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.

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.

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.

The role of amyloid beta clearance in cerebral amyloid angiopathy:more potential therapeutic targets

Cerebral amyloid angiopathy(CAA)is characterized by the deposition of amyloid β-protein(Aβ)in the leptomeningeal and cortical blood vessels,which is an age-dependent risk factor for intracerebral hemorrhage(ICH),ischemic stroke and contributes to cerebrovascular dysfunction leading to cognitive impairment.However clinical prevention and treatment of the disease is very difficult because of its occult onset and severity of the symptoms.In recent years,many anti-amyloid β immunotherapies have not demonstrated clinical efficacy in subjects with Alzheimer’s disease(AD),and the failure may be due to the deposition of Aβ in the cerebrovascular export pathway resulting in further damage to blood vessels and aggravating CAA.So decreased clearance of Aβ in blood vessels plays a crucial role in the development of CAA and AD,and identification of the molecular pathways involved will provide new targets for treatment.In this review,we mainly describe the mechanisms of Aβ clearance through vessels,especially in terms of some proteins and receptors involved in this process.

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.