Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease.Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease,appearing in about 90%of patients with early-stage Parkinson’s disease,and can often predate the diagnosis by years.Therefore,olfactory dysfunction should be considered a reliable marker of the disease.However,the mechanisms responsible for olfactory dysfunction are currently unknown.In this article,we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease.On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression levels,we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease.The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease.Therefore,therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms,highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

MicroRNAs in inflammatory bowel disease:What do we know and what can we expect?

MicroRNAs(miRNAs),small non-coding RNAs composed of 18–24 nucleotides,are potent regulators of gene expression,contributing to the regulation of more than 30%of protein-coding genes.Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells,there is an interest in exploring their importance in inflammatory bowel disease(IBD).IBD is a chronic and multifactorial disease of the gastrointestinal tract;the main forms are Crohn's disease and ulcerative colitis.Several studies have investigated the dysregulated expression of miRNAs in IBD,demonstrating their important roles as regulators and potential biomarkers of this disease.This editorial presents what is known and what is expected regarding miRNAs in IBD.Although the important regulatory roles of miRNAs in IBD are clearly established,biomarkers for IBD that can be applied in clinical practice are lacking,emphasizing the importance of further studies.Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

AD is the most common form of dementia among the aging population. The neuropathological alterations of AD are represented by the neurofibrillary tangles and extracellular amyloid plaques formation. These two hallmarks are routinely used as biomarkers for AD diagnosis and can allow the identification of the pathology in a late phase. The urgent need to develop probes for PET analysis that can be used in an early diagnosis of this disorder opened a new scenario in which new biomarkers involved in the first step of AD can be easily detected. Recently, an increasing number of studies indicated as new biomarkers P-gp, TLR4, MIR and free serum copper that are involved in the onset of AD. It has been extensively reported that a P-gp dysfunction in brain can be considered one of the causes of the ADaccumulation in brain parenchyma and that the up-regulation of inflammatory gene expression and inflammatory signaling due to MIR and TLR4 modulated the development and the progression of AD.

MicroRNAs as biomarkers of diabetic retinopathy and disease progression

Diabetes mellitus, together with its complications, has been increasing in prevalence worldwide. Its complications include cardiovascular disease(e.g., myocardial infarction, stroke), neuropathy, nephropathy, and eye complications(e.g., glaucoma, cataracts, retinopathy, and macular edema). In patients with either type 1 or type 2 diabetes mellitus, diabetic retinopathy is the leading cause of visual impairment or blindness. It is characterized by progressive changes in the retinal microvasculature. The progression from nonproliferative diabetic retinopathy to a more advanced stage of moderate to severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy occurs very quickly after diagnosis of mild nonproliferative diabetic retinopathy. The etiology of diabetic retinopathy is unclear, and present treatments have limited effectiveness. Currently diabetic retinopathy can only be diagnosed by a trained specialist, which reduces the population that can be examined. A screening biomarker of diabetic retinopathy with high sensitivity and specificity would aid considerably in identifying those individuals in need of clinical assessment and treatment. The majority of the studies reviewed identified specific microRNAs in blood serum/plasma able to distinguish diabetic patients with retinopathy from those without retinopathy and for the progresion of the disease from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy. In addition,certain microRNAs in vitreous humor were dysregulated in proliferative diabetic retinopathy compared to controls. A very high percentage of patients with diabetic retinopathy develop Alzheimer’s disease. Thus, identifying diabetic retinopathy by measurement of suitable biomarkers would also enable better screening and treatment of those individuals at risk of Alzheimer’s disease.

The Serum Exosome Derived MicroRNA-135a,-193b, and-384 Were Potential Alzheimer's Disease Biomarkers

Objective MicroRNAs （miRs） are attractive molecules to be considered as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer＇s disease （AD）. The goal of this study was to explore their potential value as biomarkers for the diagnosis of AD.Methods The expression levels of exosomal miR-135a, -193b, and -384 in the serum from mild cognitive impairment （MCI）, dementia of Alzheimer-type （DAT）, Parkinson＇s disease with dementia （PDD）, and vascular dementia （VaD） patients were measured with a real-time quantitative reverse transcriptase PCR （qRT-PCR） method.Results Both serum exosome miR-135a and miR-384 were up-regulated while miR-193b was down-regulated in serum of AD patients compared with that of normal controls. Exosome miR-384 was the best among the three miRs to discriminate AD, VaD, and PDD. Using the cut-off value could better interpret these laboratory test results than reference intervals in the AD diagnosis. ROC curve showed that the combination of miR-135a, -193b, and -384 was proved to be better than a particular one for early AD diagnosis.Conclusion Our results indicated that the exosomal miRs in the serum were not only potential biomarker of AD early diagnosis, but might also provide novel insights into the screen and prevention of the disease.

MicroRNA-135a in ABCA1-labeled Exosome is a Serum Biomarker Candidate for Alzheimer’s Disease

Objective In the present study,the ABCA1 was used as a label to capture specific exosomes,the level of ABCA1-labeled exosomal microRNA-135 a(miR-135 a)was evaluated for the diagnosis of Alzheimer’s disease(AD),especially in patients with early stages of AD.Methods This is a preliminary research focused on the levels of ABCA1 in WBCs,RBCs,HT-22 cells,and neuron cells.The diagnostic value of ABCA1-labeled exosomal miR-135 a was examined using the CSF and serum of APP/PS1 double transgenic mice,and 152 patients with SCD,131 patients with MCI,198 patients with DAT,and 30 control subjects.Results The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs(P<0.05).The levels of ABCA1-labeled exosomal miR-135 a increased in the CSF of MCI and DAT group compared to those of control group(P<0.05),slightly increased(P>0.05)in the serum of SCD patient group,and significantly increased in MCI and DAT patient groups compared to those of the control group(P<0.05).Conclusion This study outlines a method to capture specific exosomes and detect them using immunological methods,which is more efficient for early diagnosis of AD.

MicroRNAs expression influence in ulcerative colitis and Crohn's disease:A pilot study for the identification of diagnostic biomarkers

BACKGROUND Inflammatory bowel disease(IBD)comprises two distinct diseases,Crohn’s disease(CD)and ulcerative colitis(UC),both of which are chronic,relapsing inflammatory disorders of the gastrointestinal tract with a mostly unknown etiology.The incidence and prevalence of IBD are continually increasing,indicating the need for further studies to investigate the genetic determinants of these diseases.Since microRNAs(miRNAs)regulate protein translation via complementary binding to mRNA,discovering differentially expressed miRNAs(DE)in UC or CD patients could be important for diagnostic biomarker identification,assisting in the appropriate disease differentiation progressing the understanding of IBD pathogenesis.AIM To determine the miRNA expression profile in UC and CD patients and the potential pathophysiological contributions of differentially expressed miRNA.METHODS A total of 20 formalin-fixed paraffin-embedded colonic samples were collected from the Pathology Department of Botucatu Medical School at São Paulo State University(Unesp).The diagnosis of UC or CD was based on clinical,endoscopic,radiologic,and histological criteria and confirmed by histopathological analysis at the time of selection.The TaqMan™Array Human MicroRNA A+B Cards Set v3.0(Applied Biosystems™)platform was used to analyze 754 miRNAs.Targets of DE-miRNAs were predicted using miRNA Data Integration Portal(mirDIP)and the miRNA Target Interaction database(MiRTarBase).All statistical analyses were conducted using GraphPad Prism software.Parametric and nonparametric data were analyzed using t-tests and Mann-Whitney U tests,respectively.RESULTS The results showed that of the 754 miRNAs that were initially evaluated,643 miRNAs were found to be expressed in at least five of the patients who were diagnosed with either CD or UC;the remaining 111 miRNAs were not considered to be expressed in these patients.The expression levels of 28 miRNAs were significantly different between the CD and UC patients(P≤0.05);13 miRNAs demonstrated a fold-change in expression level greater than 1.Five miRNAs with a downregulated expression were selected for enrichment analysis.The miRNAs whose expression levels were significantly lower in UC patients than in CD patients were enriched in certain signaling pathways that were mostly correlated with cancer-related processes and respective biomarkers.CONCLUSION MiRNAs could be used to differentiate UC from CD,and differently expressed miRNAs could help explain the distinct pathophysiology of each disease.

Enhancing Parkinson’s Disease Diagnosis Accuracy Through Speech Signal Algorithm Modeling

Parkinson’s disease(PD),one of whose symptoms is dysphonia,is a prevalent neurodegenerative disease.The use of outdated diagnosis techniques,which yield inaccurate and unreliable results,continues to represent an obstacle in early-stage detection and diagnosis for clinical professionals in the medical field.To solve this issue,the study proposes using machine learning and deep learning models to analyze processed speech signals of patients’voice recordings.Datasets of these processed speech signals were obtained and experimented on by random forest and logistic regression classifiers.Results were highly successful,with 90%accuracy produced by the random forest classifier and 81.5%by the logistic regression classifier.Furthermore,a deep neural network was implemented to investigate if such variation in method could add to the findings.It proved to be effective,as the neural network yielded an accuracy of nearly 92%.Such results suggest that it is possible to accurately diagnose early-stage PD through merely testing patients’voices.This research calls for a revolutionary diagnostic approach in decision support systems,and is the first step in a market-wide implementation of healthcare software dedicated to the aid of clinicians in early diagnosis of PD.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Magnetic resonance imaging markers for early diagnosis of Parkinson's disease

Parkinson＇s disease （PD） is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called ＂prodromal＂, where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging （MRI） and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.

Need for multiple biomarkers to adjust parameters of closed-loop deep brain stimulation for Parkinson's disease

Closed-loop deep brain stimulation（DBS）：DBS has been established as a surgical therapy for movement disorders and select neuropsychiatric disorders.Various efforts to improve the clinical outcomes of the procedure have been previously made.Several factors affect the DBS clinical outcomes such as lead position,programming technique,

Alpha-synuclein in body fluids as a diagnostic biomarker for Parkinson’s disease

Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(SN)and the formation ofα-synuclein(α-syn)containing inclusion bodies(Lewy pathology)in the surviving neurons.Diagnosis of PD is still based on clinical features.However,owing to the complexity,heterogeneity,and overlapping of its symptoms with other Parkinsonian disorders,correct diagnosis of PD remains a challenge,especially in the early stages.Therefore,there is an urgent need for biomarkers that can help correctly diagnose PD,differentiate PD from other Parkinsonian disorders,monitor the progression of the disease,and evaluate the therapeutic efficacy.Various molecules have been investigated for their utility in diagnosing PD,among whichα-syn is the most extensively investigated one due to its close implication in the etiology and pathogenesis of PD and related diseases.During the past decade,various species ofα-syn,including total,oligomeric,and phosphorylatedα-syn in various tissues,have been investigated for their utility as a potential biomarker for PD diagnosis and differential diagnosis.Various forms ofα-syn in body fluids,including cerebrospinal fluid(CSF),blood plasma,and saliva,are among the ones that are extensively investigated,since the body fluids are relatively accessible compared to the peripheral tissues.The aim of this review is to summarize the progress of studies on the utility ofα-syn in body fluid as a biomarker for PD diagnosis and differential diagnosis.

Digital Biomarker Identification for Parkinson’s Disease Using a Game-Based Approach

Despite the fact that their neurobiological processes and clinical criteria are well-established, early identification remains a significant hurdle to effective, disease-modifying therapy and prolonged life quality. Gaming on computers, gaming consoles, and mobile devices has become a popular pastime and provides valuable data from several sources. High-resolution data generated when users play commercial digital games includes information on play frequency as well as performance data that reflects low-level cognitive and motor processes. In this paper, we review some methods present in the literature that is used for identification of digital biomarkers for Parkinson’s disease. We also present a machine learning method for early identification of problematic digital biomarkers for Parkinson’s disease based on tapping activity from Farcana-Mini players. However, more data is required to reach a complete evaluation of this method. This data is being collected, with their consent, from players who play Farcana-Mini. Data analysis and a full assessment of this method will be presented in future work.

Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.

MicroRNAs in Parkinson's disease and emerging therapeutic targets

Parkinson＇s disease（PD） is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species（ROS） and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.

Novel biomarkers of fibrosis in Crohn's disease

Fibrosis represents a major challenge in Crohn's disease(CD),and many CD patients will develop fibrotic strictures requiring treatment throughout their lifetime.There is no drug that can reverse intestinal fibrosis,and so endoscopic balloon dilatation and surgery are the only effective treatments.Since patients may need repeated treatments,it is important to obtain the diagnosis at an early stage before strictures become symptomatic with extensive fibrosis.Several markers of fibrosis have been proposed,but most need further validation.Biomarkers can be measured either in biological samples obtained from the serum or bowel of CD patients,or using imaging tools and tests.The ideal tool should be easily obtained,costeffective,and reliable.Even more challenging is fibrosis occurring in ulcerative colitis.Despite the important burden of intestinal fibrosis,including its detrimental effect on outcomes and quality of life in CD patients,it has received less attention than fibrosis occurring in other organs.A common mechanism that acts via a specific signaling pathway could underlie both intestinal fibrosis and cancer.A comprehensive overview of recently introduced biomarkers of fibrosis in CD is presented,along with a discussion of the controversial areas remaining in this field.

A multiple-tissue-specific magnetic resonance imaging model for diagnosing Parkinson’s disease: a brain radiomics study

Brain radiomics can reflect the characteristics of brain pathophysiology.However,the value of T1-weighted images,quantitative susceptibility mapping,and R2*mapping in the diagnosis of Parkinson’s disease(PD)was underestimated in previous studies.In this prospective study to establish a model for PD diagnosis based on brain imaging information,we collected high-resolution T1-weighted images,R2*mapping,and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019.According to the inclusion time,123 PD patients and 121 healthy controls were assigned to train the diagnostic model,while the remaining 106 subjects were assigned to the external validation dataset.We extracted 1408 radiomics features,and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset.The informative features so identified were then used to construct a diagnostic model for PD.The constructed model contained 36 informative radiomics features,mainly representing abnormal subcortical iron distribution(especially in the substantia nigra),structural disorganization(e.g.,in the inferior temporal,paracentral,precuneus,insula,and precentral gyri),and texture misalignment in the subcortical nuclei(e.g.,caudate,globus pallidus,and thalamus).The predictive accuracy of the established model was 81.1±8.0%in the training dataset.On the external validation dataset,the established model showed predictive accuracy of 78.5±2.1%.In the tests of identifying early and drug-naïve PD patients from healthy controls,the accuracies of the model constructed on the same 36 informative features were 80.3±7.1%and 79.1±6.5%,respectively,while the accuracies were 80.4±6.3%and 82.9±5.8%for diagnosing middle-to-late PD and those receiving drug management,respectively.The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8±6.9%and 79.1±6.5%,respectively.In conclusion,the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis.

Proteomics of serum exosomes identified fibulin-1 as a novel biomarker for mild cognitive impairment

Mild cognitive impairment(MCI)is a prodrome of Alzheimer’s disease pathology.Cognitive impairment patients often have a delayed diagnosis because there are no early symptoms or conventional diagnostic methods.Exosomes play a vital role in cell-to-cell communications and can act as promising biomarkers in diagnosing diseases.This study was designed to identify serum exosomal candidate proteins that may play roles in diagnosing MCI.Mass spectrometry coupled with tandem mass tag approach-based non-targeted proteomics was used to show the differentially expressed proteins in exosomes between MCI patients and healthy controls,and these differential proteins were validated using immunoblot and enzyme-linked immunosorbent assays.Correlation of cognitive performance with the serum exosomal protein level was determined.Nanoparticle tracking analysis suggested that there was a higher serum exosome concentration and smaller exosome diameter in individuals with MCI compared with healthy controls.We identified 69 exosomal proteins that were differentially expressed between MCI patients and healthy controls using mass spectrometry analysis.Thirty-nine exosomal proteins were upregulated in MCI patients compared with those in control patients.Exosomal fibulin-1,with an area under the curve value of 0.81,may be a biomarker for an MCI diagnosis.The exosomal protein signature from MCI patients reflected the cell adhesion molecule category.In particular,higher exosomal fibulin-1 levels correlated with lower cognitive performance.Thus,this study revealed that exosomal fibulin-1 is a promising biomarker for diagnosing MCI.

External anal sphincter electromyography in multiple system atrophy:implications for diagnosis,clinical correlations,and novel insights into prognosis

Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early diagnosis of multiple system atrophy is of utmost impo rtance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients.The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging marke rs supporting diagnosis of multiple system atrophy.Nonetheless,especially in the early disease stage,it can be challenging to differentiate multiple system atrophy from mimic disorders,in particular Parkinson’s disease.Electromyography of the external anal sphincter represents a useful neurophysiological tool for diffe rential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration,which is a pathological hallmark of multiple system atrophy.However,the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controve rsial reports in the literature.In this review,after a brief ove rview of the electrophysiological methodology,we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography.We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electro myography.Finally,we repo rted recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.

Mitochondrial sensitive probe with aggregation-induced emission characteristics for early brain diagnosis of Parkinson’s disease

The early diagnosis of Parkinson’s disease(PD)provides opportunities for early intervention to slow the progression of neurological degeneration in patients,particularly as the aging population increases in our society.Among a series of pathological features of PD,mitochondria abnormalities have been identified as central event that occurs at the early stage of PD.However,the method for detecting mitochondrial abnormalities-associated early PD has not been fully developed.We herein report a specifically mitochondrial targeting probe(named TPA-BT-SCP)that is able to characterize mitochondria abnormalities for early diagnosis of PD and monitor PD neurodegenerative progress.The probe is an aggregation-induced emission(AIE)probe with a strong positive charge,a 3D distorted molecular structure,and a separated HOMO-LUMO distribution,designed with unique molecular design guidelines.Our research demonstrated that TPA-BT-SCP could emit stable and strong fluorescence,and rapidly accumulate in mitochondria due to the negative charge.After intranasal administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,TPA-BT-SCP successfully bypassed the blood−brain barrier to light up the brain,allowing the grading of PD severity based on its high sensitivity.Taken together,this work develops a novel AIE probe that exhibits dramatically high sensitivity to mitochondrial changes and enables noninvasive diagnosis of early PD in the brain.