Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic ...Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.展开更多
Objective: To estimate prevalence, incidence, and rate of progression of mild cognitive impairment (MCI) to dementia and correlated vascular risk factors wit h incident MCI and its progression to dementia. Methods: Th...Objective: To estimate prevalence, incidence, and rate of progression of mild cognitive impairment (MCI) to dementia and correlated vascular risk factors wit h incident MCI and its progression to dementia. Methods: The authors evaluated 2 ,963 individuals from the population-based sample of 5,632 subjects 65 to 84 y ears old, at the first (1992 to 1993) and second survey (1995 to 1996) of the It alian Longitudinal Study on Aging (ILSA), with a 3.5- year follow-up. Dementi a, Alzheimer disease (AD), vascular dementia (VaD), other types of dementia, and MCI were classified using current clinical criteria. Results: Among the 2,963 p articipants, 139 MCI patients were diagnosed at the first ILSA survey. During th e 3.5- year followup, 113 new events of MCI were diagnosed with an estimated in cidence rate of 21.5 per 1,000 person-years. We found a progression rate to de mentia (all causes) of 3.8/100 person-years. Specific progression rates for AD , VaD, and other types of dementia were 2.3, 1.3, and 0.3/100 person-years. Fu rthermore,age was a risk factor for incident MCI (RR: 5.93, 95% CI: 3.17 to 11 .10), while education was protective (RR: 0.06, 95% CI: 0.03 to 0.10), and ser um total cholesterol evidenced a borderline nonsignificant trend for a protectiv e effect. There was a nonsignificant trend for stroke as a risk factor of progre ssion of MCI to dementia. Conclusions: In this population, among those who progr essed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factor s influence incident mild cognitive impairment and the rate of progression to de mentia.展开更多
Correction:Translational Neurodegeneration(2021)10:50 https://doi.org/10.1186/s40035-021-00275-w Following publication of this article[1],the below fund-ing information is missing.European Union’s Horizon 2020,’MES-...Correction:Translational Neurodegeneration(2021)10:50 https://doi.org/10.1186/s40035-021-00275-w Following publication of this article[1],the below fund-ing information is missing.European Union’s Horizon 2020,’MES-CoBraD’(H2020-SC1-BHC-2018-2020/GA 965422 to JF).The original article[1]has been corrected.展开更多
Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may hel...Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may help advance our understanding of different neurodegenerative diseases.In this study,we investigated the diagnostic performance of plasma GFAP(pGFAP),plasma neurofilament light chain(pNfL)and their combination for frontotemporal dementia(FTD)and Alzheimer's disease(AD)and their clinical utility in predicting disease progression.Methods:pGFAP and pNfL concentrations were measured in 72 FTD,56 AD and 83 cognitively normal(CN)participants using the Single Molecule Array technology.Of the 211 participants,199 underwent cerebrospinal(CSF)analysis and 122 had magnetic resonance imaging.We compared cross-sectional biomarker levels between groups,studied their diagnostic performance and assessed correlation between CSF biomarkers,cognitive performance and cortical thickness.The prognostic performance was investigated,analyzing cognitive decline through group comparisons by tertile.Results:Unlike pNfL,which was increased similarly in both clinical groups,pGFAP was increased in FTD but lower than in AD(all P<0.01).Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD(area under the curve[AUC]:combination 0.78;pGFAP 0.7;pNfL 0.61,all P<0.05).In FTD,pGFAP correlated with cognition,CSF and plasma NfL,and cortical thickness(all P<0.05).The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD(1.40 points annually,hazard ratio[HR]3.82,P<0.005)and in AD(1.20 points annually,HR 2.26,P<0.005).Conclusions:pGFAP and pNfL levels differ in FTD and AD;and their combination is useful for distinguishing between the two diseases.pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.展开更多
Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promisin...Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promising cerebrospinal fuid(CSF)indicators of synaptic failure in AD patients.However,their value as biomarkers has not yet been determined.Methods:Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2,carboxypeptidase E(CPE),secretogranins SgIII and SgII,and Cystatin C in the cerebral cortex(n=45,provided by Bellvitge University Hospital)and CSF samples(n=66,provided by The Sant Pau Initiative on Neurodegeneration cohort)from AD patients(n=56)and age-matched controls(n=55).Results:In AD tissues,most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astro‑cytes,whereas PC1/3,PC2 and CPE were also specifcally accumulated in hippocampal granulovacuolar degeneration bodies.AD individuals displayed an overall decline of secretory proteins in the CSF.Interestingly,in AD patients,the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status.Conclusions:These results demonstrate marked alterations of neuronal-specifc prohormone convertases in CSF and cortical tissues of AD patients.The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.展开更多
文摘Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.
文摘Objective: To estimate prevalence, incidence, and rate of progression of mild cognitive impairment (MCI) to dementia and correlated vascular risk factors wit h incident MCI and its progression to dementia. Methods: The authors evaluated 2 ,963 individuals from the population-based sample of 5,632 subjects 65 to 84 y ears old, at the first (1992 to 1993) and second survey (1995 to 1996) of the It alian Longitudinal Study on Aging (ILSA), with a 3.5- year follow-up. Dementi a, Alzheimer disease (AD), vascular dementia (VaD), other types of dementia, and MCI were classified using current clinical criteria. Results: Among the 2,963 p articipants, 139 MCI patients were diagnosed at the first ILSA survey. During th e 3.5- year followup, 113 new events of MCI were diagnosed with an estimated in cidence rate of 21.5 per 1,000 person-years. We found a progression rate to de mentia (all causes) of 3.8/100 person-years. Specific progression rates for AD , VaD, and other types of dementia were 2.3, 1.3, and 0.3/100 person-years. Fu rthermore,age was a risk factor for incident MCI (RR: 5.93, 95% CI: 3.17 to 11 .10), while education was protective (RR: 0.06, 95% CI: 0.03 to 0.10), and ser um total cholesterol evidenced a borderline nonsignificant trend for a protectiv e effect. There was a nonsignificant trend for stroke as a risk factor of progre ssion of MCI to dementia. Conclusions: In this population, among those who progr essed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factor s influence incident mild cognitive impairment and the rate of progression to de mentia.
文摘Correction:Translational Neurodegeneration(2021)10:50 https://doi.org/10.1186/s40035-021-00275-w Following publication of this article[1],the below fund-ing information is missing.European Union’s Horizon 2020,’MES-CoBraD’(H2020-SC1-BHC-2018-2020/GA 965422 to JF).The original article[1]has been corrected.
基金supported by the Fondo de Investigaciones Sanitario(FIS)Institute de Salud Carlos III(P114/01126,P117/01019 and PI20/01473 to JF,PI13/01532 and PI16/01825 to RB,PI18/00335 to MCI,PI18/00435 and INT19/00016 to DA,PI17/01896 and AC19/00103to AL)+4 种基金the CIBERNED program(Program 1,Alzheimer Disease to AL)jointly funded by Fondo Europeo de Desarrollo Regional,Unión Europea,"Una manera de hacer Europa"supported by Generalitat de Catalunya(2017-SGR-547,SLT006/17/125 to DA,SLT006/17/119 to JF,SLT002/16/408 to AL)"MaratóTV3"foundation grants 20141210 to JF,044412 to RB and 20142610 to ALsupported by a grant from the Fundacio Bancaria La Caixa to RB(DABNI project).
文摘Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may help advance our understanding of different neurodegenerative diseases.In this study,we investigated the diagnostic performance of plasma GFAP(pGFAP),plasma neurofilament light chain(pNfL)and their combination for frontotemporal dementia(FTD)and Alzheimer's disease(AD)and their clinical utility in predicting disease progression.Methods:pGFAP and pNfL concentrations were measured in 72 FTD,56 AD and 83 cognitively normal(CN)participants using the Single Molecule Array technology.Of the 211 participants,199 underwent cerebrospinal(CSF)analysis and 122 had magnetic resonance imaging.We compared cross-sectional biomarker levels between groups,studied their diagnostic performance and assessed correlation between CSF biomarkers,cognitive performance and cortical thickness.The prognostic performance was investigated,analyzing cognitive decline through group comparisons by tertile.Results:Unlike pNfL,which was increased similarly in both clinical groups,pGFAP was increased in FTD but lower than in AD(all P<0.01).Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD(area under the curve[AUC]:combination 0.78;pGFAP 0.7;pNfL 0.61,all P<0.05).In FTD,pGFAP correlated with cognition,CSF and plasma NfL,and cortical thickness(all P<0.05).The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD(1.40 points annually,hazard ratio[HR]3.82,P<0.005)and in AD(1.20 points annually,HR 2.26,P<0.005).Conclusions:pGFAP and pNfL levels differ in FTD and AD;and their combination is useful for distinguishing between the two diseases.pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.
基金This work was supported by grants from the Spanish Ministry of Economy and Competitiveness(BFU2016-80868-R,MINECO/FEDER,to FA)the Spanish Ministry of Science and Innovation(PID2019-107738RB-I00,MICINN/FEDER,to FA)+2 种基金the Catalonian Government(2017SGR1255 to FA,2014SGR-0235 to AL,PERIS SLT006/17/125 to DA)the Carlos III Institute of Health,Spain(PI18/00435 to DA,PI14/1561 and PI17/01896 to AL)and the CIBERNED program(Program 1,Alzheimer Disease to AL and IF),partly funded by Fondo Europeo de Desar‑rollo Regional(FEDER),Unión Europea,“Una manera de hacer Europa”,and BBVA Foundation(to AL)We are grateful to the Generalitat de Catalunya(NB),the Ministry of Education and Vocational Training(NB)and the Universitat de Barcelona(VP)for fnancial support.
文摘Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promising cerebrospinal fuid(CSF)indicators of synaptic failure in AD patients.However,their value as biomarkers has not yet been determined.Methods:Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2,carboxypeptidase E(CPE),secretogranins SgIII and SgII,and Cystatin C in the cerebral cortex(n=45,provided by Bellvitge University Hospital)and CSF samples(n=66,provided by The Sant Pau Initiative on Neurodegeneration cohort)from AD patients(n=56)and age-matched controls(n=55).Results:In AD tissues,most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astro‑cytes,whereas PC1/3,PC2 and CPE were also specifcally accumulated in hippocampal granulovacuolar degeneration bodies.AD individuals displayed an overall decline of secretory proteins in the CSF.Interestingly,in AD patients,the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status.Conclusions:These results demonstrate marked alterations of neuronal-specifc prohormone convertases in CSF and cortical tissues of AD patients.The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.
