The role of DJ-1 in the pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder characterized clinically by bradykinesia, rigidity, tremor, gait dysfunction, and postural instability. Several genes have been identified for monogenic disorders that variably resemble Parkinson’s disease. Here, we focus on PARK7, a gene relates to an autosomal recessive form of early-onset Parkinsonism and encodes a protein named DJ-1. Though the exact role of DJ-1 needs to be elucidated, it is generally thought to be functioned as a molecular chaperone and an oxidative sensor (or antioxidative factor). We will review the protective role of DJ-1 to prevent dopaminergic neurons in the substantia nigra pars compacta (SNpc) from degeneration and how its dysfunction would lead to neurodegeneration.

Management Recommendations on Sleep Disturbance o Patients with Parkinson's Disease

INTRODUCTION Sleep disturbance is one of the most common nonmotor symptoms in Parkinson's disease (PD).Sleep disturbance affects 40-98% of PD patients in the world. In China, the prevalence of PD patients with sleep disturbance ranges from 47.66% to 89.10%. Sleep disturbance usually has adverse impact on the quality of life of PD patients. Apossible pathogenesis of PD with sleep disturbance include thalamocortical pathway degeneration and changes of neurotransmitter systems. The etiology of sleep disturbance is multifactorial,involving degeneration of areas regulating sleep,sleep structure affected by drugs,sleep disturbance induced by drug,and sleep fragmentation by multiple factors.

Prevalence of wearing-off and dyskinesia among the patients with Parkinson’s disease on levodopa therapy: a multi-center registry survey in China's Mainland

Objective:Chronic levodopa(L-dopa)treatment in Parkinson’s disease(PD)is often associated with the development of motor complications,but the corresponding epidemiological data is rare in Chinese PD patients.The present survey was to investigate the prevalence rate of wearing-off(WO)and dyskinesia among the patients with PD in China.Methods:From May 2012 to October 2012,a 3-step registry survey for wearing off(WO)and dyskinesia patients with PD receiving levodopa therapy was performed simultaneously at 28 movement disorders clinics in China.Results:There were 1,558 PD patients fulfilling the inclusion criteria.Among them,1,051 had at least one positive response of 9-item wearing off questionnaire(WOQ-9),724 and 160 patients were finally diagnosed with WO and dyskinesia by movement disorders specialists,respectively.The overall prevalence rates of WO and dyskinesia were 46.5%(95%CI 44.0%-48.9%)and 10.3%(95%CI 8.8%-11.8%),respectively.The mean score of WOQ-9 for those with WO was 3.8(SD=1.8),with movement slowness being the most common motor symptoms and pain/aching being the most common non-motor symptoms.Better improvement of motor symptoms(n=354,87.8%)and long-term disease control and drug selection(n=288,71.5%)were the two most frequently considered factors when movement disorders specialists adjusted therapeutic strategies for patients with WO.Conclusions:This survey provided the first multi-center epidemiological data of motor complications among PD patients on L-dopa therapy from China's Mainland.WO prevalence rate among Chinese PD patients was in line with,while dyskinesia prevalence rate was lower than previous reports from other Countries.

Depression, Anxiety, and Quality of Life in Paroxysmal Kinesigenic Dyskinesia Patients

Background：Paroxysmal kinesigenic dyskinesia （PKD） is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements.Under the condition of psychological burden,some patients＆#39; attacks may get worsened with longer duration and higher frequency.This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population.Methods：We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital,using Symptom Check List-90-Revised （SCL-90-R）,World Health Organization Quality of Life-100 （WHOQoL-100）,Self-Rating Depression Scale,and Self-Rating Anxiety Scale.We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data （taken from literature） by using the unpaired Student＆#39;s t-test.We applied multivariate linear regression to analyze the relationships between motor manifestations,mental health,and quality of life among PKD patients.Results：Compared with Chinese normative data taken from literature,patients with PKD exhibited significantly higher （worse） scores across all SCL-90-R subscales （somatization,obsessive-compulsive,interpersonal sensitivity,depression,anxiety,hostility,phobic anxiety,paranoid ideation,and psychoticism;P =0.000 for all） and significantly lower （worse） scores of five domains in WHOQoL-100 （physical domain,psychological domain,independence domain,social relationship domain,and general quality of life;P =0.000 for all）.Nonremission of dyskinesia episodes （P =0.011） and higher depression score （P =0.000） were significantly associated with lower levels of quality of life.The rates of depression and anxiety in patients with PKD were 41.2% （68/165） and 26.7% （44/165）,respectively.Conclusions：Depression,anxiety,and low levels of quality of life were prevalent in patients with PKD.Co-occurrence of depression and anxiety was common among these patients.Regular mental health interventions could set depression and anxiety as intervention targets.Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress,and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out,intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients.

The changing phenotype of microglia from homeostasis to disease

It has been nearly a century since the early description of microglia by Rio-Hortega;since then many more biological and pathological features of microglia have been recognized.Today,microglia are generally considered to be beneficial to homeostasis at the resting state through their abilities to survey the environment and phagocytose debris.However,when activated microglia assume diverse phenotypes ranging from fully inflamed,which involves the release of many pro-inflammatory cytokines,to alternatively activated,releasing antiinflammatory cytokines or neurotrophins,the consequences to neurons can range from detrimental to supportive.Due to the different experimental sets and conditions,contradictory results have been obtained regarding the controversial question of whether microglia are“good”or“bad.”While it is well understood that the dual roles of activated microglia depend on specific situations,the underlying mechanisms have remained largely unclear,and the interpretation of certain findings related to diverse microglial phenotypes continues to be problematic.In this review we discuss the functions of microglia in neuronal survival and neurogenesis,the crosstalk between microglia and surrounding cells,and the potential factors that could influence the eventual manifestation of microglia.

Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer’s disease

Alzheimer’s disease(AD)is an age-related neurodegenerative disorder,characterized clinically by insidious onset of memory and cognition impairment,emergence of psychiatric symptoms and behavioral disorder,and impairment of activities of daily living(ADL).Traditional Chinese medicine(TCM)is practiced in the Chinese health care system for more than 2,000 years.In recent years,scientists have isolated many novel compounds from herbs,some of which improve dementia with fewer side effects than conventional drugs and are regarded as potential anti-AD drugs.In this review,we summarize the latest research progress on TCM showing their possible role of treatment of AD and other demented diseases and possible pharmacological actions.

The role of substantia nigra sonography in the differentiation of Parkinson’s disease and multiple system atrophy

Background:The differential diagnosis of Parkinson’s disease(PD)and multiple system atrophy(MSA)remains a challenge,especially in the early stage.Here,we assessed the value of transcranial sonography(TCS)to discriminate non-tremor dominant(non-TD)PD from MSA with predominant parkinsonism(MSA-P).Methods:Eighty-six MSA-P patients and 147 age and gender-matched non-TD PD patients who had appropriate temporal acoustic bone windows were included in this study.All the patients were followed up for at least 2 years to confirm the initial diagnosis.Patients with at least one substantia nigra(SN)echogenic size≥18 mm^(2) were classified as hyperechogenic,those with at least one SN echogenic size≥25 mm^(2) was defined as markedly hyperechogenic.Results:The frequency of SN hyperechogenicity in non-TD PD patients was significantly higher than that in MSA-P patients(74.1%vs.38.4%,p<0.001).SN hyperechogenicity discriminated non-TD PD from MSA-P with sensitivity of 74.1%,specificity of 61.6%,and positive predictive value of 76.8%.If marked SN hyperechogenicity was used as the cutoff value(≥25 mm^(2)),the sensitivity decreased to 46.3%,but the specificity and positive predictive value increased to 80.2 and 80.0%.Additionally,in those patients with SN hyperechogenicity,positive correlation between SN hyperechogenicity area and disease duration was found in non-TD PD rather than in MSA-P patients.In this context,among early-stage patients with disease duration≤3 years,the sensitivity,specificity and positive predictive value of SN hyperechogenicity further declined to 69.8%,52.2%,and 66.7%,respectively.Conclusions:TCS could help discriminate non-TD PD from MSA-P in a certain extent,but the limitation was also obvious with relatively low specificity,especially in the early stage.

Cognitive impairment and the associated risk factors among the elderly in the Shanghai urban area:a pilot study from China

Objectives:Our study aimed to investigate the prevalence of cognitive impairment(CI)and the associated risk factors among elderly people in Shanghai urban area,China.Methods:A population-based survey was conducted among people aged 55 years or older in urban areas of Shanghai.Face-to-face interviews were carried out to collect information including demographic characteristics,medical history,and medication use,etc.The validated Chinese version of the Mini-Mental State Examination(MMSE)was used to screen subjects with CI,and the criteria of CI were adjusted for education levels.Results:A total of 3,176 home-living residents(≥55 years old)were included in the study.Among them,266 people(102 men and 164 women)were identified as cognition impaired,with a prevalence of 8.38%(266/3,176,95%CI:(8.26,8.49))for both genders,9.21%(102/1,107,95%CI:(9.18,9.33))for men and 7.93%(164/2,069,95%CI:(7.80,8.09))for women,respectively.Furthermore,we found that several significant risk factors,including social factors(education,number of children,marriage status,and family structure),physiological factors(age,blood glucose level,and obesity),factors on living styles(physical exercise,diet&chronic diseases),and genetic factor(ApoE),associated with CI onset.Conclusions:This study confirms the high prevalence of CI among the elderly population in the Shanghai urban in China,similar to previous epidemiologic studies in Western countries.The putative risk factors associated with CI merit further investigated.

Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson＇s Disease

Objective：The aim of this study was to summarize recent studies on nondopaminergic options for the treatment of motor symptoms in Parkinson＇s disease （PD）.Data Sources：Papers in English published in PubMed,Cochrane,and Ovid Nursing databases between January 1988 and November 2016 were searched using the following keywords：PD,nondopaminergic therapy,adenosine,glutamatergic,adrenergic,serotoninergic,histaminic,and iron chelator.We also reviewed the ongoing clinical trials in the website of clinicaltrials.gov.Study Selection：Articles related to the nondopaminergic treatment of motor symptoms in PD were selected for this review.Results：PD is conventionally treated with dopamine replacement strategies,which are effective in the early stages of PD.Long-term use oflevodopa could result in motor complications.Recent studies revealed that nondopaminergic systems such as adenosine,glutamatergic,adrenergic,serotoninergic,histaminic,and iron chelator pathways could include potential therapeutic targets for motor symptoms,including motor fluctuations,levodopa-induced dyskinesia,and gait disorders.Some nondopaminergic drugs,such as istradefylline and amantadine,are currently used clinically,while most such drugs are in preclinical testing stages.Transitioning of these agents into clinically beneficial strategies requires reliable evaluation since several agents have failed to show consistent results despite positive findings at the preclinical level.Conclusions：Targeting nondopaminergic transmission could improve some motor symptoms in PD,especially the discomfort ofdyskinesia.Although nondopaminergic treatments show great potential in PD treatment as an adjunct therapy to levodopa,further investigation is required to ensure their success.

Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease through suppressing mitochondria dysfunction

Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson’s disease(PD).The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model.Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment.JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis.These pro-apoptosis effect can be diminished by curcumin.Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP.Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.

Combination of olfactory test and substantia nigra transcranial sonopraphy in the differential diagnosis of Parkinson’s disease:a pilot study from China

Objectives:Both hyposmia and substania nigra(SN)hyperechogenicity on trascranial sonography(TCS)were risk markers for idiopathic Parkinson’s disease(PD),which was beneficial to the differential diagnosis of the disease.However,each of their single diagnostic value is often limited.The purpose of present study was to explore whether the combination of olfactory test and TCS of SN could enhance the differential diagnostic power in Chinese patients with PD.Methods:Thirty-seven patients with PD and twenty-six patients with essential tremor(ET)were evaluated on 16-item odor identification test from extended version of sniffin’sticks and TCS of SN.The frequency of hyposmia and SN hyperechogenicity in each group was compared.The sensitivity,specificity,positive predictive value(PPV)and negative predictive value(NPV)of the two clinical biomarkers were analyzed.Results:The frequency of hyposmia in patients with PD was significantly higher than in patients with ET(62.2%VS.3.8%,P=0.000).The frequency of SN hyperechogenicity in patients with PD was significantly higher than in ET subjects(48.6%VS.15.4%,P=0.006).The combination of hyposmia and SN hyperechogenicity(if either one or both present)discriminated patients with PD from ET with a sensitivity of 78.4%and 29.7%,specificity of 80.8%and 100%,PPV of 85.3%and 100%,and NPV of 72.4%and 50.0%,respectively.Conclusions:Our preliminary data suggested that the combination of hyposmia and SN hyperechogenicity could improve the diagnostic potential for discriminating Chinese patients with PD from ET.

Metabolomics:a novel approach to identify potential diagnostic biomarkers and pathogenesis in Alzheimer's disease

Although the pathogenesis of Alzheimer＇s disease （AD） is still not fully understood, it is acknowledged that intervention should be made at the early stage. Therefore, identifying biomarkers for the clinical diagnosis is critical. Metabolomics, a novel ＂omics＂, uses methods based on low-molecular-weight molecules, with high-throughput evaluation of a large number of metabolites that may lead to the identification of new disease-specific biomarkers and the elucidation of pathophysiological mechanisms. This review discusses metabolomics investigations of AD and potential future developments in this field.

Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson’s disease patients

Background:Tai Chi has been shown to improve motor symptoms in Parkinson’s disease(PD),but its long-term effects and the related mechanisms remain to be elucidated.In this study,we investigated the effects of long-term Tai Chi training on motor symptoms in PD and the underlying mechanisms.Methods:Ninety-five early-stage PD patients were enrolled and randomly divided into Tai Chi(n=32),brisk walk-ing(n=31)and no-exercise(n=32)groups.At baseline,6 months and 12 months during one-year intervention,all participants underwent motor symptom evaluation by Berg balance scale(BBS),Unified PD rating-scale(UPDRS),Timed Up and Go test(TUG)and 3D gait analysis,functional magnetic resonance imaging(fMRI),plasma cytokine and metabolomics analysis,and blood Huntingtin interaction protein 2(HIP2)mRNA level analysis.Longitudinal self-changes were calculated using repeated measures ANOVA.GEE(generalized estimating equations)was used to assess factors associated with the longitudinal data of rating scales.Switch rates were used for fMRI analysis.False discovery rate correction was used for multiple correction.Results:Participants in the Tai Chi group had better performance in BBS,UPDRS,TUG and step width.Besides,Tai Chi was advantageous over brisk walking in improving BBS and step width.The improved BBS was correlated with enhanced visual network function and downregulation of interleukin-1β.The improvements in UPDRS were asso-ciated with enhanced default mode network function,decreased L-malic acid and 3-phosphoglyceric acid,and increased adenosine and HIP2 mRNA levels.In addition,arginine biosynthesis,urea cycle,tricarboxylic acid cycle and beta oxidation of very-long-chain fatty acids were also improved by Tai Chi training.Conclusions:Long-term Tai Chi training improves motor function,especially gait and balance,in PD.The underlying mechanisms may include enhanced brain network function,reduced inflammation,improved amino acid metabolism,energy metabolism and neurotransmitter metabolism,and decreased vulnerability to dopaminergic degeneration.Trial registration This study has been registered at Chinese Clinical Trial Registry(Registration number:ChiCTR2000036036;Registration date:August 22,2020).

Genetic profiles of familial late-onset Alzheimer’s disease in China:The Shanghai FLOAD study

Compared with early-onset familial AD(FAD),the heritability of most familial lateonset 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 e4 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 e4 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.

The association between Parkinson’s disease and melanoma: a systematic review and meta-analysis

Objective:To assess the association between Parkinson’s disease(PD)and melanoma via systematic review and meta-analysis.Methods:Comprehensive search in PubMed,Web of Science,Embase and four China databases(SinoMed,WanFang data,CNKI and VIP database)of epidemiologic evidences on PD and melanoma published before April 30,2015.Studies which reported risk estimates of melanoma among PD patients or risk estimates of PD in patients with melanoma were included.Pooled odds ratios(ORs)with 95%confidence intervals(CIs)were calculated by random-effects models.Heterogeneity across studies was assessed using Cochran Q and I2 statistics.Subgroup analyses and sensitivity analyses were conducted to evaluate sources of heterogeneity.Subgroup analyses were done according to temporal relationship,geographic region and gender respectively.We assessed publication bias using the Begg and Egger test.In addition,study appraisal was done using a scale for observational studies to ensure the quality of evidence.Results:We identified 24 eligible studies on PD and melanoma with a total number of 292,275 PD patients:the pooled OR was 1.83(95%CI 1.46–2.30)overall,subgroup analyses by temporal relationship showed that risk of melanoma after PD diagnosis was significantly higher(OR 2.43,95%CI 1.77–3.32),but not before the diagnosis of PD(OR 1.09,95%CI 0.78–1.54).Subgroup analysis by geographic region showed that increased risk of melanoma in PD was found both in Europe(OR 1.44,95%CI 1.22–1.70)and in North America(OR 2.64,95%CI 1.63–4.28).Gender-specific subgroup analyses did not show difference between men(OR 1.64,95%CI 1.27–2.13)and women(OR 1.38,95%CI 1.04–1.82)in the risk of melanoma.In addition,we found the risk of non-melanoma skin cancers in PD was slightly higher(OR 1.20,95%CI 1.11–1.29)than general population.It was impossible to evaluate the association between PD and melanoma according to use of levodopa or gene polymorphism via meta-analysis since few observational or cohort studies have focused on it.Conclusions:An association between PD and melanoma was confirmed.Most of the evidences were of high quality,and the conclusion was robust.Further research is needed to explore the mechanisms underlying this relationship.

Association of Source of Memory Complaints and Increased Risk of Cognitive Impairment and Cognitive Decline： A Community-Based Study

Background： Memory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source of memory complaints on the risk of cognitive impairment and cognitive decline in a community-based cohort. Methods： Data on memory complaints and cognitive function were collected among 1840 Chinese participants （aged ≥55 years old） in an urban community at baseline interview and 5-year follow-up. Incident cognitive impairment was identified based on education-adjusted Mini-Mental State Examination score. Logistic regression model was used to estimate the association between the source of memory complaints and risk of cognitive impairment conversion and cognitive decline, after adjusting for covariates. Results： A total of 1840 participants were included into this study including 1713 normal participants and 127 cognitive impairment participants in 2009. Among 1713 normal participants in 2009, 130 participants were converted to cognitive impairment alter 5 years of follow-up. In 2014, 606 participants were identified as cognitive decline. Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment （odds ratio [OR] - 1.60, 95% confidence interval [CI]： 1.04 2.48） and cognitive decline （OR = 1.30, 95% CI： 1.01-1.68）. Furthermore, this association was more significant in males （OR = 2.10, 95% CI： 1.04-4.24 for cognitive impairment and OR - 1.87, 95% CI：1.20-2.99 for cognitive decline） and in higher education level （OR - 1.79, 95% CI： 1.02-3.15 for cognitive impairment and OR = 1.40, 95% CI：1.02-1.91 for cognitive decline）. Conclusions： Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment conversion and cognitive decline, especially in persons with male gender and high educational background.

Lack of Association Between DNMT3B Polymorphisms and Sporadic Parkinson's Disease in a Han Chinese Population

Recently, several single nucleotide polymorphisms （SNPs; rs34094401 on RAD51B, rs41309351 on CPXM1, rs143555311 on MPHOSPHIO, rs141620200 on SER- PINA1, and rs2424913 on DNMT3B） have been associated with Parkinson＇s disease （PD） in Caucasians [1-3]. Con- sidering the genetic variance among different ethnic populations, it is essential to know whether these candidate SNPs are also associated with PD in other ethnic cohorts. Therefore, we investigated these newly-reported risk SNPs in 249 PD patients and 239 controls to test their association with PD.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

Hereditary spastic paraplegia type 18 （HSP18） is a complicated form ofautosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities,dysarthria,and cognitive decline. In the year 2011,HSP18,also known as Spastic Paraplegia 18 （SPG18）,was firstly identified due to a candidate gene endoplasmic reticulum lipid raft-associated protein 2 （ERLIN2） on chromosome 8pl 1.2 in one Saudis family.During the past 5 years,another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype. Here,we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2.Patient was characterized by late-onset spasticity of lower extremities without significant speech involvement or cognitive disability.

Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy

Background:CSF1R-related leukoencephalopathy,also known as hereditary diffuse leukoencephalopathy with spheroids(HDLS),is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor(CSF1R)gene mutation.Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown.Methods:In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations,we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases.Next generation sequencing was conducted for 10 probands to confirm the diagnosis.Sanger sequencing,segregation analysis and phenotypic reevaluation were utilized to substantiate findings.Functional examination of identified mutations was further explored.Results:Clinical and neuroimaging characteristics were summarized.The average age at onset was 35.9±6.4 years(range 24–46 years old).Younger age of onset was observed in female than male(34.2 vs.39.2 years).The most common initial symptoms were speech dysfunction,cognitive decline and parkinsonian symptoms.One patient also had marked peripheral neuropathy.Brain biopsy of two cases showed typical pathological changes,including myelin loss,axonal spheroids,phosphorylated neurofilament and activated macrophages.Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons.A total of 7 pathogenic variants(4 novel,3 documented)were identified with autophosphorylation deficiency,among which c.2342C>T remained partial function of autophosphorylation.Western blotting disclosed the significantly lower level of c.2026C>T(p.R676*)than wild type.The level of microtubule associated protein 1 light chain 3-II(LC3-II),a classical marker of autophagy,was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining.Conclusions:Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis.Autophagy abnormality may play a role in the disease.Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future.However,whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled.

A case report of anti-N-methyl-d-aspartate receptor autoimmune encephalitis with sensory attack. Is limbic encephalitis only'limbic'?

To emphasize the early diagnosis and treatment of anti-N-methyl-d-aspartate-receptor (NMDAR) autoimmune encephalitis, a rare clinical condition, teratoma-related, anti-NMDAR encephalitis should be suspected if young patients present with psychiatric, movement, and sensory symptoms. Early diagnosis and treatment can decrease the mortality and disability rate.