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Associations of AT(N) biomarkers with neuropsychiatric symptoms in prechnical Alzheimer’s disease and cognitively unimpaired individuals

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Translational Neurodegeneration 2021年第1期10卷 126-139页

作者： Kok Pin Ng Hui Chiew Pedro Rosa-Neto Nagaendran Kandiah Zahinoor Ismail serge gauthier Department of Neurology National Neuroscience InstituteSingaporeSingapore Duke-NUS Medical School SingaporeSingapore Lee Kong Chian School of Medicine-Imperial College London Nanyang Technological UniversitySingaporeSingapore The McGill University Research Centre for Studies in Aging MontrealCanada Hotchkiss Brain Institute and Obrien Institute for Public Health/Departments of Psychiatry Clinical Neurosciencesand Community Health SciencesUniversity of CalgaryCalgaryAlbertaCanada

The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological *** preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired *** neuropsychiatric symptoms(NPS)are non-cognitive symptoms that are increasingly recognized as early manifestations of AD,the associations of NPS with AD pathophysiology in preclinical AD remain ***,we review the associations between NPS and AD biomarkers amyloid-(3(Aβ),tau and neurodegeneration in preclinical AD and cognitivelyunimpaired individuals in 19 eligible English-language publications(8 cross-sectional studies,10 longitudinal,1 both cross-sectional and longitudinal).The cross-sectional studies have consistently shown that NPS,particularly depressive and anxiety symptoms,are associated with higher Aβ.The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over ***,most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau *** the association of NPS and neurodegeneration,two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD,***,evidence for the association between atrophy and NPS in preclinical AD is less ***,future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N)biomarkers,NPS and cognitive decline,but also to elucidate the contribution of comorbid pathology to preclinical AD.

关键词： Neuropsychiatric symptoms Preclinical Alzheimer's disease Mild behavioral impairment Amyloid-β Hyperphosphorylated tau Neurodegeneration

Prevention strategies for Alzheimer’s disease

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Translational Neurodegeneration 2012年第1期1卷 99-102页

作者： serge gauthier Liyong Wu Pedro Rosa-Neto Jianping Jia McGill Center for studies in Aging McGill UniversityMontrealCanada Neurological Department Xuanwu HospitalCapital UniversityBeijingChina McGill Centre for Studies in Aging(MCSA) McGill University6825Boul.LaSalle BlvdMontrealQC H4H 1R3Canada

Symptomatic treatment during the dementia stage of Alzheimer’s disease(AD)cannot delay or halt the progression of this ***,prevention in the preclinical stage is likely the most effective way to decrease the incidence of this age-associated neurodegenerative condition,and its associated burden for individuals and ***,gender,family history,ApoE4,systolic blood pressure,body mass index,total cholesterol level and physical activity are all used as component of dementia risk *** have been numerous challenges in conducting primary prevention trials in *** strategies for prevention studies include studying those subjects with more risk factors for AD,such as older age,those with a positive family history of late onset AD,and those who are ApoE4 *** of these strategies is designed to increase the probability of developing AD thereby decreasing the sample size or the duration of follow *** strategy would be to target directly the pathophysiology of AD in its preclinical stages and use the biomarkers in prevention trial as surrogate *** will be done first in carriers of dominantly inherited early onset *** this research takes place networks of memory clinics must prepare to transfer new knowledge to persons interested in a preventive approach to AD.

关键词： Alzheimer disease Risk factor Prevention Clinical trial Clinical practice

In vivo tracking of tau pathology using positron emission tomography (PET) molecular imaging in small animals

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Translational Neurodegeneration 2014年第1期3卷 34-39页

作者： Eduardo Rigon Zimmer Antoine Leuzy Venkat Bhat serge gauthier Pedro Rosa-Neto Translational Neuroimaging Laboratory(TNL) McGill Center for Studies in AgingDouglas Mental Health University InstituteMcGill University6875 La Salle Blv-FBC room 3149MontrealQCH4H 1R3Canada Montreal Neurological Institute(MNI) MontrealCanada Department of Biochemistry Federal University of Rio Grande do Sul(UFRGS)Porto AlegreBrazil Department of Psychiatry McGill UniversityMontrealBrazil

Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles(NFTs)is a common feature in a wide range of neurodegenerative diseases known as tauopathies,which include Alzheimer’s disease(AD)and the frontotemporal dementias(FTDs).Although heavily investigated,the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully *** this context,several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology,aiming to achieve a better understanding of the link between tau and *** date,behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid(CSF)sampling or post-mortem ***,several novel positron emission tomography(PET)radiopharmaceuticals targeting tau tangles have been developed,allowing for non-invasive in vivo quantification of tau *** with tau transgenic models and micro-PET,these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD *** this review,we briefly describe some of the most important insights for understanding the biological basis of tau pathology,and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.

关键词： Positron emission tomography Tau molecular agents Tau rodent models Tauopathies

Is ApoE ɛ 4 a good biomarker for amyloid pathology in late onset Alzheimer’s disease?

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Translational Neurodegeneration 2016年第1期5卷 161-164页

作者： Maowen Ba Min Kong Xiaofeng Li KokPin Ng PedroRosa-Neto serge gauthier Department of Neurology Yuhuangding Hospital Affiliated to Qingdao Medical UniversityQingdaoShandong 264000People’s Republic of China McGill Centre for Studies in Aging McGill UniversityDouglas Institute6825 Lasalle BoulMontrealQC H4H 1R3Canada Department of Neurology Yantaishan HospitalYantai CityShandong 264000People’s Republic of China Department of Neurology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010People’s Republic of China Department of Neurology National Neuroscience Institute SingaporeSingaporeSingapore

Amyloid plaques are pathological hallmarks of Alzheimer’s Disease(AD)and biomarkers such as cerebrospinal fluid(CSF)β-amyloid 1–42(Aβ1-42)and amyloid positron emission tomographic(PET)imaging are important in diagnosing amyloid pathology in vivo.ɛ4 allele of the Apolipoprotein E gene(ApoEɛ4),which is a major genetic risk factor for late onset AD,is an important genetic biomarker for AD *** has been shown that ApoEɛ4 is involved in Aβdeposition and formation of amyloid *** have suggested the utility of peripheral blood ApoEɛ4 in AD diagnosis and risk *** it is still a matter of debate whether ApoEɛ4 status would improve prediction of amyloid pathology and represent a cost-effective alternative to amyloid PET or CSF Aβin resource-limited settings in late onset *** research suggest that the mean prevalence of PET amyloid-positivity is 95%in ApoEɛ4-positive AD *** short review aims to provide an updated information on the relationship between ApoEɛ4 and amyloid biomarkers.

关键词： Apolipoprotein Eɛ4 Alzheimer’s disease Amyloid

Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer's disease

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Translational Neurodegeneration 2021年第1期10卷 1-11页

作者： Kok Pin Ng Tharick A.Pascoal Sulantha Mathotaarachchi Yiong Huak Chan Lai Jiang Joseph Therriault Andrea L.Benedet Monica Shin Nagaendran Kandiah Celia M.T.Greenwood Pedro Rosa-Neto serge gauthier Dominantly Inherited Alzheimer Network Alzheimer's Disease Research Unit McGill Centre for Studies in AgingMcGill UniversityMontrealQuebecCanada Translational Neuroimaging Laboratory The McGill University Research Centre for Studies in AgingMontrealCanada Departm ent of Neurology National Neuroscience InstituteSingapore CitySingapore Biostatistics Unit Yong Loo Lin School of MedicineNational University of SingaporeSingapore CitySingapore Lady Davis Institute McGill UniversityMontrealCanada Department of Epidemiology Biostatistics and Occupational HealthMcGill UniversityMontrealCanada 不详

Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)***,the role of NPS as an early marker of pathophysiological progression in AD remains *** inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic ***,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing *** this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation ***:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier *** interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and *** factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q *** the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression ***:A total of 119 mutation carriers and 102 non-carriers were *** interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation *** neuropsychiatric subsyndromes of agitation,disinhibition,irritability

关键词： Neuropsychiatric symptoms Dominantly inherited Alzheimer’s disease Metabolic correlates

Expert Consensus on Clinical Diagnostic Criteria for Fatal Familial Insomnia

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Chinese Medical Journal 2018年第13期131卷 1613-1617页

作者： Li-Yong Wu Shu-Qin Zhan Zhao-Yang Huang Bin Zhang Tao Wang Chun-Feng Liu Hui Lu Xiao-Ping Dong Zhi-Ying Wu Jie-Wen Zhang Ji-Hui Zhang Zhong-Xin Zhao Fang Han Yah Huang Jun Lu serge gauthier Jian-Ping Jia Yu-Ping Wang Department of Neurology Xuan Wu Hospital Capital Medical University Belling 100053 China Department of Psychiatry Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Neurorogy Second Affiliated Hospital of Soochow University Suzhou Jiangsu 215004 China State Key Laboratory for Infectious Disease Prevention and Control National Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and Prevention Beijing 100050 China Department of Neurology and Research Center of Neurology Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China Department of Neurology Henan Provincial People's Hospital Zhengzhou Henan 450003 China Department of Psychiatry Faculty of Medicine The Chinese University of Hong Kong Shatin NT Hong Kong SAR 000000 China Department of Neurology Changzheng Hospital The Second Military Medical University Shanghai 200003 China Department of Respiratory Medicine Peking University People's Hospital Beijing 100044 China Department of Neurology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China Department of Neurology Program in Neuroscience and Division of Sleep Medicine Harvard Medical School and Beth Israel Deaconess Medical Center Boston 02215 MA USA McGill Centre for Studies in Aging Alzheimer's Disease Research Unit Montreal H4H 1R3 Canada

INTRODUCTION Fatal familial insomnia （FFI） is a serious and rare prion disease, which was first reported by Lugaresi et al. in *** diagnosis of FFI might be important for early and sufficient counseling of patients and their relatives, also concerning the risk of inheritance, and potentially also for treatment studies. However, the diagnosis of FFI might be difficult because of the heterogeneity of clinical features, low sensitivity of diagnostic tests, and absence of family history. The aim of the present study was to develop a clinical scheme and diagnostic criteria for FFI based on our research and expert consensus.

关键词： HUMAN PRION DISEASES CREUTZFELDT-JAKOB-DISEASE PROTEIN NEUROPATHOLOGY DEGENERATION FEATURES DISORDERS THALAMUS MUTATION ONSET

Perspectives on a collaborative Canada-China research program on diagnostic biomarkers for pre-dementia stages of Alzheimer’s disease

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Journal of Translational Neuroscience 2017年第3期2卷 1-6页

作者： serge gauthier Jianping Jia Sylvie Belleville Simon Cloutier Dessa Sadovnick Colleen Guimond Laura Robb Mario Masellis Guy A Rouleau Liyong Wu Pedro Rosa-Neto McGill Center for Studies in Aging Douglas Mental Health Research Institute Montreal H4H IR3 Canada Innovation Center for Neurological Disorders Department of Neurology Xuanwu Hospital Capital Medical University Beijing 100053 China Beijing Key Laboratory of Geriatric Cognitive Disorders Beijing 100053 China Clinical Center for Neurodegenerative Disease and Memory Impairment Capital Medical University Beijing 100053 China Center of Alzheimer's Disease Beijing Institute for Brain Disorders Beijing 100053 China Key Laboratory of Neurodegenerative Diseases Ministry of Education Beijing 100053 China National Clinical Research Center for Geriatric Disorders Beijing 100053 China Institut Universitaire de Gériatrie de Montréal Montréal H3W IW5 Canada Department of Medical Genetics University of British Columbia Vancouver V6T IZ4 Canada Division of Neurology Department of Medical Genetics University of British Columbia Vancouver V6T IZ4 Canada Division of Neurology/Department of Medicine Sunnybrook Health Sciences Centre University of Toronto Toronto M5S 3H7 Canada Hurvitz Brain Sciences Research Program Sunnybrook Research Institute Toronto M4N 3M5 Canada Montreal Neurological Institute Montréal H3A 2B4 Canada Department of Neurology Xuanwu Hospital Capital Medical University Beijing 100053 China

As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The registration networks have collected hundreds of pedigrees, for which genetic screening, neuropsycholog-ical tests and amyloid and tau imaging was used to study diagnostic biomarkers for preclinical and mild cognitive impairment （MCI） stages of AD. Besides identifying ped-igrees with novel mutations in presenilins （PSENs）/amy-loid precursor protein （APP）, the program has benefted training of Chinese research fellows, AD clinical trials forprevention,the ethical concernsfor clinical fndings, and other collaborative projects with Chinese investiga-tors. Further research of the collaborative program may facilitate the testing and clinical use of novel treatments for EOFAD and late onset AD and contribute to dementia prevention strategies in Canada and China.

关键词： registration network early-onset fa-milial Alzheimer’s disease (EOFAD) mutation neuro-psychological testing

Cerebrospinal fluid phosphorylated tau,visinin-like protein-1,and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer’s disease

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Translational Neurodegeneration 2018年第1期7卷 221-232页

作者： Hua Zhang Kok Pin Ng Joseph Therriault Min Su Kang Tharick APascoal Pedro Rosa-Neto serge gauthier the Alzheimer’s Disease Neuroimaging Initiative Department of Neurology the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Neurology National Neuroscience InstituteSingaporeSingapore The McGill University Research Centre for Studies in Aging McGill UniversityMontrealCanada 不详

Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CSF)are newly discovered markers indicating neuronal damage and microglial activation,*** tau(p-tau)reflects the neuropathology of Alzheimer’s disease(AD)and is useful as diagnostic markers for ***,it is unknown whether these biomarkers have similar or complementary information in ***:We stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database into cognitively normal(CN),stable mild cognitive impairment(sMCI),progressive MCI(pMCI),and dementia due to *** of covariance(ANOVA)and chi-square analyses,Spearman correlation,and logistic regression models were performed to test the demographic,associations between biomarkers,and diagnostic accuracies,*** mixed-effects models were used to evaluate the effects of CSF amyloid-β(Aβ)on above biomarkers within diagnostic groups,the combination of diagnostic group and Aβstatus as predictor,and CSF biomarkers as predictors of AD features,including cognition measured by Mini–Mental State Examination(MMSE)and brain structure and white matter hyperintensity(WMH)measured by magnetic resonance imaging(MRI).Results:P-tau,VILIP-1,and YKL-40 were all predictors of AD diagnosis,but combinations of biomarkers did not improve the diagnostic accuracy(AUC 0.924 for p-tau,VILIP-1,and YKL-40)compared to p-tau(AUC 0.922).P-tau and VILIP-1 were highly correlated(r=0.639,p<0.001)and strongly associated with Aβpathology across clinical stages of AD,while YKL-40 was correlated with Aβpathology in CN and AD ***-1 was associated with acceleration of cognitive decline,hippocampal atrophy,and expansion of ventricles in longitudinal ***-40 was associated with hippocampal atrophy at baseline and follow-up,while p-tau was only associated with worsening WMH at ***:CSF levels of p-tau,VILIP-1,and YKL-40 may have uti

关键词： Alzheimer’s disease Amyloid-β Chitinase-3-like protein 1 Phosphorylated tau Visinin-like protein-1