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1.
Neurology ; 96(22): e2673-e2684, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34550903

RESUMO

OBJECTIVE: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study. METHODS: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes. RESULTS: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB). CONCLUSIONS: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Progressão da Doença , Modelos Estatísticos , Fármacos Neuroprotetores/uso terapêutico , Resultado do Tratamento , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
2.
Alzheimers Res Ther ; 13(1): 138, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389066

RESUMO

BACKGROUND: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-ß (Aß) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. METHODS: We included 533 individuals (178 Aß-negative cognitively unimpaired (CU) subjects, 105 Aß-positive CU subjects, 122 Aß-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. RESULTS: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aß-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. CONCLUSIONS: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
3.
Neurobiol Aging ; 107: 42-52, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34375908

RESUMO

Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid1-42 (Aß42). Interactions for Aß42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aß42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aß42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD.

4.
Neurobiol Aging ; 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34340865

RESUMO

Late-onset Alzheimer's disease (AD) has a significant genetic component, but the molecular mechanisms through which genetic risk factors contribute to AD pathogenesis are unclear. We screened for genetic sharing between AD and the blood levels of 615 metabolites to elucidate how the polygenic architecture of AD affects metabolomic profiles. We retrieved summary statistics from genome-wide association studies of AD and the metabolite blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 31 metabolites, all of which were lipids, we identified and replicated genetic sharing with AD. We also found a positive genetic concordance - implying that genetic risk factors for AD are associated with higher blood levels - for 16 of the 31 replicated metabolites. In the brain, lipids and their intermediate metabolites have essential structural and functional roles, such as forming and dynamically regulating synaptic membranes. Our results imply that genetic risk factors for AD affect lipid levels, which may be leveraged to develop novel treatment strategies for AD.

5.
Brain Behav ; 11(8): e2237, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34105906

RESUMO

BACKGROUND AND PURPOSE: Temporal lobe epilepsy secondary to hippocampal sclerosis is related to epileptogenic networks rather than a focal epileptogenic source. Graph-theoretical gray and white matter networks may help to identify alterations within these epileptogenic networks. METHODS: Twenty-seven patients with hippocampal sclerosis and 14 controls underwent magnetic resonance imaging, including 3D-T1, fluid-attenuated inversion recovery, and diffusion tensor imaging. Subject-specific structural gray and white matter network properties (normalized path length, clustering, and small-worldness) were reconstructed. Group differences and differences between those with higher and lower seizure burden (<4 vs. ≥4 average monthly seizures in the last year) in network parameters were evaluated. Additionally, correlations between network properties and disease-related variables were calculated. RESULTS: All patients with hippocampal sclerosis as one group did not have altered gray or white matter network properties (all p > .05). Patients with lower seizure burden had significantly lower gray matter small-worldness and normalized clustering compared to controls and those with higher seizure burden (all p < .04). A higher number of monthly seizures was significantly associated with increased gray and white matter small-worldness, indicating a more rigid network. CONCLUSION: Overall, there were no differences in network properties in this group of patients with hippocampal sclerosis. However, patients with lower seizure burden had significantly lower gray matter network indices, indicating a more random organization. The correlation between higher monthly seizures and a more rigid network is driven by those with higher seizure burden, who presented a more rigid network compared to those with a lower seizure burden.


Assuntos
Epilepsia do Lobo Temporal , Substância Branca , Encéfalo , Imagem de Tensor de Difusão , Epilepsia do Lobo Temporal/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose/patologia , Convulsões/diagnóstico por imagem , Convulsões/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
6.
Alzheimers Dement (Amst) ; 13(1): e12182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969174

RESUMO

Introduction: We evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aß)1- 42-ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aß1- 42 alone. Methods: We selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aß1- 42, phosphorylated tau (p-tau), and total tau (t-tau) were measured with Elecsys and Lumipulse assays, and Aß1-40 with Lumipulse. CSF cut-points were defined using receiver operating characteristic (ROC) for amyloid PET positivity. Results: For both Elecsys and Lumipulse the p-tau/Aß1- 42, Aß1- 42/Aß1- 40, and t-tau/Aß1- 42 ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aß1- 42 alone (Elecsys 85%; Lumipulse 84%). Discussion: Biomarker ratios p-tau/Aß1- 42, Aß1- 42/Aß1- 40, t-tau/Aß1- 42 on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.

7.
Alzheimers Dement ; 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33991015

RESUMO

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

9.
Ann Neurol ; 89(5): 987-1000, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33583080

RESUMO

OBJECTIVE: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aß) aggregation as measured by the Aß1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aß production (beta-secretase 1, Aß1-40, and Aß1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aß production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aß aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aß1-38 in one twin correlated with Aß1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aß production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aß production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aß and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987-1000.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Depressão/psicologia , Meio Ambiente , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Gêmeos Monozigóticos , Proteínas tau/líquido cefalorraquidiano
10.
Artigo em Inglês | MEDLINE | ID: mdl-33493651

RESUMO

BACKGROUND: Impaired clinical and cognitive insight are prevalent in schizophrenia and relate to poorer outcome. Good insight has been suggested to depend on social cognitive and metacognitive abilities requiring global integration of brain signals. Impaired insight has been related to numerous focal gray matter (GM) abnormalities distributed across the brain suggesting dysconnectivity at the global level. In this study, we test whether global integration deficiencies reflected in gray matter network connectivity underlie individual variations in insight. METHODS: We used graph theory to examine whether individual GM-network metrics relate to insight in patients with a psychotic disorder (n = 114). Clinical insight was measured with the Schedule for the Assessment of Insight-Expanded and item G12 of the Positive and Negative Syndrome Scale, and cognitive insight with the Beck Cognitive Insight Scale. Individual GM-similarity networks were created from GM-segmentations of T1-weighted MRI-scans. Graph metrics were calculated using the Brain Connectivity Toolbox. RESULTS: Networks of schizophrenia patients with poorer clinical insight showed less segregation (i.e. clustering coefficient) into specialized subnetworks at the global level. Schizophrenia patients with poorer cognitive insight showed both less segregation and higher connectedness (i.e. lower path length) of their brain networks, making their network topology more "random". CONCLUSIONS: Our findings suggest less segregated processing of information in patients with poorer cognitive and clinical insight, in addition to higher connectedness in patients with poorer cognitive insight. The ability to take a critical perspective on one's symptoms (clinical insight) or views (cognitive insight) might depend especially on segregated specialized processing within distinct subnetworks.

11.
Brain Cogn ; 148: 105660, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421942

RESUMO

Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring.


Assuntos
Demência Frontotemporal , Música , Doenças Neurodegenerativas , Atrofia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Cognição Social
12.
Ann Clin Transl Neurol ; 8(2): 348-358, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421355

RESUMO

OBJECTIVE: To investigate the relationship between amyloid-ß (Aß) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aß status determined by [18 F]-flutemetamol PET (normal = Aß - vs. abnormal = Aß+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aß on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aß+. Compared to Aß-, Aß+ individuals showed steeper decline on memory (ß ± SE = -0.26 ± 0.09), and processing speed (ß ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aß+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aß abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aß pathology.

13.
Alzheimers Res Ther ; 13(1): 2, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397464

RESUMO

BACKGROUND: As Alzheimer's disease (AD) pathology presents decades before dementia manifests, unbiased biomarker cut-points may more closely reflect presence of pathology than clinically defined cut-points. Currently, unbiased cerebrospinal fluid (CSF) tau cut-points are lacking. METHODS: We investigated CSF t-tau and p-tau cut-points across the clinical spectrum using Gaussian mixture modelling, in two independent cohorts (Amsterdam Dementia Cohort and ADNI). RESULTS: Individuals with normal cognition (NC) (total n = 1111), mild cognitive impairment (MCI) (total n = 1213) and Alzheimer's disease dementia (AD) (total n = 1524) were included. In both cohorts, four CSF t- and p-tau distributions and three corresponding cut-points were identified. Increasingly high tau subgroups were characterized by steeper MMSE decline and higher progression risk to AD (cohort/platform-dependent HR, t-tau 1.9-21.3; p-tau 2.2-9.5). LIMITATIONS: The number of subjects in some subgroups and subanalyses was small, especially in the highest tau subgroup and in tau PET analyses. CONCLUSIONS: In two independent cohorts, t-tau and p-tau levels showed four subgroups. Increasingly high tau subgroups were associated with faster clinical decline, suggesting our approach may aid in more precise prognoses.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Peptídeos beta-Amiloides , Biomarcadores , Progressão da Doença , Humanos , Fragmentos de Peptídeos , Prognóstico , Proteínas tau
14.
Alzheimers Dement ; 17(2): 205-214, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32886448

RESUMO

INTRODUCTION: Our aim was to study whether systemic metabolites are associated with magnetic resonance imaging (MRI) measures of brain and hippocampal atrophy and white matter hyperintensities (WMH). METHODS: We studied associations of 143 plasma-based metabolites with MRI measures of brain and hippocampal atrophy and WMH in three independent cohorts (n = 3962). We meta-analyzed the results of linear regression analyses to determine the association of metabolites with MRI measures. RESULTS: Higher glucose levels and lower levels of three small high density lipoprotein (HDL) particles were associated with brain atrophy. Higher glucose levels were associated with WMH. DISCUSSION: Glucose levels were associated with brain atrophy and WMH, and small HDL particle levels were associated with brain atrophy. Circulating metabolites may aid in developing future intervention trials.

15.
Brain Commun ; 2(2): fcaa177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376987

RESUMO

Biomarkers are needed to monitor disease progression in Alzheimer's disease. Grey matter network measures have such potential, as they are related to amyloid aggregation in cognitively unimpaired individuals and to future cognitive decline in predementia Alzheimer's disease. Here, we investigated how grey matter network measures evolve over time within individuals across the entire Alzheimer's disease cognitive continuum and whether such changes relate to concurrent decline in cognition. We included 190 cognitively unimpaired, amyloid normal (controls) and 523 individuals with abnormal amyloid across the cognitive continuum (preclinical, prodromal, Alzheimer's disease dementia) from the Alzheimer's Disease Neuroimaging Initiative and calculated single-subject grey matter network measures (median of five networks per individual over 2 years). We fitted linear mixed models to investigate how network measures changed over time and whether such changes were associated with concurrent changes in memory, language, attention/executive functioning and on the Mini-Mental State Examination. We further assessed whether associations were modified by baseline disease stage. We found that both cognitive functioning and network measures declined over time, with steeper rates of decline in more advanced disease stages. In all cognitive stages, decline in network measures was associated with concurrent decline on the Mini-Mental State Examination, with stronger effects for individuals closer to Alzheimer's disease dementia. Decline in network measures was associated with concurrent cognitive decline in different cognitive domains depending on disease stage: In controls, decline in networks was associated with decline in memory and language functioning; preclinical Alzheimer's disease showed associations of decline in networks with memory and attention/executive functioning; prodromal Alzheimer's disease showed associations of decline in networks with cognitive decline in all domains; Alzheimer's disease dementia showed associations of decline in networks with attention/executive functioning. Decline in grey matter network measures over time accelerated for more advanced disease stages and was related to concurrent cognitive decline across the entire Alzheimer's disease cognitive continuum. These associations were disease stage dependent for the different cognitive domains, which reflected the respective cognitive stage. Our findings therefore suggest that grey matter measures are helpful to track disease progression in Alzheimer's disease.

16.
medRxiv ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33173883

RESUMO

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.

17.
Transl Psychiatry ; 10(1): 403, 2020 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-33223526

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.


Assuntos
Doença de Alzheimer , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Biomarcadores , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fragmentos de Peptídeos , Proteínas tau/genética
18.
Brain Commun ; 2(2): fcaa102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954344

RESUMO

Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer's disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer's disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset -9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer's disease, which is alike sporadic Alzheimer's disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer's disease.

19.
Neurology ; 95(17): e2378-e2388, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32788242

RESUMO

OBJECTIVE: To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. METHOD: We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF ß-amyloid1-42 (Aß42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate. RESULTS: Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aß42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19-0.84], p < 0.001; p-Tau = 0.44 [0.11-0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], p < 0.001; p-Tau = 0.52 [0.26-0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], p = 0.002; p-Tau = 0.47 [0.16-0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], p < 0.001; p-Tau = 0.38 [0.15-0.61] p = 0.002) but not in SCD. CONCLUSIONS: Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Progressão da Doença , Feminino , Genótipo , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Caracteres Sexuais , Proteínas tau/líquido cefalorraquidiano
20.
Mol Neurodegener ; 15(1): 36, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552841

RESUMO

BACKGROUND: Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach. METHODS: We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups. RESULTS: In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01). CONCLUSION: We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.

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