Biomarkers for Parkinson’s Disease: How Good Are They?

Parkinson’s disease(PD)is a complex neurodegenerative disorder with no cure in sight.Clinical challenges of the disease include the inability to make a definitive diagnosis at the early stages and difficulties in predicting the disease progression.The unmet demand to identify reliable biomarkers for early diagnosis and management of the disease course of PD has attracted a lot of attention.However,only a few reported candidate biomarkers have been tried in clinical practice at the present time.Studies on PD biomarkers have often overemphasized the discovery of novel identity,whereas efforts to further evaluate such candidates are rare.Therefore,we update the new development of biomarker discovery in PD and discuss the standard process in the evaluation and assessment of the diagnostic or prognostic value of the identified potential PD biomarkers in this review article.Recent developments in combined biomarkers and the current status of clinical trials of biomarkers as outcome measures are also discussed.We believe that the combination of different biomarkers might enhance the specificity and sensitivity over a single measure that might not be sufficient for such a multiplex disease.     

Current view and perspectives in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), identiifed as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no cu-rative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientiifc knowledge in the ifeld of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent ad-vances and promising therapeutics and biomarkers in the ifeld of ALS.     

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer＇s disease

Alzheimer＇s disease （AD） is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging （structural magnetic resonance imaging （MRI）, diffusion MRI, and functional MRI） and neurophysiological techniques （electroencephalography and magnetoencephaJography） with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment （MCI）, the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks （i.e., connectomics） and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.     

Tandem Mass Tag-based proteomics analysis reveals the vital role of inflammation in traumatic brain injury in a mouse model

Proteomics is a powerful tool that can be used to elucidate the underlying mechanisms of diseases and identify new biomarkers. Therefore, it may also be helpful for understanding the detailed pathological mechanism of traumatic brain injury(TBI). In this study, we performed Tandem Mass Tag-based quantitative analysis of cortical proteome profiles in a mouse model of TBI. Our results showed that there were 302 differentially expressed proteins in TBI mice compared with normal mice 7 days after in...     

Preliminary examination of early neuroconnectivity features in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MRI

During the last decades,advances in the understanding of genetic,cellular,and microstructural alterations associated to Huntington's disease(HD)have improved the understanding of this progressive and fatal illness.However,events related to early neuropathological events,neuroinflammation,deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown.Ultra-high field diffusion MRI(UHFD-MRI)techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD.In addition,it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers.Moreover,qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events,compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration.The application of ultra-high field diffusion-MRI technology in animal models,particularly the R6/1 mice(a common preclinical mammalian model of HD),provide the opportunity to analyze alterations in a physiologically intact model of the disease.Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented,further application of different diffusion MRI techniques used in combination like diffusion tensor imaging,and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter.Thus,the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.     

Increased activation of the caudate nucleus and parahippocampal gyrus in Parkinson's disease patients with dysphagia after repetitive transcranial magnetic stimulation: a case-control study

Repetitive transcranial magnetic stimulation(r TMS)has been shown to effectively improve impaired swallowing in Parkinson's disease(PD)patients with dysphagia.However,little is known about how r TMS affects the corresponding brain regions in this patient group.In this casecontrol study,we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy,Capital Medical University.The patients received high-frequency r TMS of the motor cortex once per day for 10 successive days.Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls.The results revealed that before treatment,PD patients with dysphagia showed greater activation in the precentral gyrus,supplementary motor area,and cerebellum compared with healthy controls,and this enhanced activation was weakened after treatment.Furthermore,before treatment,PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus,caudate nucleus,and left thalamus compared with healthy controls,and this activation increased after treatment.In addition,PD patients with dysphagia reported improved subjective swallowing sensations after r TMS.These findings suggest that swallowing function in PD patients with dysphagia improved after r TMS of the motor cortex.This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus.The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University(approval No.2018 bkky017)on March 6,2018 and was registered with Chinese Clinical Trial Registry(registration No.Chi CTR 1800017207)on July 18,2018.     

Structural and functional alterations in the brains of patients with anisometropic and strabismic amblyopia:a systematic review of magnetic resonance imaging studies

Amblyopia is the most common cause of vision loss in children and can persist into adulthood in the absence of effective intervention.Previous clinical and neuroimaging studies have suggested that the neural mechanisms underlying strabismic amblyopia and anisometropic amblyopia may be different.Therefore,we performed a systematic review of magnetic resonance imaging studies investigating brain alterations in patients with these two subtypes of amblyopia;this study is registered with PROSPERO(reg...     

The role of cofilin in age-related neuroinflammation

Aging brain becomes susceptible to neurodegenerative diseases due to the shifting of microglia and astrocyte phenotypes to an active“pro-inflammatory”state,causing chronic low-grade neuroinflammation.Despite the fact that the role of neuroinflammation during aging has been extensively studied in recent years,the underlying causes remain unclear.The identification of relevant proteins and understanding their potential roles in neuroinflammation can help explain their potential of becoming biomarkers in the aging brain and as drug targets for prevention and treatment.This will eventually reduce the chances of developing neurodegenerative diseases and promote healthier lives in the elderly.In this review,we have summarized the morphological and cellular changes in the aging brain,the effects of age-related neuroinflammation,and the potential role of cofilin-1 during neuroinflammation.We also discuss other factors contributing to brain aging and neuroinflammation.     

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

Amyotrophic lateral sclerosis(ALS) and motor neuron diseases(MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons(UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons(MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro "disease in dish" and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.     

Cortical spreading depression-induced preconditioning in the brain

Cortical spreading depression is a technique used to depolarize neurons. During focal or global ischemia, cortical spreading depression-induced preconditioning can enhance tolerance of further injury. Howev-er, the underlying mechanism for this phenomenon remains relatively unclear. To date, numerous issues exist regarding the experimental model used to precondition the brain with cortical spreading depression, such as the administration route, concentration of potassium chloride, induction time, duration of the protection provided by the treatment, the regional distribution of the protective effect, and the types of neurons responsible for the greater tolerance. In this review, we focus on the mechanisms underlying cor-tical spreading depression-induced tolerance in the brain, considering excitatory neurotransmission and metabolism, nitric oxide, genomic reprogramming, inlfammation, neurotropic factors, and cellular stress response. Speciifcally, we clarify the procedures and detailed information regarding cortical spreading de-pression-induced preconditioning and build a foundation for more comprehensive investigations in the ifeld of neural regeneration and clinical application in the future.     

Peripheral Lymphocyte Subsets as a Marker of Parkinson’s Disease in a Chinese Population

In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson's disease(PD) to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer(NK) cells and CD3+, CD3+CD4+, CD3+CD8+, and CD19+ lymphocytes from peripheral blood were determined by immunostaining and flow cytometric analysis and the percentages of these CD+ T cells were calculated. The ratio of regulatory T(Treg)/helper T 17(Th17) lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis.The results showed that the percentage of NK cells was higher in advanced PD patients than in controls(22.92% ±10.08% versus 19.76% ± 10.09%, P = 0.006), while CD3+ T cells are decreased(62.93% ± 9.27% versus65.75% ± 9.13%, P = 0.005). The percentage of CD19+B cells in male patients was lower(P = 0.021) than in female patients, whereas NK cells were increased(P \ 0.0001). The scores on the Unified Parkinson's Disease Rating Scale(UPDRS) and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in earlyonset patients(P = 0.024 and P = 0.007, respectively). The percentage of CD19+ B cells in patients with UPDRS scores[24 was lower than in those with scores \24(10.17% ±4.19% versus 12.22% ± 5.39%, P = 0.009). In addition, the Treg/Th17 ratio in female patients was higher than that in female controls(13.88 ± 6.32 versus 9.94 ± 4.06, P =0.042). These results suggest that the percentages of NK cells,CD3+ T cells, and CD19+ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.     

Non-coding RNAs and stem cells:the dream team for neural regeneration in Parkinson’s disease?

Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,which causes decreased secretion of dopamine leading to tremors,bradykinesia and rigid muscle movement.The development of PD is complex and needs to be better understood.Current treatment strategies primarily involve targeting disease symptoms,however,since there is a continuous loss of dopaminergic neurons in the brain,PD appears to be incurable.Moreover,treatment strategies often carry severe side effects related to dopamine production,where too little or too much can cause debilitating issues such as dyskinesia.The pool of neural stem/progenitor cells(NSCs)located in sub-ventricular zone and hippocampal dentate gyrus,proliferate and are responsible to give rise to neurons and glia in response to any cellular damage.Though this activation of NSCs is highly regulated,it is insufficient to overcome the loss of dopaminergic neurons in PD.In this line,non-coding RNAs(ncRNAs)are involved in the underlying mechanisms of PD and are known to have important functional roles in neural regeneration(Acharya et al.,2020).Thus,the study of ncRNAs in NSC activation and adult neurogenesis post PD development is an extremely attractive area of research with significant clinical application potential.     

帕金森病患者肌肉疲劳的实时表面肌电图反应

To explore the mechanisms underlying exercise-induced local muscle fatigue in patients with idiopathic Parkinson’s disease (PD),we used surface electromyography to record myoelectric signals from the tibialis anterior muscle during isometric contraction-induced fatigue until exhaustion.The results revealed no significant differences between patients with idiopathic PD and healthy controls in maximum voluntary contraction of the tibialis anterior muscle.The basic characteristics of surface electromyography were also similar between the two groups.The duration of isometric contraction at 50% maximum voluntary contraction was shortened in PD patients.In addition,PD patients exhibited a stronger increase in mean square amplitude,but a weaker decrease in median frequency and mean power frequency compared with healthy controls during isometric contraction.The skeletal muscles of PD patients revealed specificity of surface electromyography findings,indicating increased fatigability compared with healthy controls.     

Endothelial progenitor cells as a therapeutic option in intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is the most severe cerebrovascular disease, which represents a leading cause of death and disability in developed countries. However, therapeutic options are limited, so is mandatory to investigate repairing processes after stroke in order to develop new therapeutic strategies able to promote brain repair processes. Therapeutic angiogenesis and vasculogenesis hold promise to improve outcome of ICH patients. In this regard, circulating endothelial progenitor cells (EPCs) have recently been suggested to be a marker of vascular risk and endothelial function. Moreover, EPC levels have been associated with good neurological and functional outcome as well as reduced residual hematoma volume in ICH patients. Finally, experimental and clinical studies indicate that EPC might mediate endothelial cell regeneration and neovascularization. Therefore, EPC-based therapy could be an excellent therapeutic option in ICH. In this mini-review, we discuss the present status of knowledge about the possible therapeutic role of EPCs in ICH, molecular mechanisms, and the future perspectives and strategies for their use in clinical practice.     

Positron emission tomography imaging for the assessment of mild traumatic brain injury and chronic traumatic encephalopathy: recent advances in radiotracers

A chronic phase following repetitive mild traumatic brain injury can present as chronic traumatic encephalopathy in some cases,which requires a neuropathological examination to make a definitive diagnosis.Positron emission tomography(PET)is a molecular imaging modality that has high sensitivity for detecting even very small molecular changes,and can be used to quantitatively measure a range of molecular biological processes in the brain using different radioactive tracers.Functional changes have also been reported in patients with different forms of traumatic brain injury,especially mild traumatic brain injury and subsequent chronic traumatic encephalopathy.Thus,PET provides a novel approach for the further evaluation of mild traumatic brain injury at molecular levels.In this review,we discuss the recent advances in PET imaging with different radiotracers,including radioligands for PET imaging of glucose metabolism,tau,amyloid-beta,γ-aminobutyric acid type A receptors,and neuroinflammation,in the identification of altered neurological function.These novel radiolabeled ligands are likely to have widespread clinical application,and may be helpful for the treatment of mild traumatic brain injury.Moreover,PET functional imaging with different ligands can be used in the future to perform largescale and sequential studies exploring the time-dependent changes that occur in mild traumatic brain injury.     

Primary report of noninvasive impedance monitoring of cerebral hematoma and edema in patients with intracerebral hemorrhage

Background and Objective Brain edema is one of the most important clinical process in many diseases. Tissue impedance monitoring offers a non-invasive, bedside, rapid, and reliable technique for the monitoring of the brain edema. Methods We use a bioelectrical impedance(BEI) monitoring unit to record the brain impedance in the healthy volunteer and the patients with intracerebral hemorrhage. Percent of BEI variations were calculation. Results and Conclusions Brain BEI haven f any difference between both hemispheres in normal ones. In 48hrs, BEI value at hematoma-side was obviously decreased; after 48hrs, BEI value was obviously increased and continue to tenth day. Brain bioelectrical impedance monitoring, particularly noninvasively, is a first time in this field. The primary results show brain BEI could reflect the evolution of cerebral hematoma and edema.     

Hyposmia： a possible biomarker of Parkinson＇s disease

Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson＇s disease （PD） that antedates the typical motor symptoms by several years. It occurs in -90% of early-stage cases of PD. In addition to the high prevalence, the occurrence of hyposmia may also predict a higher risk of PD. Investigations into hyposmia and its relationship with PD may help elucidate the underlying pathogenic mechanisms. This review provides an update of olfactory dysfunction in PD and its potential as a biomarker for this devastating disease.     

Imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 may contribute to hemorrhage in cerebellar arteriovenous malformations

In this study,we determined the expression levels of matrix metalloproteinase-2 and-9 and matrix metalloproteinase tissue inhibitor-1 and-2 in brain tissues and blood plasma of patients undergoing surgery for cerebellar arteriovenous malformations or primary epilepsy(control group).Immunohistochemistry and enzyme-linked immunosorbent assay revealed that the expression of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with cerebellar arteriovenous malformations than in patients with primary epilepsy.The ratio of matrix metalloproteinase-9 to matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with hemorrhagic cerebellar arteriovenous malformations compared with those with non-hemorrhagic malformations.Matrix metalloproteinase-2 and matrix metalloproteinase tissue inhibitor-2 levels were not significantly changed.These findings indicate that an imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1,resulting in a relative overabundance of matrix metalloproteinase-9,might be the underlying mechanism of hemorrhage of cerebellar arteriovenous malformations.     

Progression of motor symptoms in Parkinson’s disease

Parkinson’s disease(PD)is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms-rigidity,bradykinesia and tremor-due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms.However,the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.