Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The...Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The aim of this study is to analyze the association between these two non-motor symptoms. Methods: Consecutive subjects with Parkinson’s disease attending the Movement Disorders Outpatient Clinic were included. The presence of ICDs was assessed using the Questionnaire for Impulse Control Disorders Rating Scale. RBD was diagnosed by an overnight, single night polysomnography. Results: Fifty-five consecutive subjects with Parkinson’s disease were included. The prevalence of ICDs and related behaviors was 23.6% (ICD in 14.5% and related behaviors in 9.1%). RBD was diagnosed in 47.2% of the patients. No differences were found in the frequency of ICDs and related behaviors when comparing subjects with and without RBD (23% versus 24.1%, p = 0.926, respectively). Conclusion: No association between the presence of RBD and the frequency of ICDs in subjects with Parkinson’s disease was found.展开更多
Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority amo...Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority among researchers.The study’s objective was to measure tear levels of cytokines in subjects with PD and their association with motor features and the presence of dry eye symptoms.Methods:A total of 16 subjects with PD and 16 age-and sex-matched controls were included.Movement Disorders Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS),Hoehn and Yahr(HY)stage scale,Montreal Cognitive Assessment(MoCA),tear break-up time(TBUT),blink rate(BR),Dry Eye Questionnaire 5(DEQ-5)were examined,and pro-inflammatory cytokines[interleukin(IL)-1β,IL-6,IL-8,IL-10,IL-12p70 and tumor necrosis factor-alpha(TNF-α)]were quantified in tears using the BD Cytometric Bead Array Human Inflammatory Cytokine Kit.Results:Higher tear TNF-αwere quantified in PD compared to controls(2.94±3.95 vs.0.33±0.49 pg/mL,P=0.008).According to DEQ-5,50.0%(n=8)of PD subjects and 12.5%(n=2)controls had dry eye disease(DED).No differences were found in cytokines concentrations between PD patients with DED compared to those without DED.IL-8 was associated with the HY stage,TBUT,DEQ-5,and a better MoCA score.A higher BR correlated moderately with a lower HY stage(r=−0.645,P=0.007),and DED patients have lower BR in PD(12.14±2.54 vs.9.0±2.06 blinks/minute,P=0.031).Conclusions:PD patients have higher levels of TNF-αin tears than age-and sex-matched HC.IL-8 in tears may be both involved in the severity of the disease and in the development of DED in PD.In addition,our findings suggest that as HY stage increases,indicating a more advanced stage,BR decreases,indicating greater motor impairment.Conversely,the presence of DED is associated with higher levels of bradykinesia in PD patients,suggesting a potential relationship between DED and motor impairment severity.展开更多
Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired ins...Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases.At the receptor level,in aging and Alzheimer’s disease(AD)models,the amount of insulin receptors and their functions are decreased.Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels.Furthermore,diabetes mellitus(DM)and insulin resistance are associated with age-related cognitive decline,increased levels ofβ-amyloid peptide,phosphorylation of tau protein;oxidative stress,pro-inflammatory cytokine production and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mildobesity and insulin resistance without influencing brain size and apoptosis development.Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size anddevelopment, and contributes to behavior changes. Insulin is synthesized locally in the brain andis released from the neurons. Here, we reviewed proposed pathophysiological hypotheses toexplain increased risk of dementia in the presence of DM. Regardless of the exact sequence ofevents leading to neurodegeneration, there is strong evidence that mitochondrial dysfunctionplays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrialdysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable tothose induced in wild-type mice treated with sucrose, which is consistent with the proposal thatmitochondrial alterations are associated with DM and contribute to AD development. Alterationsin insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidantcapacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing andsystemic metabolism, and could be a specific target for therapeutic strategies to decreasealterations associated with age-related cognitive decline.展开更多
A randomized, double blind, and active reference-controlled study was carried out among 116 patients suffering from idiopathic Parkinson’s disease (PD). The aim of the study was to compare the safety and efficacy of ...A randomized, double blind, and active reference-controlled study was carried out among 116 patients suffering from idiopathic Parkinson’s disease (PD). The aim of the study was to compare the safety and efficacy of alpha-dihydroergocryptine (DHEC) vs. pramipexole (PRAM) as an adjunct symptomatic therapy to levodopa in PD patients. The motor symptoms, assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) III subscale, was identified as efficacy target. Fifty-six patients were randomized to DHEC and 60 to PRAM. Patients included were under constant levodopa dose for at least 3 months before entering the study, with baseline UPDRS III ≥14. They underwent a 16-week treatment. Out of the 116 included patients, 85 (39 in DHEC group and 46 in PRAM group, respectively) completed the study protocol. In DHEC group, UPDRS III decreased by 24.2% from baseline at week 10 and by 28.1% at week 16. In PRAM group, UPDRS III decreased by 27.1% from baseline at week 10 and by 29.2% at week 16. The data were highly significant展开更多
Pilates therapy improves core muscle function and axial stability but its effects on balance in idiopathic Parkinson’s disease (IPD) have not been evaluated. The objective of this study was to evaluate the effects of...Pilates therapy improves core muscle function and axial stability but its effects on balance in idiopathic Parkinson’s disease (IPD) have not been evaluated. The objective of this study was to evaluate the effects of a Pilates exercise program on postural stability and balance confidence in people with IPD. Ten IPD patients (Hoehn & Yahr Stage 1-3) with a history of falls or nearfalls had the following assessments before and after completion of a 6-week supervised Pilates exercise program: Activities-Specific Balance Confidence Scale (ABC);Berg Balance Scale (BBS);Schwab and England Scale (SES);Unified Parkinson’s Disease Rating Scale (UPDRS);pull-test;timed-up-and-go (TUG);5-metre walk;static and dynamic posturography. There were significant improvements in BBS score, 5-metre walk time and TUG after the training program, as well as improvement trends in some posturographic measures. Participants also reported improved balance confidence with Activities of Daily Living (ADLs). Our findings suggest that Pilates therapy can be beneficial in IPD and warrants further evaluation in a larger study.展开更多
Absence status is the most common form of non-convulsive status epilepticus and is characterized by confusion with varying degrees of memory loss and cognitive impairment. Patients and Method: Three children were sent...Absence status is the most common form of non-convulsive status epilepticus and is characterized by confusion with varying degrees of memory loss and cognitive impairment. Patients and Method: Three children were sent to neurological consultation due to behavioral alterations and a prolonged confused state;they were hospitalized and treated with sodium diphenylhydantoinate (DPH) IV at a dose of 10 mg/Kg. Results: The duration of symptoms varied from 6 months to 10 days. All three patients presented with global mental alterations, showing slowness in response and action. The electroencephalogram showed a pattern of slow, generalized stem and poly-stem-wavelengths of 3 - 4 Hz, which were registered for one hour. After the DPH bolus, the attack spontaneously ended in the 3 patients and upon examination all three presented with amnesia of the events occurring during the attack. In the follow-up, two of the patients did not experience further episodes and they showed normal scholastic achievement. The third patient however, after suffering a 6-month status epilepticus, failed the school year and finished his elementary education until the age of 15, experiencing similar difficulties with his secondary education. Discussion: Non-convulsive status epilepticus is more difficult to diagnose mainly because the manifestations are predominantly psychiatric and can be confused with other diseases or with an overdose of anti- convulsive drugs. A prolonged state of mental confusion, with no other explanation, should alert the attending physician to take an electroencephalogram in order to confirm the diagnosis. In our patients, DPH immediately controlled paroxysmal activity. We can therefore conclude that the problem is not in the treatment, but rather in making the correct diagnosis.展开更多
Freezing of gait (FOG) is common in patients with Parkinson disease (PD) and responds poorly to medical treatment. Botulinum toxin A (BTX-A) injections into calf muscles decreased FOG in previous open-label studies. T...Freezing of gait (FOG) is common in patients with Parkinson disease (PD) and responds poorly to medical treatment. Botulinum toxin A (BTX-A) injections into calf muscles decreased FOG in previous open-label studies. The authors conducted a randomized double-blind placebo-controlled crossover study of BTX-A vs placebo in 12 subjects with PD and FOG. No significant improvement with BTX-A was found using subjective and objective measures.展开更多
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 f...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.展开更多
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), is the most common cause of inherited cerebral small vessel disease, inherited stroke and inherited vascular dement...Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), is the most common cause of inherited cerebral small vessel disease, inherited stroke and inherited vascular dementia. It is not infrequent for CADASIL to be mistaken and mistreated for multiple sclerosis (MS). A much less frequent but existing scenario is the co-occurrence of CADASIL and MS (or MS-like inflammatory condition). Such patients may present with spinal cord lesions, brain or spinal cord enhancing lesions, positive oligoclonal bands and high IgG index in the cerebrospinal fluid and good response to corticosteroids or immunomodulating treatments. CADASIL through various mechanisms may trigger or modulate autoimmune reactions, and either be complicated by an inflammatory component or cause an MS-like disorder.展开更多
Currently, neurodegenerative diseases are viewed as proteinopathies. In this context, a specific protein or peptide is involved in the pathogenesis of the disease by missfolding, polymerization, reduced degradation an...Currently, neurodegenerative diseases are viewed as proteinopathies. In this context, a specific protein or peptide is involved in the pathogenesis of the disease by missfolding, polymerization, reduced degradation and final accumulation in the form of insoluble inclusions leading to neurodegeneration by various interacting mechanisms[1,2].展开更多
Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution...Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.展开更多
文摘Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The aim of this study is to analyze the association between these two non-motor symptoms. Methods: Consecutive subjects with Parkinson’s disease attending the Movement Disorders Outpatient Clinic were included. The presence of ICDs was assessed using the Questionnaire for Impulse Control Disorders Rating Scale. RBD was diagnosed by an overnight, single night polysomnography. Results: Fifty-five consecutive subjects with Parkinson’s disease were included. The prevalence of ICDs and related behaviors was 23.6% (ICD in 14.5% and related behaviors in 9.1%). RBD was diagnosed in 47.2% of the patients. No differences were found in the frequency of ICDs and related behaviors when comparing subjects with and without RBD (23% versus 24.1%, p = 0.926, respectively). Conclusion: No association between the presence of RBD and the frequency of ICDs in subjects with Parkinson’s disease was found.
基金supported by Hospital Fundacion Nuestra Senora de la Luz,Private Assistance Institution.
文摘Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority among researchers.The study’s objective was to measure tear levels of cytokines in subjects with PD and their association with motor features and the presence of dry eye symptoms.Methods:A total of 16 subjects with PD and 16 age-and sex-matched controls were included.Movement Disorders Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS),Hoehn and Yahr(HY)stage scale,Montreal Cognitive Assessment(MoCA),tear break-up time(TBUT),blink rate(BR),Dry Eye Questionnaire 5(DEQ-5)were examined,and pro-inflammatory cytokines[interleukin(IL)-1β,IL-6,IL-8,IL-10,IL-12p70 and tumor necrosis factor-alpha(TNF-α)]were quantified in tears using the BD Cytometric Bead Array Human Inflammatory Cytokine Kit.Results:Higher tear TNF-αwere quantified in PD compared to controls(2.94±3.95 vs.0.33±0.49 pg/mL,P=0.008).According to DEQ-5,50.0%(n=8)of PD subjects and 12.5%(n=2)controls had dry eye disease(DED).No differences were found in cytokines concentrations between PD patients with DED compared to those without DED.IL-8 was associated with the HY stage,TBUT,DEQ-5,and a better MoCA score.A higher BR correlated moderately with a lower HY stage(r=−0.645,P=0.007),and DED patients have lower BR in PD(12.14±2.54 vs.9.0±2.06 blinks/minute,P=0.031).Conclusions:PD patients have higher levels of TNF-αin tears than age-and sex-matched HC.IL-8 in tears may be both involved in the severity of the disease and in the development of DED in PD.In addition,our findings suggest that as HY stage increases,indicating a more advanced stage,BR decreases,indicating greater motor impairment.Conversely,the presence of DED is associated with higher levels of bradykinesia in PD patients,suggesting a potential relationship between DED and motor impairment severity.
文摘Insulin,a key pleiotropic hormone,regulates metabolism through several signaling pathways in target tissues including skeletal muscle,liver,and brain.In the brain,insulin modulates learning and memory,and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases.At the receptor level,in aging and Alzheimer’s disease(AD)models,the amount of insulin receptors and their functions are decreased.Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels.Furthermore,diabetes mellitus(DM)and insulin resistance are associated with age-related cognitive decline,increased levels ofβ-amyloid peptide,phosphorylation of tau protein;oxidative stress,pro-inflammatory cytokine production and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mildobesity and insulin resistance without influencing brain size and apoptosis development.Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size anddevelopment, and contributes to behavior changes. Insulin is synthesized locally in the brain andis released from the neurons. Here, we reviewed proposed pathophysiological hypotheses toexplain increased risk of dementia in the presence of DM. Regardless of the exact sequence ofevents leading to neurodegeneration, there is strong evidence that mitochondrial dysfunctionplays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrialdysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable tothose induced in wild-type mice treated with sucrose, which is consistent with the proposal thatmitochondrial alterations are associated with DM and contribute to AD development. Alterationsin insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidantcapacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing andsystemic metabolism, and could be a specific target for therapeutic strategies to decreasealterations associated with age-related cognitive decline.
文摘A randomized, double blind, and active reference-controlled study was carried out among 116 patients suffering from idiopathic Parkinson’s disease (PD). The aim of the study was to compare the safety and efficacy of alpha-dihydroergocryptine (DHEC) vs. pramipexole (PRAM) as an adjunct symptomatic therapy to levodopa in PD patients. The motor symptoms, assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) III subscale, was identified as efficacy target. Fifty-six patients were randomized to DHEC and 60 to PRAM. Patients included were under constant levodopa dose for at least 3 months before entering the study, with baseline UPDRS III ≥14. They underwent a 16-week treatment. Out of the 116 included patients, 85 (39 in DHEC group and 46 in PRAM group, respectively) completed the study protocol. In DHEC group, UPDRS III decreased by 24.2% from baseline at week 10 and by 28.1% at week 16. In PRAM group, UPDRS III decreased by 27.1% from baseline at week 10 and by 29.2% at week 16. The data were highly significant
文摘Pilates therapy improves core muscle function and axial stability but its effects on balance in idiopathic Parkinson’s disease (IPD) have not been evaluated. The objective of this study was to evaluate the effects of a Pilates exercise program on postural stability and balance confidence in people with IPD. Ten IPD patients (Hoehn & Yahr Stage 1-3) with a history of falls or nearfalls had the following assessments before and after completion of a 6-week supervised Pilates exercise program: Activities-Specific Balance Confidence Scale (ABC);Berg Balance Scale (BBS);Schwab and England Scale (SES);Unified Parkinson’s Disease Rating Scale (UPDRS);pull-test;timed-up-and-go (TUG);5-metre walk;static and dynamic posturography. There were significant improvements in BBS score, 5-metre walk time and TUG after the training program, as well as improvement trends in some posturographic measures. Participants also reported improved balance confidence with Activities of Daily Living (ADLs). Our findings suggest that Pilates therapy can be beneficial in IPD and warrants further evaluation in a larger study.
文摘Absence status is the most common form of non-convulsive status epilepticus and is characterized by confusion with varying degrees of memory loss and cognitive impairment. Patients and Method: Three children were sent to neurological consultation due to behavioral alterations and a prolonged confused state;they were hospitalized and treated with sodium diphenylhydantoinate (DPH) IV at a dose of 10 mg/Kg. Results: The duration of symptoms varied from 6 months to 10 days. All three patients presented with global mental alterations, showing slowness in response and action. The electroencephalogram showed a pattern of slow, generalized stem and poly-stem-wavelengths of 3 - 4 Hz, which were registered for one hour. After the DPH bolus, the attack spontaneously ended in the 3 patients and upon examination all three presented with amnesia of the events occurring during the attack. In the follow-up, two of the patients did not experience further episodes and they showed normal scholastic achievement. The third patient however, after suffering a 6-month status epilepticus, failed the school year and finished his elementary education until the age of 15, experiencing similar difficulties with his secondary education. Discussion: Non-convulsive status epilepticus is more difficult to diagnose mainly because the manifestations are predominantly psychiatric and can be confused with other diseases or with an overdose of anti- convulsive drugs. A prolonged state of mental confusion, with no other explanation, should alert the attending physician to take an electroencephalogram in order to confirm the diagnosis. In our patients, DPH immediately controlled paroxysmal activity. We can therefore conclude that the problem is not in the treatment, but rather in making the correct diagnosis.
文摘Freezing of gait (FOG) is common in patients with Parkinson disease (PD) and responds poorly to medical treatment. Botulinum toxin A (BTX-A) injections into calf muscles decreased FOG in previous open-label studies. The authors conducted a randomized double-blind placebo-controlled crossover study of BTX-A vs placebo in 12 subjects with PD and FOG. No significant improvement with BTX-A was found using subjective and objective measures.
文摘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.
文摘Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), is the most common cause of inherited cerebral small vessel disease, inherited stroke and inherited vascular dementia. It is not infrequent for CADASIL to be mistaken and mistreated for multiple sclerosis (MS). A much less frequent but existing scenario is the co-occurrence of CADASIL and MS (or MS-like inflammatory condition). Such patients may present with spinal cord lesions, brain or spinal cord enhancing lesions, positive oligoclonal bands and high IgG index in the cerebrospinal fluid and good response to corticosteroids or immunomodulating treatments. CADASIL through various mechanisms may trigger or modulate autoimmune reactions, and either be complicated by an inflammatory component or cause an MS-like disorder.
文摘Currently, neurodegenerative diseases are viewed as proteinopathies. In this context, a specific protein or peptide is involved in the pathogenesis of the disease by missfolding, polymerization, reduced degradation and final accumulation in the form of insoluble inclusions leading to neurodegeneration by various interacting mechanisms[1,2].
基金the Edmond J Safra Philanthropic Foundation,the Krembil Foundation,and the Rossy FoundationThe funding bodies did not take part in design of the study,in collection,analysis,or interpretation of data,or in writing the manuscript.
文摘Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.