibition of ROCK1 could be a potential therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Introduction: The increasing prevalence of Alzheimer's disease and related dementias (ADRD) presents both a burden and an opportunity for intervention. This study aims to estimate the impacts of health insurance and resources on the burden attributed to ADRD., Method: Data were mainly collected from global databases for ADRD. Analysis of variance, Pearson correlation, random-effects, and fixed-effects model analyses were used in this study., Results: Although the current medical expenditures were increasing and out of pocket (OOP) expenditures were declining generally in various countries, the collected global data showed an increased burden of ADRD on patients both physically and economically. Furthermore, health resources were negatively associated with disability-adjusted life years (DALY), death, and years of life lost (YLL), but were otherwise positively associated with years of life lived with disability (YLD)., Discussion: Effective measures should be considered to cope with the rising burden. Meanwhile, there is an urgent call for constructive and sustainable rational plans and global collaboration., Highlights: We explored how health insurance and resources affect Alzheimer's disease and related dementias (ADRD)-related burden. Health insurance and resources were imbalanced among four income level groups. Health insurance and resources may decrease the total ADRD burden primarily from a reduction in death-related burden. Health insurance and resources may increase disability-related burden., (© 2022 the Alzheimer's Association.)

Introduction: We investigated the association between Alzheimer's disease (AD) and the risk of cancer in the Chinese population., Methods: In this retrospective cohort study, multivariate Cox proportional hazard regression analysis was used to determine the correlation between AD and the risk of various cancers, as shown by hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: Of 8097 AD patients, the HR for all subsequent cancers was 0.822 (95% CI, 0.728-0.928; P = .002). Among them, three specific cancers were associated with AD: lung cancer (HR, 0.656; 95% CI, 0.494- 0.871; P = .004), prostate and testicular cancer (HR, 0.414; 95% CI, 0.202-0.847; P = .016), and lymphoma (HR, 2.202; 95% CI, 1.005-4.826; P = .049)., Conclusion: Patients with AD might have a lower chance of developing several cancers, including lung cancer and prostate and testicular cancer. Meanwhile, a positive association between AD and a higher incident rate of lymphoma was observed., (© 2021 the Alzheimer's Association.)

Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer's disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE ε4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 [5.6%, 95% CI (1.8%, 12.5%)], followed by coding variants of TREM2 (4.4%, 95%CI (1.2%, 10.9%)) and novel mutations of ACE [3.3%, 95%CI (0.7%, 9.4%)]. Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE ε4 status. Evidence from the Alzheimer's disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP., (© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Background: Identifying risk factors and mortality of individuals with Alzheimer's disease (AD) could have important implications for the clinical management of AD., Objective: This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases., Methods: One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated., Results: Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944-1.563). Employing Cox's proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort., Conclusion: This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.

Background: In addition to the increasing evidence for a molecular mechanism of rho kinase 1 ( ROCK1 ) in Alzheimer's disease (AD), there are several published studies regarding the relationship between ROCK1 gene polymorphisms and neurological diseases. However, it is unknown whether there is an association between the polymorphisms of ROCK1 and AD. We sought to identify the potential association between ROCK1 gene polymorphisms and AD in the Chinese Han population., Methods: A total of 295 patients with AD and 206 healthy controls from multiple centers were enrolled in this study. Three single-nucleotide polymorphisms (SNPs) (rs35996865, rs11873284, and rs2127958) in ROCK1 gene were analyzed using Sanger sequencing., Results: We did not find any significant differences between AD and control groups with regards to the frequency of these three ROCK1 polymorphisms. Further, the three SNP genotype frequencies and allele frequencies did not show significant differences between patients of AD and controls in APOE4 -stratified subjects (P>0.01). Additionally, the three SNPs did not show significant differences even when adopting a four-inheritance model by logistic regression., Conclusions: This is the first multicenter pilot study to evaluate the contribution of ROCK1 genetic variance to AD risk. Our data demonstrated that the ROCK1 gene may not influence the risk of AD by interacting with APOE among Chinese Han people., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.

Frontotemporal dementia (FTD) is the second most common neurodegenerative  cause of early-onset dementia. FTD has an important genetic component contributing to its pathogenic mechanisms. Currently, extensive research on neuroimaging biomarkers and neurochemical biomarkers in FTD is being conducted to address the clinical need for a sensitive and specific diagnostic marker. Here, we review the advances in genetics, biomarkers and treatment of FTD and how this may represent a shift towards precision medicine. To advance the clinical use of precision medicine, big data cohort for genotype/phenotype research and multidisciplinary team approaches are necessary.

Background: Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical., Case Presentation: A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients., Conclusion: The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS).

Background: Mutations in microtubule associated protein tau (MAPT), progranulin (GRN), chromosome 9 open-reading frame 72 (C9orf72) and CHCHD10 genes have been reported causing frontotemporal dementia (FTD) in different populations. However, collective analysis of mutations in these four genes in Chinese FTD patients has not been reported yet., Methods: The aim of this study was to investigate the genetic features of Chinese patients with MAPT, GRN, C9orf72 or CHCHD10 gene mutations in an FTD cohort recruited from multi clinical centers in Shanghai metropolitan areas, China. MAPT, GRN and CHCHD10 genes were analysed by direct sequencing, and C9orf72 hexanucleotide repeat expansion was analysed by repeat-primed PCR in 82 patients with sporadic FTD. The identified gene variants were screened in 400 age matched controls., Results: We found one known pathogenic variant (rs63750959) and one novel mutation (NG&#95;007398.1: g.120962C>T; H299Y) of MAPT gene, one novel variant (c.750C>A; D250E) of GRN gene and two novel mutations in CHCHD10 gene (c.63C>T, no AA change; c.71G>A, P24L). No abnormal C9orf72 gene hexanucleotide repeat expansion was identified in this cohort. Collectively, genetic testing could discover 4.9% sporadic FTD patients with genetic causes. In addition, MAPT and CHCHD10 might be more important genes affecting Chinese with FTD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Alzheimer's disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model). In vitro over-expression of ROCK1 leads to a decrease in Aβ secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aβ. Reciprocally, overexpression of APP/Aβ promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aβ secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.

Sound evidence indicates that microRNAs (miRNAs) are aberrantly expressed in Alzheimer's disease (AD) patients. We performed a systematic review and meta-analysis to investigate the role of miRNA in AD pathogenesis and their clinical diagnostic value; a systematic review of literature and meta-analysis of clinical trials were performed. In the systematic review, 236 papers were included, and we reviewed the dysregulated miRNA expression in different parts of AD patients in order to identify the relationship between aberrantly expressed miRNAs and AD pathology. In the subsequent meta-analysis, seven studies were statistically analyzed with the following results: pooled sensitivity 0.86 (95%CI 0.79-0.90), pooled specificity 0.87 (95%CI 0.72-0.95), diagnostic odds ratio (28.29), and the area under the curve (0.87). In conclusion, our review indicated that aberrant expression of various miRNAs plays an important role in the pathological process of AD, and statistical analysis of quantitative studies reveal the potential value of specific miRNAs in the diagnosis of AD.

The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer's disease (AD).

Mass spectrometry (MS)-based proteomics has developed into a battery of approaches that is exceedingly adept at identifying with high mass accuracy and precision any of the following: oxidative damage to proteins (redox proteomics), phosphorylation (phosphoproteomics), ubiquitination (diglycine remnant proteomics), protein fragmentation (degradomics), and other posttranslational modifications (PTMs). Many studies have linked these PTMs to pathogenic mechanisms of neurodegeneration. To date, identifying PTMs on specific pathology-associated proteins has proven to be a valuable step in the evaluation of functional alteration of proteins and also elucidates biochemical and structural explanations for possible pathophysiological mechanisms of neurodegenerative diseases. This review provides an overview of methods applicable to the identification and quantification of PTMs on proteins and enumerates historic, recent, and potential future research endeavours in the field of proteomics furthering the understanding of PTM roles in the pathogenesis of neurodegeneration.

Previous studies have demonstrated altered metabolites in samples of Alzheimer's disease (AD) patients. However, the sample size from many of them is relatively small and the metabolites are relatively limited. Here we applied a comprehensive platform using ultraperformance liquid chromatography-time-of-flight mass spectrometry and gas chromatography-time-of-flight mass spectrometry to analyze plasma samples from AD patients, amnestic mild cognitive impairment (aMCI) patients, and normal controls. A biomarker panel consisting of six plasma metabolites (arachidonic acid, N,N-dimethylglycine, thymine, glutamine, glutamic acid, and cytidine) was identified to discriminate AD patients from normal control. Another panel of five plasma metabolites (thymine, arachidonic acid, 2-aminoadipic acid, N,N-dimethylglycine, and 5,8-tetradecadienoic acid) was able to differentiate aMCI patients from control subjects. Both biomarker panels had good agreements with clinical diagnosis. The 2 panels of metabolite markers were all involved in fatty acid metabolism, one-carbon metabolism, amino acid metabolism, and nucleic acid metabolism. Additionally, no altered metabolites were found among the patients at different stages, as well as among those on anticholinesterase medication and those without anticholinesterase medication. These findings provide a comprehensive global plasma metabolite profiling and may contribute to making early diagnosis as well as understanding the pathogenic mechanism of AD and aMCI.

Purpose: Recently, a large genome-wide association study has revealed that polymorphism of alleles and genotypes in rs3,764,650 within ABCA7 gene is associated with Alzheimer disease in whites. We conducted a case-control study to investigate whether these susceptible genetic variants are risk factors for sporadic Alzheimer disease (SAD) in Chinese Han population., Design and Methods: A total of 633 participants consisting of 350 SAD and 283 nondemented elderly controls matched for sex and age were recruited and genetic variants in ABCA7 (rs3,764,650) were genotyped using DNA sequencing., Results: On the basis of allele and genotype frequencies in both groups, we found a significant association (P=0.004) between ABCA7 genotypes and SAD in Chinese Han population, and the results were influenced by age and ApoEε4 status. ApoEε4-carrier and aging are linked to enhancing ABCA7 risk-associated SAD. However, the prevalence of the minor allele G in rs3,764,650 within ABCA7 showed no significant difference between the 2 groups in this study., Conclusions: ABCA7 (rs3,764,650) was associated with SAD in the Chinese population, with both ApoEε4-carrier and aging being factors enhancing its risk.