Language dysfunction correlates with cognitive impairments in older adults without dementia mediated by amyloid pathology.

Background: Previous studies have explored the application of non-invasive biomarkers of language dysfunction for the early detection of Alzheimer's disease (AD). However, language dysfunction over time may be quite heterogeneous within different diagnostic groups. Method: Patient demographics and clinical data were retrieved from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database for the participants without dementia who had measures of cerebrospinal fluid (CSF) biomarkers and language dysfunction. We analyzed the effect of longitudinal neuropathological and clinical correlates in the pathological process of semantic fluency and confrontation naming. The mediation effects of AD biomarkers were also explored by the mediation analysis. Result: There were 272 subjects without dementia included in this analysis. Higher rates of decline in semantic fluency and confrontation naming were associated with a higher risk of progression to MCI or AD, and a greater decline in cognitive abilities. Moreover, the rate of change in semantic fluency was significantly associated with Aß deposition, while confrontation naming was significantly associated with both amyloidosis and tau burden. Mediation analyses revealed that both confrontation naming and semantic fluency were partially mediated by the Aß aggregation. Conclusion: In conclusion, the changes in language dysfunction may partly stem from the Aß deposition, while confrontation naming can also partly originate from the increase in tau burden. Therefore, this study sheds light on how language dysfunction is partly constitutive of mild cognitive impairment and dementia and therefore is an important clinical predictor.

Comparison of Cognitive Intervention Strategies for Individuals With Alzheimer's Disease: A Systematic Review and Network Meta-analysis.

Accumulating evidence has shown the effectiveness of cognitive interventions, which can be divided into cognitive training (CT), cognitive stimulation (CS), cognitive rehabilitation (CR), and combined interventions (i.e., cognitive interventions combined with other non-pharmacological interventions such as physical exercise), in individuals with Alzheimer's disease (AD). However, the effectiveness of cognitive interventions varies greatly among studies and more comprehensive studies are required. We aimed to evaluate whether the current evidence shows that cognitive interventions are effective at improving cognition, neuropsychiatric symptoms, depression, quality of life, and basic activities of daily living among individuals with possible or probable AD. Randomized controlled trials of all types of cognitive intervention were identified for inclusion in pairwise and network meta-analyses. There was a moderate and statistically significant post-intervention improvement in global cognition among individuals with AD for all types of cognitive intervention compared to control interventions (39 studies, g = 0.43, 95% CI: 0.28 to 0.58, p < 0.01; Q = 102.27, df = 38, p < 0.01; I2 = 61.97%, τ2 = 0.13). Regarding the specific types of cognitive intervention, combined interventions had the highest surface under the cumulative ranking curve (SUCRA) value (90.7%), followed by CT (67.8%), CS (53.4%), and lastly CR (28.9%). Significant effects of cognitive interventions were also found for working memory, verbal memory, verbal fluency, confrontation naming, attention, neuropsychiatric symptoms, basic activities of daily living, and quality of life.

A meta-analysis of the diagnostic utility of biomarkers in cerebrospinal fluid in Parkinson's disease.

Biomarkers play important roles in the diagnosis and differential diagnosis of Parkinson's disease (PD). Thus, we carried out a systematic review and meta-analysis evaluating the diagnostic utility of cerebrospinal fluid (CSF) biomarkers to distinguish PD from atypical parkinsonian syndromes (APSs) and controls. Data for PD and APS and controls were extracted from 123 studies that reported the concentration of CSF biomarkers. Comparisons were presented using pooled Hedges' g. Sources of heterogeneity were evaluated using meta-regression, and subgroup and sensitivity analyses. We found that compared with controls, PD patients had lower levels of amyloid beta 1-42, phosphorylated tau, total tau, total α-synuclein, Zn, DJ-1, and YKL-40, and higher levels of oligomeric and phosphorylated α-synuclein. Moreover, lower CSF levels of neurofilament light chain, t-tau, YKL-40, and C-reactive protein were found in PD patients compared to those with multiple system atrophy. PD patients also had lower levels of NFL and higher levels of Aß42 compared with patients with progressive supranuclear palsy. Reduced levels of p-tau and t-tau and higher Aß42 levels were found in PD patients compared with patients with dementia with Lewy bodies. Finally, reduced NFL levels were found in patients with PD compared with patients with cortical basal degeneration. Therefore, we believe that the combinations of t-α-syn, Aß42, and NFL could be promising biomarkers for the differential diagnosis of PD and APSs.

Prevalence and clinical aspects of depression in Parkinson's disease: A systematic review and meta­analysis of 129 studies.

Depression is one of the most important non-motor symptoms in Parkinson's disease (PD), but its prevalence and related clinical characteristics are unclear. To this end, we performed a systematic review and meta-analysis based on 129 studies, including 38304 participants from 28 countries. Overall, the prevalence of depression in PD was 38 %. When compared with patients without depression, those with depression had a younger age of onset, a lower education level, longer disease duration, higher UPDRS-III, higher H&Y staging scale, and lower MMSE, SE-ADL scores. We observed that depression was associated with female patients, patients carrying the GBA1 mutation, freezing of gait (FOG), apathy, anxiety and fatigue. Our results suggest that depression is an independent, frequent non-motor symptom in PD, appearing in the early stage and persisting throughout the disease duration. In addition, several clinical characteristics and motor and non-motor symptoms appeared to be associated with depression and negatively impacted on quality of life.

Diagnostic utility of fluid biomarkers in multiple system atrophy: a systematic review and meta-analysis.

BACKGROUND: Multiple system atrophy (MSA) is an adult onset, fatal neurodegenerative disease. However, no reliable biomarker is currently available to guide clinical diagnosis and help to determine the prognosis. Thus, a comprehensive meta-analysis is warranted to determine effective biomarkers for MSA and provide useful guidance for clinical diagnosis. METHODS: A comprehensive literature search was made of the PubMed, Embase, Cochrane and Web of Science databases for relevant clinical trial articles for 1984-2019. Two review authors examined the full-text records, respectively, and determined which studies met the inclusion criteria. We estimated the mean difference, standard deviation and 95% confidence intervals. RESULTS: A total of 28 studies and 11 biomarkers were included in our analysis. Several biomarkers were found to be useful to distinguish MSA patients from healthy controls, including the reduction of phosphorylated tau, α-synuclein (α-syn), 42-amino-acid form of Aß and total tau (t-tau), the elevation of neurofilament light-chain protein (NFL) in cerebrospinal fluid, the elevation of uric acid and reduction of homocysteine and coenzyme Q10 in plasma. Importantly, α-syn, NFL and t-tau could be used to distinguish MSA from Parkinson's disease (PD), indicating that these three biomarkers could be useful biomarkers in MSA diagnosis. CONCLUSION: The findings of our meta-analysis demonstrated diagnostic biomarkers for MSA. Moreover, three biomarkers could be used in differential diagnosis of MSA and PD. The results could be helpful for the early diagnosis of MSA and the accuracy of MSA diagnosis.

Bioinformatic gene analysis for potential therapeutic targets of Huntington's disease in pre-symptomatic and symptomatic stage.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by psychiatric symptoms, serious motor and cognitive deficits. Certain pathological changes can already be observed in pre-symptomatic HD (pre-HD) patients; however, the underlying molecular pathogenesis is still uncertain and no effective treatments are available until now. Here, we reanalyzed HD-related differentially expressed genes from the GEO database between symptomatic HD patients, pre-HD individuals, and healthy controls using bioinformatics analysis, hoping to get more insight in the pathogenesis of both pre-HD and HD, and shed a light in the potential therapeutic targets of the disease. METHODS: Pre-HD and symptomatic HD differentially expressed genes (DEGs) were screened by bioinformatics analysis Gene Expression Omnibus (GEO) dataset GSE1751. A protein-protein interaction (PPI) network was used to select hub genes. Subsequently, Gene Ontology (GO) enrichment analysis of DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of hub genes were applied. Dataset GSE24250 was downloaded to verify our hub genes by the Kaplan-Meier method using Graphpad Prism 5.0. Finally, target miRNAs of intersected hub genes involved in pre-HD and symptomatic HD were predicted. RESULTS: A total of 37 and 985 DEGs were identified in pre-HD and symptomatic HD, respectively. The hub genes, SIRT1, SUZ12, and PSMC6, may be implicated in pre-HD, and the hub genes, FIS1, SIRT1, CCNH, SUZ12, and 10 others, may be implicated in symptomatic HD. The intersected hub genes, SIRT1 and SUZ12, and their predicted target miRNAs, in particular miR-22-3p and miR-19b, may be significantly associated with pre-HD. CONCLUSION: The PSMC6, SIRT1, and SUZ12 genes and their related ubiquitin-mediated proteolysis, transcriptional dysregulation, and histone metabolism are significantly associated with pre-HD. FIS1, CCNH, and their related mitochondrial disruption and transcriptional dysregulation processes are related to symptomatic HD, which might shed a light on the elucidation of potential therapeutic targets in HD.

MicroRNAs Dysregulation and Metabolism in Multiple System Atrophy.

Multiple system atrophy (MSA) is an adult onset, fatal disease, characterized by an accumulation of alpha-synuclein (α-syn) in oligodendroglial cells. MicroRNAs (miRNAs) are small non-coding RNAs involved in post-translational regulation and several biological processes. Disruption of miRNA-related pathways in the central nervous system (CNS) plays an important role in the pathogenesis of neurodegenerative diseases, including MSA. While the exact mechanisms underlying miRNAs in the pathogenesis of MSA remain unclear, it is known that miRNAs can repress the translation of messenger RNAs (mRNAs) that regulate the following pathogenesis associated with MSA: autophagy, neuroinflammation, α-syn accumulation, synaptic transmission, oxidative stress, and apoptosis. In this review, the metabolism of miRNAs and their functional roles in the pathogenesis of MSA are discussed, thereby highlighting miRNAs as potential new biomarkers for the diagnosis of MSA and in increasing our understanding of the disease process.

Single nucleotide polymorphisms, variable number tandem repeats and allele influence on serotonergic enzyme modulators for aggressive and suicidal behaviors: A review.

The serotonergic system plays key regulatory roles in cognition and emotion. Several lines of evidence suggest that genetic variation is associated with aggressive and suicidal behaviors. Genetic studies have largely focused on three types of variations: single nucleotide polymorphisms (SNPs), variable number tandem repeats (VNTRs), and alleles. 95 published papers (49 papers for aggression and 46 for suicide) were reviewed to summarize the impact of SNPs, VNTRs, and alleles of tryptophan hydroxylase (TPH, the rate-limiting enzyme in serotonin [5-HT] synthesis), 5-HT transporter (5-HTT), serotonergic receptors, monoamine oxidase (an enzyme that catalyzes 5-HT degradation) on aggression and suicidal behaviors. These study samples include healthy controls, psychiatric disease patients, and animal models. This article mainly reviews studies on the relationship between 5-HT transmissions and genetic variations involved in aggression (particularly impulsive aggression) or suicide in people with different ethnicities and psychiatric disorders. We found that most SNPs, VNTRs, and alleles exerted influences on aggression or suicide. Only A128C in TPH1, A138G in 5-HT2A, and L type in the VNTR of monoamine oxidase A (MAOA) affected both aggression and suicide. The associations between some genetic variations and aggression/suicide may be influenced by gender, age, ethnicity, psychiatric disease, and even parenting or prenatal stress. These findings may help clarify how genetic and environmental factors influence the development of aggressive and suicidal behaviors.

Transcriptional Dysregulation and Post-translational Modifications in Polyglutamine Diseases: From Pathogenesis to Potential Therapeutic Strategies.

Polyglutamine (polyQ) diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat in the coding region of their respective associated genes. PolyQ diseases mainly display progressive degeneration of the brain and spinal cord. Nine polyQ diseases are known, including Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six forms of spinocerebellar ataxia (SCA). HD is the best characterized polyQ disease. Many studies have reported that transcriptional dysregulation and post-translational disruptions, which may interact with each other, are central features of polyQ diseases. Post-translational modifications, such as the acetylation of histones, are closely associated with the regulation of the transcriptional activity. A number of groups have studied the interactions between the polyQ proteins and transcription factors. Pharmacological drugs or genetic manipulations aimed at correcting the dysregulation have been confirmed to be effective in the treatment of polyQ diseases in many animal and cellular models. For example, histone deaceylase inhibitors have been demonstrated to have beneficial effects in cases of HD, SBMA, DRPLA, and SCA3. In this review, we describe the transcriptional and post-translational dysregulation in polyQ diseases with special focus on HD, and we summarize and comment on potential treatment approaches targeting disruption of transcription and post-translation processes in these diseases.

The role of endoplasmic reticulum stress in neurodegenerative disease.

The endoplasmic reticulum (ER) is an important organelle involved in cellular homeostasis and control of protein quality. Unfolded protein response (UPR) is a cellular response to ER stress and promotes cell survival. Severe or prolonged stress activates apoptosis signaling to trigger cell death. In mammals, the UPR is initiated by three major ER stress sensors, including inositol-requiring transmembrane kinase 1, double-stranded RNA-activated protein kinase-like ER kinase and activating transcription factor 6. UPR dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, which is characterized by the accumulation and aggregation of misfolded proteins. ER stress mediates the pathogenesis of psychiatric diseases, such as depression, schizophrenia, sleep fragmentation and post-traumatic stress disorder. The role of UPR in the neuropathology of humans, cell lines and animal models, is established. Therefore, inhibition of specific ER mediators may contribute to the treatment and prevention of neurodegeneration. Preclinical studies have shed light on the potential therapeutic strategies. Here, we will review the evidence of UPR activation in neurodegenerative disorders and psychiatric diseases along with the methodology.