Development and validation of a screening instrument for cognitive fluctuation in patientswith neurocognitive disorder with Lewy bodies(NCDLB):the Mayo Fluctuations Scale-Thai version

Background Prevalence of neurocognitive disorder with Lewy bodies （NCDLB） is low in Asian populations, which may partially refect its diagnostic diffculty. The Mayo Fluctuations Scale, a short questionnaire that evaluates cognitive fuctuation, has been shown to signifcantly differentiate NCDLB from Alzheimer＇s disease.Aim This study aimed to develop the Mayo Fluctuations Scale-Thai version and assess its validity to screen NCDLB in an elderly population.Methods The Mayo Fluctuations Scale was translated into Thai. The process involved back-translation, cross-cultural adaptation, feld testing of the prefnal version, as well as fnal adjustments. From all patients attending the Psychiatric and Memory Clinic at Ramathibodi Hospital, 135 patients accompanied by their primary caregivers were included. Caregivers were interviewed by research assistants using a four-item scale, and psychiatrists determined patients＇ diagnosis based on the diagnostic and statistical manual of mental disorders （DSM）-5 criteria. Evaluations performed by psychiatrists and research assistants were blinded.Results Seventeen participants had been diagnosed with major NCDLB. At a cut-off score of 2 or over, the Mayo Fluctuations Scale exhibited excellent performance to differentiate major NCDLB from other major neurocognitive disorders （NCDs）, with a sensitivity of 94.1% and a specifcity of 71.4%, and acceptable performance to differentiate mild NCDLB from other mild NCDs, with a sensitivity of 60% and a specifcity of 93.1%.Conclusion The Mayo Fluctuations Scale-Thai version is an excellent screening tool for major NCDLB and an acceptable tool that may be used with other additional tests for mild NCDLB. The tool is practical for use in memory and psychiatric clinics. Further validation studies in participants with other specifc clinical conditions are required.

Correlation between Alzheimer’s Disease and Dementia with Lewy Bodies Scores Using VSRAD Advance

The objective of the study was to explore the relationship between the indicators of Alzheimer’s disease and dementia with Lewy bodies using the voxel-based specific regional analysis system for Alzheimer’s Disease (VSRAD) advance. Among 36 patients with suspected dementia, patients with Alzheimer’s disease and dementia with Lewy bodies were identified using VSRAD advance from March 1 to October 30, 2019. All patients underwent brain Magnetic Resonance Imaging (MRI). We diagnosed Alzheimer’s disease using Volume of Interest (VOI) in the Medial Temporal Lobe (MTL) atrophy ratio > 2 and dementia with Lewy bodies using both VOI in the MTL atrophy ratio ≤ 2 and gray/white matter atrophy ratio ≥ 0.2. The correlation between the indicators of Alzheimer’s disease and dementia with Lewy bodies was calculated. The number of patients classified as having Alzheimer’s disease and dementia with Lewy bodies was 25 and 11, respectively. In the Alzheimer’s disease group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem gray matter was r = -0.40 (p = 0.045). In dementia with Lewy bodies group, the correlation coefficient between the extent of gray matter atrophy and the severity of atrophy in the dorsal brainstem white matter was r = -0.78 (p < 0.01). Using VSRAD advance, gray matter atrophy and dorsal brainstem grey/white matter atrophy were found to be negatively correlated in Alzheimer’s disease and dementia with Lewy bodies.

Can we clinically diagnose dementia with Lewy bodies yet?

Dementia with Lewy Bodies(DLB)was initially identified and confirmed primarily by pathology,but is soon to be incorporated into the Diagnostic and Statistical Manual criteria as a clinical disease entity.Despite these advances over more than 20 years,current data suggest that the sensitivity of accurate clinical diagnosis of DLB is still very low,although there is mounting evidence that supportive features may increase diagnostic accuracy.Although DLB remains easy to identify pathologically with different cellular pathologies differentiating it from other dementia syndromes,pathological identification using only Lewy body pathology has been shown to be inaccurate due to overlap with patients without dementia symptoms.A number of studies now suggest that a combination of cellular pathologies,which include α-synuclein and β-amyloid deposition as well as dopamine denervation,assist with differentiating this dementia syndrome from others.The clinical and pathological overlap with the tauopathy of Alzheimer’s disease still remains to be clarified.To determine more robust and independent clinicopathological correlates from Alzheimer’s disease,longitudinal prospective studies,using specific clinical batteries on dementia patients reaching the proposed criteria for DLB,with post-mortem assessment of the multiple pathologies associated with dementia,are required.Identifying genetic causes for DLB is another approach to investigate the pathogenesis of DLB.However this approach has been hindered to date by difficulties with identifying DLB clinically.The use of novel techniques is likely to advance knowledge on the pathogenesis of DLB and assist with redefining clinical and pathologic diagnostic criteria.To achieve the goal of more accurate clinical diagnosis of DLB,breakthroughs are necessary on the pathogenesis of DLB.

Clinical features of dementia with lewy bodies in 35 Chinese patients

Objective:To investigate the clinical features of dementia with Lewy bodies(DLB)in a Chinese population.Methods:Computer-based online searches through China Biology Medicine disc and China National Knowledge Infrastructure were performed to collect case reports of DLB published between 1980 and 2012.Clinical characteristics were analyzed.Results:A total of 18 studies comprising 35 patients(26 males and 9 females)were included.The mean age at onset was 67.2±9.8 years.Onset was characterized by memory impairment and accounted for 58.8%of all cases,followed by parkinsonism(11.8%),visual hallucinations(8.8%),and compulsive personality disorder(2.9%).The other patients(17.6%)presented two of the three core features of DLB at onset.With disease progression,parkinsonism was reported in 100%of cases,followed by visual hallucinations(97.1%),psychiatric symptoms(85.7%),severe neuroleptic sensitivity(81.8%),fluctuating cognition(68.6%),repeated falls(40.0%),sleep disorders(22.9%),and transient loss of consciousness(17.1%).26 patients who were subjected to Mini-Mental State Examination scored≤24.10 patients presented relative preservation of hippocampus and medial temporal lobe structures on CT/MRI scan.Occipital hypometabolism occurred in 2 of 3 patients who underwent SPECT/PET perfusion scan.12 patients showed an increasing of slow frequency activity on EEG,prominently in frontal and temporal lobes.Conclusions:DLB often strikes elderly individuals.Its clinical core features are dementia,fluctuating cognition,recurrent visual hallucinations and spontaneous features of parkinsonism.Neuropsychological,neuroimaging and EEG examinations may improve the diagnostic accuracy and discriminate DLB from other dementias.

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.

Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas.The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated.In this observational study,we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases(LBDs)and Alzheimer disease(AD),shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration.We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival.Disease progression in LBDs correlated positively with poly(ADP-Ribose)and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts,indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes.Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine(8-oxo-d G)and myeloperoxidase concentrations in the striatum,suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism ofβ-amyloid entering the mitochondria and subsequent free radicals generation.Patients with lower striatal 8-oxo-d G and myeloperoxidase levels had a survival advantage in AD.The age of onset also affected disease progression.Tissue requests for the postmortem biochemistry,genetics,and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center(ADRC)Biospecimens Committee(ethics approval reference number:T1705,approval date:August 6,2019).Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health&Safety Biological Safety Committee(approval code:3739,approval date:February 25,2020).Radioactive Material Authorization was approved by the Washington University Environmental Health&Safety Radiation Safety Committee(approval code:1056,approval date:September 18,2019).

Angiotensin-(1–7)reducesα-synuclein aggregation by enhancing autophagic activity in Parkinson's disease

Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain elusive.In this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model.We investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 weeks.We found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia nigra.Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 hours.After binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated cells.Primary dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 hours.Angiotensin-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated cells.We conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease.Therefore,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's disease.All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval No.DWSY-2000932)in January 2020.

Associated mortality risk of atypical antipsychotic medication in individuals with dementia

BACKGROUND Antipsychotic medications such as risperidone,olanzapine and aripiprazole are used to treat psychological and behavioural symptoms among dementia patients.Current evidence indicate prescription rates for antipsychotics vary and wider consensus to evaluate clinical epidemiological outcomes is limited.AIM To investigate the potential impact of atypical antipsychotics on the mortality of patients with dementia.METHODS A retrospective clinical cohort study was developed to review United Kingdom Clinical Record Interactive Search system based data between January 1,2013 to December 31,2017.A descriptive statistical method was used to analyse the data.Mini Mental State Examination(MMSE)scores were used to assess the severity and stage of disease progression.A cox proportional hazards model was developed to evaluate the relationship between survival following diagnosis and other variables.RESULTS A total of 1692 patients were identified using natural language processing of which,587 were prescribed olanzapine,quetiapine or risperidone(common group)whilst 893(control group)were not prescribed any antipsychotics.Patients prescribed olanzapine showed an increased risk of death[hazard ratio(HR)=1.32;95%confidence interval(CI):1.08-1.60;P<0.01],as did those with risperidone(HR=1.35;95%CI:1.18-1.54;P<0.001).Patients prescribed quetiapine showed no significant association(HR=1.09;95%CI:0.90-1.34;P=0.38).Factors associated with a lower risk of death were:High MMSE score at diagnosis(HR=0.72;95%CI:0.62-0.83;P<0.001),identifying as female(HR=0.73;95%CI:0.64-0.82;P<0.001),and being of a White-British ethnic group(HR=0.82;95%CI:0.72-0.94;P<0.01).CONCLUSION A significant mortality risk was identified among those prescribed olanzapine and risperidone which contradicts previous findings although the study designs used were different.Comprehensive research should be conducted to better assess clinical epidemiological outcomes associated with diagnosis and therapies to improve clinical management of these patients.

Knowledge domain and emerging trends in visual hallucination research:A scientometric analysis

BACKGROUND Visual hallucination(VH)refers to a spontaneous visual perception without corresponding external stimuli and often occurs in ophthalmological and neuropsychiatric disorders.It is associated with poor quality of life,and increased patient hospitalization and nursing home admission.To date,a scientometric analysis of research on VH is lacking.AIM To objectively summarize the features of VH research and gain insights into the emerging trends in research on VH.METHODS CiteSpace V was used in this article.Publication outputs,document types,geographic distributions,co-authorship status,research hotspots,and co-citation status were analyzed.A total of 2176 original articles and 465 reviews were included in the database downloaded from the Web of Science Core Collection.We selected the top 50 most cited or occurring articles or items to create a visualized network with a 1-year interval.In the document co-citation analysis stage,we performed clustering analysis on co-cited references,and log likelihood tests were used to name the clusters.RESULTS The results showed that most publications can be classified into neurology,sports,and ophthalmology studies.In addition,North America,Europe,Asia and Australia published the most documents.Some well-known authors have always had a leading role in this field;meanwhile,new authors keep emerging.A relatively stable cooperation has been formed among many authors.Furthermore,neuropsychiatric symptom and functional connectivity are the top hotspots.Research on VH in dementia with Lewy bodies and Parkinson’s disease(PD)have received much attention.Studies on VH in PD are likely to be the new emerging trends in the future,especially the mechanisms of VH.CONCLUSION Research on VH has formed a complete system.More large-scale clinical and indepth basic research are required to better understand the mechanisms underlying VH,which will contribute to our understanding of the pathophysiology and therapeutic options for VH.

Longitudinal evolution of cortical thickness signature reflecting Lewy body dementia in isolated REM sleep behavior disorder:a prospective cohort study

Background The isolated rapid-eye-movement sleep behavior disorder(iRBD)is a prodromal condition of Lewy body disease including Parkinson’s disease and dementia with Lewy bodies(DLB).We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD.Methods We enrolled 22 DLB patients,44 healthy controls,and 50 video polysomnography-proven iRBD patients.Participants underwent 3-T magnetic resonance imaging(MRI)and clinical/neuropsychological evaluations.We characterized DLB-related whole-brain cortical thickness spatial covariance pattern(DLB-pattern)using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls.We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients.With repeated MRI data during the follow-up in our prospective iRBD cohort,we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia.Finally,we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort.Results The DLB-pattern was characterized by thinning of the temporal,orbitofrontal,and insular cortices and relative preservation of the precentral and inferior parietal cortices.The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction(Trail Making Test-A and B:R=−0.55,P=0.024 and R=−0.56,P=0.036,respectively)as well as visuospatial impairment(Rey-figure copy test:R=−0.54,P=0.0047).The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters(Pearson’s correlation,R=0.74,P=6.8×10−4)but no significant change in parkinsonism-first phenoconverters(R=0.0063,P=0.98).The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33[1.16-74.12].The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2%accuracy.Conclusion Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population.Replication studies would further validate the utility of this imaging marker in iRBD.

What can imaging tell us about cognitive impairment and dementia?

Dementia is a contemporary global health issue with far reaching consequences, not only for affected individuals and their families, but for national and global socio-economic conditions. The hallmark feature of dementia is that of irreversible cognitive decline, usually affecting memory, and impaired activities of daily living. Advances in healthcare worldwide have facilitated longer life spans, increasing the risks of developing cognitive decline and dementia in late life. Dementia remains a clinical diagnosis. The role of structural and molecular neuroimaging in patients with dementia is primarily supportive role rather than diagnostic, American and European guidelines recommending imaging to exclude treatable causes of dementia, such as tumor, hydrocephalus or intracranial haemorrhage, but also to distinguish between different dementia subtypes, the commonest of which is Alzheimer&#x02019;s disease. However, this depends on the availability of these imaging techniques at individual centres. Advanced magnetic resonance imaging (MRI) techniques, such as functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy, and molecular imaging techniques, such as 18F fluoro-deoxy glucose positron emission tomography (PET), amyloid PET, tau PET, are currently within the realm of dementia research but are available for clinical use. Increasingly the research focus is on earlier identification of at risk preclinical individuals, for example due to family history. Intervention at the preclinical stages before irreversible brain damage occurs is currently the best hope of reducing the impact of dementia.

Depressive symptoms in neurodegenerative diseases

Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer's disease and related conditions like Parkinson's disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have aparticular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment.

Alpha-synuclein and Parkinson disease

OBJECTIVE： To review the recent progresses on the studies of α -synuclein in the pathogenesis of Parkinson disease （PD） and look into the perspective of α -synuclein as a new therapy target. DATA SOURCES： To search the literatures on the progresses of PD studies, especially on the structure, gene expression of α-synuclein and the pathogenesis of PD in Medline from January 1998 to February 2007. Search terms were ＂Parkinson＇s disease, α-synuclein＂ in English. STUDY SELECTION： Initial check the data and choose the original and review articles directly linked to the role of α-synuclein in PD pathogenesis and screening out indirectly discussing articles. Collect the full text and trace the quoting articles and the quoted articles. Only the latest reviews were chosen in Chinese articles. DATA EXTRACTION： There were 424 articles on α-synuclein and its role in the pathogenesis of PD and 43 articles directly related with α-synuclein were chosen among which 12 were reviews. DATA SYNTHESIS： α-synuclein is a kind of soluble protein expressed in pre-synapse in central nervous system encoded by gene in homologous chromosome 4q21. It has physiological function in modulating the stability of membrane and neural plasticity. There is a close relationship between gene mutation in α -synuclein and the pathogenesis of PD. Environmental and genetic factors can induce the misfolding of α-synuclein, and secondary structural change can result in oligomer formation which induces a series of cascade reaction to damage dopaminergic system subsequently. Cell and animal transgenic and non-transgenic models are established recently and the important role of α-synuclein in the pathogenesis both of familial and sporadic PD is confirmed. Studies reveal that inhibiting the aggregation of α-synuclein can prevent its neurotoxicity; gene parkin can intercept the cell death pathway triggered by the aggregation of α-synuclein in cytoplasm. CONCLUSION： Gene mutation ofα-synuclein and the impairment in its structure and function are important in the pathogenesis of PD. Intervention of the gene mutations and abnormal protein aggregation ofα-synuclein may be a new strategy for preventing and treating PD.

Alpha-tubulin deacetylase as a potential and novel target for the prevention of Parkinson's disease progression

Parkinson＇s disease （PD） is the second most common neurodegenerative disorder and is characterized by its progressive course. The current therapies are aimed at alleviating symptoms by rescuing the unbalanced physiological dopamine metabolism and recovery of damaged neuronal circuits. However, these strategies result in insufficient clinical benefits for many patients and fail to halt disease progression. Therefore, new therapeutic targets could serve as the gateway against PD degeneration. One pathological hallmark of PD is the formation of intracytoplasmic protein inclusions or Lewy bodies, in neurons. Recent studies have suggested that Lewy bodies are formed similarly to aggresomes, and results have supported the concept that the novel cellular organelle, the aggresome, is a cytoprotective response that sequesters and facilitates clearance of potentially toxic protein aggregates. In addition, a-tubulin deacetylase has been shown to regulate aggresome formation and rescue neural cell viability in response to misfolded protein. Therefore, the regulation of aggresome formation to trigger cellular self-protection system could arrest PD progression. The present study discusses research progress related to Lewy bodies, aggresomes, and histone deacetylases, with an emphasis on histone deacetylase 6 and sirtuin type 2.

The role of quercetin on the survival of neuron-like PC12 cells and the expression of α-synuclein

Both genetic and environmental factors are important in the pathogenesis of Parkinson＇s disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson＇s disease, genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin（100, 500, 1,000 μM） and then together with various drugs such as 1-methyl-4-phenylpyridinium（MPP＋; a free radical generator）, 6-hydroxydopamine（6-OHDA; a free radical generator）, ammonium chloride（an autophagy inhibitor）, and nocodazole（an aggresome inhibitor）. Cell viability was determined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltertazolium bromide（MTT） assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations（100 and 500 μM） of quercetin but decreased at higher concentration（1,000 μM）. Quercetin exerted neuroprotective effect against MPP＋, ammonium chloride and nocodazole at 100 μM. MPP＋ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson＇s disease pathogenesis needs further investigation.

Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia

Background Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders.In this study,we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease(PD),PD with dementia(PDD)and dementia with Lewy bodies(DLB)donors,and its association with pathology load and MRI measures of atrophy and diffusivity.Methods Using a within-subject post-mortem MRI-pathology approach,we included 9 PD,12 PDD/DLB and 18 age-matched control donors.Cortical thickness and mean diffusivity(MD)metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI.After autopsy,pathological hallmarks(pSer129-αSyn,p-tau and amyloid-βload)together with neurofilament light-chain(NfL)and phosphorylated-neurofilament medium-and heavy-chain(p-NfM/H)immunoreactivity were quantified in seven cortical regions,and studied in detail with confocal-laser scanning microscopy.The correlations between MRI and pathological measures were studied using linear mixed models.Results Compared to controls,p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB,whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB.NfL-positive neurons showed degenerative morphological features and axonal fragmentation.The increased p-NfM/H correlated with p-tau load,and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB.Lastly,neuro-filament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.Conclusions Taken together,increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden.Importantly,we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

Beyond the synucleinopathies:alpha synuclein as a driving force in neurodegenerative comorbidities

The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted fact.A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain.Beyond the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease.In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception,the potential role that aSyn may have in these disorders has received relatively little attention.In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities.In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies,we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins,including tau,TDP-43,amyloid-βand prion protein,in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology.We conclude that a growing body of evidence,encompassing neuropathology studies in human brain,animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction,cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities.We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.

Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases： Clinical Assessments, Biomarkers, and Treatment

Objective： Rapid eye movement sleep behavior disorder （RBD） is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson＇s disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. Data Sources： Using the combined keywords： ＂RBD＂, ＂neurodegenerative disease＂, ＂Parkinson disease＂, and ＂magnetic resonance imaging＂, the PubMed/MEDLINE literature search was conducted up to January 1, 2018. Study Selection： A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. Results： Single-nucleotide polymorphisms in SCARB2 （rs6812193） and MAPT （rs12185268） were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. Conclusions： More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated. There is a need for more treatnaent trials to determine the effectiveness of interventions of RBD on preventing the conversion to neurodegenerative diseases.

Cerebrospinal fluid amyloid beta and tau proteins in atypical Parkinsonism: a review

Progressive supranuclear palsy,corticobasal degeneration,multiple system atrophy and dementia with Lewy bodies are the most common causes of atypical Parkinsonism and enter the differential diagnosis of Parkinson's disease.multiple system atrophy,dementia with Lewy bodies and Parkinson's disease are synucleinopathies,whereas progressive supranuclear palsy and corticobasal degeneration are tauopathies.Multiple cerebrospinal fluid markers have been applied on cohorts of patients with Parkinsonism,with the aim to develop biomarkers for these disorders.Total tau(τΤ),phosphorylated tau at threonine 181(τP-181)and amyloid-beta with 42 amino acids(Aβ42)are considered classical biomarkers for Alzheimer's disease.The aim of the present study is to review the literature regarding these classical cerebrospinal fluid biomarkers in cohorts with Parkinsonism,as well as present data on novel approaches regarding analysis of these proteins.